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  • 1. Ashton, M
    et al.
    Johansson, L
    Thornqvist, A S
    Svensson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat1999In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 29, no 2, p. 195-204Article in journal (Refereed)
    Abstract [en]

    1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg(-1)) or i.p. (50 mg.kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95 % confidence interval: 10.4, 13.0) l.h(-1).kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) I.h(-1).kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was similar to 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8+/-2.0%) compared with the female rat (11.7+/-2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.

  • 2. Asimus, S.
    et al.
    Elsherbiny, Doaa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hai, T.N.
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Huong, N.V.
    Petzold, M.G.
    Simonsson, Ulrika S.H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ashton, M.
    Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects.2007In: Fundamental & Clinical Pharmacology, ISSN 0767-3981, E-ISSN 1472-8206, Vol. 21, no 3, p. 307-316Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate which principal human cytochrome P450 (CYP450) enzymes are affected by artemisinin and to what degree the artemisinin derivatives differ with respect to their respective induction and inhibition capacity. Seventy-five healthy adults were randomized to receive therapeutic oral doses of artemisinin, dihydroartemisinin, arteether, artemether or artesunate for 5 days (days 1–5). A six-drug cocktail consisting of caffeine, coumarin, mephenytoin, metoprolol, chlorzoxazone and midazolam was administered orally on days −6, 1, 5 and 10 to assess the activities of CYP1A2, CYP2A6, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Four-hour plasma concentrations of parent drugs and corresponding metabolites and 7-hydroxycoumarin urine concentrations were quantified by liquid chromatography-tandem mass spectrometry. The 1-hydroxymidazolam/midazolam 4-h plasma concentration ratio (CYP3A) was increased on day 5 by artemisinin [2.66-fold (98.75% CI: 2.10–3.36)], artemether [1.54 (1.14–2.09)] and dihydroartemisinin [1.25 (1.06–1.47)] compared with day −6. The S-4'-hydroxymephenytoin/S-mephenytoin ratio (CYP2C19) was increased on day 5 by artemisinin [1.69 (1.47–1.94)] and arteether [1.33 (1.15–1.55)] compared with day −6. The paraxanthine/caffeine ratio (CYP1A2) was decreased on day 1 after administration of artemisinin [0.27 (0.18–0.39)], arteether [0.70 (0.55–0.89)] and dihydroartemisinin [0.73 (0.59–0.90)] compared with day −6. The α-hydroxymetoprolol/metoprolol ratio (CYP2D6) was lower on day 1 compared with day −6 in the artemisinin [0.82 (0.70–0.96)] and dihydroartemisinin [0.83 (0.71–0.96)] groups, respectively. In the artemisinin-treated subjects this decrease was followed by a 1.34-fold (1.14–1.58) increase from day 1 to day 5. These results show that intake of artemisinin antimalarials affect the activities of several principal human drug metabolizing CYP450 enzymes. Even though not significant in all treatment groups, changes in the individual metrics were of the same direction for all the artemisinin drugs, suggesting a class effect that needs to be considered in the development of new artemisinin derivatives and combination treatments of malaria.

  • 3.
    Björnsson, Marcus A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norberg, Ake
    Kalman, Sigridur
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A two-compartment effect site model describes the bispectral index after different rates of propofol infusion2010In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 37, no 3, p. 243-255Article in journal (Refereed)
    Abstract [en]

    Different estimates of the rate constant for the effect site distribution (k(e0)) of propofol, depending on the rate and duration of administration, have been reported. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment. In a cross-over study, 21 healthy volunteers were randomised to receive a 1 min infusion of 2 mg/kg of propofol at one occasion, and a 1 min infusion of 2 mg/kg of propofol immediately followed by a 29 min infusion of 12 mg kg(-1) h(-1) of propofol at another occasion. Arterial plasma concentrations of propofol were collected up to 4 h after dosing, and BIS was collected before start of infusion and until the subjects were fully awake. The population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM VI. A four-compartment PK model with time-dependent elimination and distribution described the arterial propofol concentrations, and was used as input to the pharmacodynamic model. A standard effect compartment model could not accurately describe the delay in the effects of propofol for both regimens, whereas a two-compartment effect site model significantly improved the predictions. The two-compartment effect site model included a central and a peripheral effect site compartment, possibly representing a distribution within the brain, where the decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal E-max model.

  • 4.
    Björnsson, Marcus A
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Norberg, Åke
    Kalman, Sigridur
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers2015In: Anesthesia and Analgesia, ISSN 0003-2999, E-ISSN 1526-7598, Vol. 121, no 4, p. 904-913Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers.

    METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1-6 mg/kg), a 30-minute infusion (1-81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM.

    RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12-2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6 µg/mL and a γ of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between-subject variability in EC50 was 37%. An effect compartment model, with a half-life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations.

    CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased half-life with increasing dose. The distribution to the effect site was fast and together with the short plasma half-life led to a fast onset and offset of effects.

  • 5.
    Björnsson, Marcus A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration2011In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 71, no 6, p. 899-906Article in journal (Refereed)
    Abstract [en]

    AIMS To describe pain intensity (PI) measured on a visual analogue scale (VAS) and dropout due to request for rescue medication after administration of naproxcinod, naproxen or placebo in 242 patients after wisdom tooth removal. METHODS Non-linear mixed effects modelling was used to describe the plasma concentrations of naproxen, either formed from naproxcinod or from naproxen itself, and their relationship to PI and dropout. Goodness of fit was assessed by simultaneous simulations of PI and dropout. RESULTS Baseline PI for the typical patient was 52.7 mm. The PI was influenced by placebo effects, using an exponential model, and by naproxen concentrations using a sigmoid E-max model. Typical maximal placebo effect was a decrease in PI by 20.2%, with an onset rate constant of 0.237 h-1. EC50 was 0.135 mu mol l-1. A Weibull time-to-event model was used for the dropout, where the hazard was dependent on the predicted PI and by the PI at baseline. Since the dropout was not at random, it was necessary to include the simulated dropout in visual predictive checks (VPC) of PI. CONCLUSIONS This model describes the relationship between drug effects, PI and the likelihood of dropout after naproxcinod, naproxen and placebo administration. The model provides an opportunity to describe the effects of other doses or formulations, after dental extraction. VPC created by simultaneous simulations of PI and dropout provides a good way of assessing the goodness of fit when there is informative dropout.

  • 6.
    Björnsson, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Performance of Nonlinear Mixed Effects Models in the Presence of Informative Dropout2015In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 17, no 1, p. 245-255Article in journal (Refereed)
    Abstract [en]

    Informative dropout can lead to bias in statistical analyses if not handled appropriately. The objective of this simulation study was to investigate the performance of nonlinear mixed effects models with regard to bias and precision, with and without handling informative dropout. An efficacy variable and dropout depending on that efficacy variable were simulated and model parameters were reestimated, with or without including a dropout model. The Laplace and FOCE-I estimation methods in NONMEM 7, and the stochastic simulations and estimations (SSE) functionality in PsN, were used in the analysis. For the base scenario, bias was low, less than 5% for all fixed effects parameters, when a dropout model was used in the estimations. When a dropout model was not included, bias increased up to 8% for the Laplace method and up to 21% if the FOCE-I estimation method was applied. The bias increased with decreasing number of observations per subject, increasing placebo effect and increasing dropout rate, but was relatively unaffected by the number of subjects in the study. This study illustrates that ignoring informative dropout can lead to biased parameters in nonlinear mixed effects modeling, but even in cases with few observations or high dropout rate, the bias is relatively low and only translates into small effects on predictions of the underlying effect variable. A dropout model is, however, crucial in the presence of informative dropout in order to make realistic simulations of trial outcomes.

  • 7.
    Boström, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine2008In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 108, no 3, p. 495-505Article in journal (Refereed)
    Abstract [en]

    Background The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of un-bound oxycodone and morphine to investigate the influence of blood-brain barrier transport on differences in potency between these drugs. Methods: Microdialysis was used to obtain unbound concentrations in brain and blood. The antinociceptive effect of each drug was assessed using the hot water tail-flick method. Population pharmacokinetic modeling was used to describe the bloodbrain barrier transport of morphine as the rate (Cl.) and extent (K-p,K-uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,,,, is the ratio of the unbound concentration in brain to that in blood at steady state. Results: The six-fold difference in K-p,K-uu between oxycodone and morphine implies that, for the same unbound concentration in blood, the concentrations of unbound oxycodone in brain will be six times higher than those of morphine. A joint pharmacokinetic-pharmacodynamic model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the pharmacodynamic parameters of the drugs. A power model using Effect = Baseline + Slope center dot C-gamma best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. Conclusions: For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.

  • 8.
    Boström, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue2004In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 21, p. 2565-2576Article in journal (Refereed)
    Abstract [en]

    Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

  • 9.
    Boström, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    In Vivo Blood-Brain Barrier Transport of Oxycodone in the Rat: Indications for Active Influx and Implications for Pharmacokinetics/Pharmacodynamics2006In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 34, no 9, p. 1624-1631Article in journal (Refereed)
    Abstract [en]

    The blood-brain barrier (BBB) transport of oxycodone was studied in rats. Microdialysis probes were inserted into the striatum and vena jugularis. Ten animals were given a bolus dose followed by a 120-min constant rate infusion to study the steady-state concepts of oxycodone BBB equilibration. Another 10 animals were given a 60-min constant rate infusion to study the rate of equilibration across the BBB. Oxycodone-D3 was used as a calibrator for the microdialysis experiments. The samples were analyzed with a liquid chromatography-tandem mass spectrometry method and a population pharmacokinetic model was used to simultaneously fit all the data using NONMEM. A two-compartment model which allowed for a delay between the venous and arterial compartments best described the pharmacokinetics for oxycodone in blood and plasma, whereas a one-compartment model was sufficient to describe the pharmacokinetics in the brain. The BBB transport of oxycodone was parameterized as CL(in) and K(p,uu). CL(in) describes the clearance of oxycodone across the BBB into the brain, whereas K(p,uu) describes the extent of drug equilibration across the BBB. CL(in) across the BBB was estimated to 1910 microl/min x g brain. K(p,uu) was estimated to 3.0, meaning that the unbound concentration of oxycodone in brain was 3 times higher than in blood, which is an indication of active influx of oxycodone at the BBB. This is the first evidence of an opioid having an unbound steady-state concentration in brain that is higher than unity, which can explain potency discrepancies between oxycodone and other opioids.

  • 10.
    Boström, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC8332005In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 5, p. 1060-1066Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

  • 11. Brokjaer, Anne
    et al.
    Kreilgaard, Mads
    Olesen, Anne Estrup
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Christrup, Lona Louring
    Dahan, Albert
    Drewes, Asbjorn Mohr
    Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration - A dose escalation study2015In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 68, p. 78-86Article in journal (Refereed)
    Abstract [en]

    Introduction: To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods: This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results: A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%1 and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion: A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated. (C) 2014 Elsevier B.V. All rights reserved.

  • 12.
    Chen, Chunli
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ortega, Fatima
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
    Rullas, Joaquin
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
    Alameda, Laura
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
    Angulo-Barturen, Iñigo
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.; Art Discovery TAD, Biscay Sci & Technol Pk,BIC Bizkaia Bldg,612, Bizkaia 48160, Basque Country, Spain.
    Ferrer, Santiago
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Madrid, Spain.
    Svensson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The multistate tuberculosis pharmacometric model: a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model2017In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 44, no 2, p. 133-141Article in journal (Refereed)
    Abstract [en]

    The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg-1·day-1; Days 1–8; 5 each dose level) and were sacrificed on Day 9. Twenty mice received oral rifampicin (30 mg·kg-1·day-1; up to 8 days) and were sacrificed on Days 2, 3, 4 and 9 (5 each day). The MTP model was linked to a rifampicin population pharmacokinetic model to describe the change in colony forming units (CFU) in the lungs over time. The transfer rates between the different bacterial states were fixed to estimates from in vitro data. The MTP model described well the change in CFU over time after different exposure levels of rifampicin in an acute tuberculosis mouse model. Rifampicin significantly inhibited the growth of fast-multiplying bacteria and stimulated the death of fast- and slow-multiplying bacteria. The data did not support an effect of rifampicin on non-multiplying bacteria possibly due to the short duration of the study. The pharmacometric modelling framework using the MTP model can be used to perform investigations and predictions of the efficacy of anti-tubercular drugs against different bacterial states.

  • 13.
    Chen, Chunli
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Northeast Agr Univ, Coll Vet Med, 600 Changjiang Rd, Harbin 150030, Heilongjiang, Peoples R China. Heilongjiang Key Lab Anim Dis Control & Pharmaceu, 600 Changjiang Rd, Harbin 150030, Heilongjiang, Peoples R China..
    Wicha, Sebastian G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Knegt, Gerjo
    Erasmus MC, Department of Medical Microbiology and Infectious Disease, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
    Ortega, Fatima
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
    Alameda, Laura
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
    Veronica, Sousa
    Diseases of Developing World Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760, Tres Cantos, Madrid, Spain.
    de Steenwinkel, Jurriaan
    Erasmus MC, Department of Medical Microbiology and Infectious Disease, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Assessing Pharmacodynamic Interactions in Mice using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models2017In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, no 11, p. 787-797Article in journal (Other academic)
    Abstract [en]

    The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log(10) colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log(10) CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development.

  • 14.
    Chen, Chunli
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wicha, Sebastian G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nordgren, Rikard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Comparisons of analysis methods for assessment of pharmacodynamic interactions including design recommendations2018In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, article id 77Article in journal (Refereed)
    Abstract [en]

    Quantitative evaluation of potential pharmacodynamic (PD) interactions is important in tuberculosis drug development in order to optimize Phase 2b drug selection and ultimately to define clinical combination regimens. In this work, we used simulations to (1) evaluate different analysis methods for detecting PD interactions between two hypothetical anti-tubercular drugs in in vitro time-kill experiments, and (2) provide design recommendations for evaluation of PD interactions. The model used for all simulations was the Multistate Tuberculosis Pharmacometric (MTP) model linked to the General Pharmacodynamic Interaction (GPDI) model. Simulated data were re-estimated using the MTP–GPDI model implemented in Bliss Independence or Loewe Additivity, or using a conventional model such as an Empirical Bliss Independence-based model or the Greco model based on Loewe Additivity. The GPDI model correctly characterized different PD interactions (antagonism, synergism, or asymmetric interaction), regardless of the underlying additivity criterion. The commonly used conventional models were not able to characterize asymmetric PD interactions, i.e., concentration-dependent synergism and antagonism. An optimized experimental design was developed that correctly identified interactions in ≥ 94% of the evaluated scenarios using the MTP–GPDI model approach. The MTP–GPDI model approach was proved to provide advantages to other conventional models for assessing PD interactions of anti-tubercular drugs and provides key information for selection of drug combinations for Phase 2b evaluation.

  • 15.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aulin, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hu, Yanmin
    Coates, Anthony R M
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 4, p. 964-974Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.

    METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships.

    RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively.

    CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.

  • 16.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goutelle, Sylvain
    Conte, John E., Jr.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A pharmacometric pulmonary model predicting the extent and rate of distribution from plasma to epithelial lining fluid and alveolar cells-using rifampicin as an example2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 3, p. 313-319Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to develop a drug-unspecific approach to pharmacometric modeling for predicting the rate and extent of distribution from plasma to epithelial lining fluid (ELF) and alveolar cells (AC) for data emanating from studies involving bronchoalveolar lavage (BAL) sampling, using rifampicin (RIF) as an example. Data consisting of RIF plasma concentrations sampled at approximately 2 and 4 h postdose and ELF and AC concentrations quantified from one BAL sample, taken at approximately 4 h postdose, in 40 adult subjects without tuberculosis was used as an example for model development. This study emphasized the usage of drug-specific plasma pharmacokinetics (PK) for a correct characterization of plasma to pulmonary distribution. As such, RIF PK was described using absorption transit compartments and a one compartment distribution model coupled with an enzyme turn-over model. The ELF and AC distribution model consisted of characterization of the rate of distribution of drug from plasma to ELF and AC by two distribution rate constant, k (ELF) and k (AC), respectively. The extent of distribution to ELF and AC was described by unbound ELF/plasma concentration ratio (R (ELF/unbound-plasma)) and unbound AC/plasma concentration ratio (R (AC/unbound-plasma)) which typical values were predicted to be 1.28 and 5.5, respectively. The model together with a drug-specific plasma PK description provides a tool for handling data from both single and multiple BAL sampling designs and directly predicts the rate and extent of distribution from plasma to ELF and AC. The model can be further used to investigate design aspects of optimized BAL studies.

  • 17.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goutelle, Sylvain
    Conte, John E., Jr.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Model Predicting Penetration of Rifampicin from Plasma to Epithelial Lining Fluid and Alveolar Cells2013In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 40, no S1, p. S68-S69Article in journal (Other academic)
  • 18.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution2015In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 42, no 6, p. 699-708Article in journal (Refereed)
    Abstract [en]

    Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid a parts per thousand yen LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

  • 19.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wicha, Sebastian G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Vogel, Corne P.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.
    de Steenwinkel, Jurriaan E. M.
    Erasmus MC, Dept Med Microbiol & Infect Dis, Rotterdam, Netherlands.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 2, p. 437-447Article in journal (Refereed)
    Abstract [en]

    Background: Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development.

    Methods: In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure-response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug's potency (EC50) by the combining drug(s).

    Results: All combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity.

    Conclusions: With the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens.

  • 20.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Wicha, Sebastian G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Vogel, Corné
    Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
    de Steenwinkel, Jurriaan E.M.
    Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A model informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions in early tuberculosis drug developmentManuscript (preprint) (Other academic)
    Abstract [en]

    Tuberculosis treatment involves the use of multiple drugs and therefore there is a risk of not only pharmacokinetic interactions but also pharmacodynamic interactions. From many perspectives identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting. Thus, the aim of this work was to develop a model-informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions of drug combinations in order to inform early anti-tuberculosis drug development. In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The Multistate Tuberculosis Pharmacometric model was used to characterize the natural growth and exposure-response relationships of each drug after mono-exposure. Pharmacodynamic interactions during combination exposure were characterized using the General Pharmacodynamic Interaction model with successful separation of each drug’s effect on the potency (EC50) of the other drugs. The approach outlined in this work constitutes groundwork for model informed input to the development of new and enhancement of existing anti-tuberculosis combination regimens.

  • 21.
    Elsherbiny, Doaa A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Asimus, Sara A.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ashton, Michael
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens2008In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 2, p. 203-217Article in journal (Refereed)
    Abstract [en]

    The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4'-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8-16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug-drug interactions is minimized.

  • 22.
    Elsherbiny, Doaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cohen, Karen
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Smith, Peter
    McIlleron, Helen
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients2009In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 65, no 1, p. 71-80Article in journal (Refereed)
    Abstract [en]

    The aim was to develop a model to describe the population pharmacokinetics of nevirapine in South African human immunodeficiency virus (HIV)-infected patients who were taking nevirapine-based antiretroviral therapy concomitantly or in the absence of rifampicin-based tuberculosis therapy. Patients were divided into two groups: (1) patients receiving   nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n = 27) in whom blood samples were obtained before and not less than 14 days after they completed tuberculosis therapy; (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n = 26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling   with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated. Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k(a)) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration-time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ = 0.025 mg/L). The developed model adequately describes nevirapine population   pharmacokinetics in a South African population when taken with/and in the absence of rifampicin treatment. The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis.

  • 23.
    Elsherbiny, Doaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ren, Yuan
    McIlleron, Helen
    Maartens, Gary
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children2010In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 66, no 10, p. 1017-1023Article in journal (Refereed)
    Abstract [en]

    The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1).

    Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m(2) (274, 309) and ritonavir 301 mg/m(2) (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m(2) [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m(2) [249, 289] twice daily).

    Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir C-min was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval.

    Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.

  • 24.
    Faraj, Alan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Robin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diacon, Andreas H.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patientsManuscript (preprint) (Other academic)
    Abstract [en]

    Tuberculosis (TB) drug development is dependent on informative trials to secure development of new antibiotics and combination regimens. Clofazimine (CFZ) and pyrazinamid (PZA) are important components of recommended standard multi-drug treatments of TB. Paradoxically, in a Phase IIa trial aiming to define the early bactericidal activity (EBA) of CFZ and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis we characterized statistically significant exposure-response relationships for both drugs that could explain the original findings of increase in colony forming units (CFU) with CFZ treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make right decisions for advancement to further development. We propose that this quantitative semi-mechanistic approach provides a rational framework for analysing Phase IIa EBA studies, and can accelerate anti-TB drug development.

  • 25. Forsman, L. Davies
    et al.
    Scohn, T.
    Simonsson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bruchfeld, J.
    Larsson, M.
    Jureen, P.
    Sturegard, E.
    Giske, C. G.
    Angeby, K.
    Intra- and Extracellular Activities of Trimethoprim-Sulfamethoxazole against Susceptible and Multidrug-Resistant Mycobacterium tuberculosis2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 12, p. 7557-7559Article in journal (Refereed)
    Abstract [en]

    We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC(0-24)/MIC) using >= 25 as a potential target, the cumulative fraction response was >= 90% at doses of >= 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

  • 26.
    Forsman, Lina Davies
    et al.
    Karolinska Inst, Dept Med, Div Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Niward, Katarina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Infect Dis, Linkoping, Sweden.
    Hu, Yi
    Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai, Peoples R China;Fudan Univ, Key Lab Publ Hlth Safety, Shanghai, Peoples R China.
    Zheng, Rongrong
    Xiamen City Ctr Dis Control, Dept TB & AIDS Prevent, Xiamen, Peoples R China.
    Zheng, Xubin
    Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai, Peoples R China;Fudan Univ, Key Lab Publ Hlth Safety, Shanghai, Peoples R China.
    Ke, Ran
    Xiamen City Ctr Dis Control, Dept TB & AIDS Prevent, Xiamen, Peoples R China.
    Cai, Weiping
    Xiamen City Ctr Dis Control, Dept TB & AIDS Prevent, Xiamen, Peoples R China.
    Hong, Chao
    Xiamen City Ctr Dis Control, Dept TB & AIDS Prevent, Xiamen, Peoples R China.
    Li, Yang
    Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai, Peoples R China;Fudan Univ, Key Lab Publ Hlth Safety, Shanghai, Peoples R China.
    Gao, Yazhou
    Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai, Peoples R China;Fudan Univ, Key Lab Publ Hlth Safety, Shanghai, Peoples R China.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Dept Microbiol, Stockholm, Sweden.
    Paues, Jakob
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Linkoping Univ, Dept Infect Dis, Linkoping, Sweden.
    Kuhlin, Johanna
    Karolinska Inst, Dept Med, Div Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eliasson, Erik
    Karolinska Univ Hosp, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden.
    Alffenaar, Jan-Willem
    Univ Groningen, Univ Med Ctr Groningen, Dept Clin Pharm & Pharmacol, Groningen, Netherlands.
    Mansjo, Mikael
    Publ Hlth Agcy Sweden, Dept Microbiol, Stockholm, Sweden.
    Hoffner, Sven
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Xu, Biao
    Fudan Univ, Sch Publ Hlth, Dept Epidemiol, Shanghai, Peoples R China;Fudan Univ, Key Lab Publ Hlth Safety, Shanghai, Peoples R China.
    Schon, Thomas
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Kalmar Cty Hosp, Dept Clin Microbiol & Infect Dis, Kalmar, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Dept Med, Div Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study2018In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, no 9, article id e023899Article in journal (Refereed)
    Abstract [en]

    Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB.

    Methods and analysis: Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960.

    Ethics and dissemination: This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. Trial registration number NCT02816931; Pre-results.

  • 27.
    Gupta, Neeraj
    et al.
    Millennium Pharmaceut Inc, Cambridge, MA 02139 USA.
    Bottino, Dean
    Millennium Pharmaceut Inc, Cambridge, MA 02139 USA.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Musante, Cynthia J.
    Pfizer Inc, Cambridge, MA USA.
    Bueters, Tjerk
    Merck & Co Inc, Kenilworth, NJ USA.
    Rieger, Theodore R.
    Pfizer Inc, Cambridge, MA USA.
    Macha, Sreeraj
    Sanofi, Bridgewater, NJ USA.
    Chenel, Marylore
    Servier, Suresnes, France.
    Fancourt, Craig
    Merck & Co Inc, Kenilworth, NJ USA.
    Kanodia, Jitendra
    Theravance Biopharma US Inc, San Francisco, CA USA.
    Nayak, Satyaprakash
    Pfizer Inc, Cambridge, MA USA.
    Transforming Translation Through Quantitative Pharmacology for High-Impact Decision Making in Drug Discovery and Development2019In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535Article in journal (Refereed)
  • 28. Gupta, S
    et al.
    Svensson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ashton, M
    In vitro evidence for auto-induction of artemisinin metabolism in the rat2001In: European journal of drug metabolism and pharmacokinetics, ISSN 0378-7966, E-ISSN 2107-0180, Vol. 26, no 3, p. 173-178Article in journal (Refereed)
    Abstract [en]

    Artemisinin disappearance rate was more rapid in incubations with liver microsomes from rats pre-treated with oral artemisinin (60 mg/kg/day for 5 days) compared with microsomes from control animals. A single pathway Michaelis-Menten saturable elimination model was fitted to the concentration-time data of artemisinin incubations by non-linear regression. Model parameters were obtained after fitting results for each animal separately and by pooling data for pre-treated and control animals. Parameter estimates (% coefficient of variation) from fitting the pooled data was maximum velocities (V-max) = 1.8 (12) mmole/min/mg protein and Michaelis constants (K-m) = 20 (22) muM for artemisinin pre-treated and V-max = 0.85 (35) mmole/min/mg protein and K-m = 67 (52) muM for control animals indicating a 2-fold increase in V-max and a 3-fold decrease in Km with microsomes from artemisinin pre-treated animals. Estimates of intrinsic clearance in microsomes from the pre-treated animals were 8-fold higher compared with controls. Thus, artemisinin appears to be a potent auto-inducer of drug metabolism in rats as has also been observed in humans. The present findings suggest caution in the interpretation of repeat-dose rat toxicity studies with artemisinin unless its pharmacokinetics are simultaneously monitored, since during multiple administration, the exposure of the drug will not be constant over time.

  • 29. Hassan, M
    et al.
    Svensson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ljungman, P
    Bjorkstrand, B
    Olsson, H
    Bielenstein, M
    Abdel-Rehim, M
    Nilsson, C
    Johansson, M
    Karlsson, M O
    A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients1999In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 48, no 5, p. 669-677Article in journal (Refereed)
    Abstract [en]

    Aims This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. Methods Fourteen patients received a combination of CP (6 g m(-2)), thiotepum (500 mg m(-2)) and carboplatin (800 mg m(-2)) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. Results CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 1 h(-1) (90% C.I. 0.92-2.58) and 1.14 1 h(-1) (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. Conclusions The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.

  • 30.
    Jansson, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elsherbiny, Doaa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika SH
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma and urine by liquid chromatography/tandem mass spectrometry2006In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 20, no 3, p. 463-572Article in journal (Refereed)
    Abstract [en]

    A sensitive method using enantiospecific liquid chromatography/tandem mass spectrometry detection for the quantitation of S- and R-mephenytoin as well as its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma and urine has been developed and validated. Plasma samples were prepared by protein precipitation with acetonitrile, while urine samples were diluted twice with the mobile phase before injection. The analytes were then separated on a chiral alpha(1)-acid glycoprotein (AGP) column and thereafter detected, using electrospray ionization tandem mass spectrometry. In plasma, the lower limit of quantification (LLOQ) was 1 ng/mL for S- and R-4'-hydroxymephenytoin and S-nirvanol and 3 ng/mL for R-nirvanol and S- and R-mephenytoin. In urine, the LLOQ was 3 ng/mL for all compounds. Resulting plasma and urine intra-day precision values (CV) were <12.4% and <6.4%, respectively, while plasma and urine accuracy values were 87.2-108.3% and 98.9-104.8% of the nominal values, respectively. The method was validated for plasma in the concentration ranges 1-500 ng/mL for S- and R-4'-hydroxymephenytoin, 1-1000 ng/mL for S-nirvanol, and 3-1500 ng/mL for R-nirvanol and S- and R-mephenytoin. The validated concentration range in urine was 3-5000 ng/mL for all compounds. By using this method, the metabolic activities of two human drug-metabolizing enzymes, cytochrome P450 (CYP) 2C19 and CYP2B6, were simultaneously characterized.

  • 31.
    Jansson, Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ashton, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simultaneous enantiospecific separation and quantitation of mephenytoin and its metabolites nirvanol and 4'-hydroxymephenytoin in human plasma by liquid chromatography2003In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 791, no 1-2, p. 179-191Article in journal (Refereed)
    Abstract [en]

    A high-performance liquid chromatographic method for the enantiospecific quantitation of S- and R-mephenytoin and its metabolites S- and R-nirvanol and S- and R-4'-hydroxymephenytoin in plasma is described. The compounds were separated using a reversed-phase C(2) column in tandem with a chiral alpha(1)-acid glycoprotein column and were detected using ultraviolet detection at 205 nm. The lower limit of quantification was 10 ng/ml for all compounds using 0.5 ml human plasma (intra-day coefficient of variation <13%, accuracy <+/-20%). The method was validated for human plasma in the concentration range 10-2000 ng/ml for each of the six compounds. The method allows for the simultaneous characterisation of the metabolic capacity of two human drug-metabolising enzymes, CYP2C19 and CYP2B6, and may be used when investigating polymorphisms or changes in activity of these two enzymes.

  • 32.
    Jauslin, Petra M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Silber, Hanna E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Frey, Nicolas
    Gieschke, Ronald
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Jorga, Karin
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 10, p. 1244-1255Article in journal (Refereed)
    Abstract [en]

    An integrated model for the glucose-insulin system describing oral glucose tolerance test data was developed, extending on a previously introduced model for intravenous glucose provocations. Model extensions comprised the description of glucose absorption by a chain of transit compartments with a mean transit time of 35 minutes, a bioavailability of 80%, and a representation of the incretin effect, expressed as a direct effect of the glucose absorption rate on insulin secretion. The ability of the model to predict the incretin effect was assessed by simulating the observed difference in insulin response following an oral glucose tolerance test compared with an isoglycemic glucose infusion mimicking an oral glucose tolerance test profile. The extension of the integrated glucose-insulin model to gain information from oral glucose tolerance test data considerably expands its range of applications because the oral glucose tolerance test is one of the most common glucose challenge experiments for assessing the efficacy of hypoglycemic agents in clinical drug development.

  • 33.
    Juul, Rasmus Vestergaard
    et al.
    Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 160, Copenhagen, Denmark..
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kreilgaard, Mads
    Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 160, Copenhagen, Denmark..
    Christrup, Lona Louring
    Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 160, Copenhagen, Denmark..
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lund, Trine Meldgaard
    Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 160, Copenhagen, Denmark..
    Analysis of opioid consumption in clinical trials: a simulation based analysis of power of four approaches2017In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 44, no 4, p. 325-333Article in journal (Refereed)
    Abstract [en]

    Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15-62% reduction in morphine consumption. Trials were simulated with duration of 24-96 h. Monte Carlo simulation and re-estimation were performed to determine sample size required to demonstrate efficacy with 80% power using t test, Mann-Whitney rank sum test, time-to-event (TTE) modeling and RTTE modeling. Precision of efficacy estimates for RTTE models were evaluated in 500 simulations. A sample size of 50 patients was required to detect 37% morphine sparing effect with at least 80% power in a 24 h trial with RTTE modeling whereas the required sample size was 200 for Mann-Whitney, 180 for t-test and 76 for TTE models. Extending the trial duration from 24 to 96 h reduced the required sample size by 3.1 fold with RTTE modeling. Precise estimate of potency was obtained with a RTTE model accounting for both morphine effects and time-varying covariates on opioid consumption. An RTTE analysis approach proved better suited for demonstrating efficacy of opioid sparing analgesics than traditional statistical tests as a lower sample size was required due the ability to account for time-varying factors including PK.

  • 34.
    Juul, Rasmus Vestergaard
    et al.
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lund, Trine Meldgaard
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Rasmussen, Sten
    Aalborg Univ Hosp, Orthopaed Surg Res Unit, Aalborg, Denmark.;Aalborg Univ Hosp, Dept Clin Med, Aalborg, Denmark..
    Kreilgaard, Mads
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Christrup, Lona Louring
    Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain2016In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 5, p. 1093-1103Article in journal (Refereed)
    Abstract [en]

    To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses a parts per thousand yenaEuro parts per thousand 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.

  • 35.
    Juul, Rasmus Vestergaard
    et al.
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Rasmussen, Sten
    Aalborg Univ Hosp, Orthopaed Surg Res Unit, Aalborg, Denmark.;Aalborg Univ Hosp, Dept Clin Med, Aalborg, Denmark..
    Kreilgaard, Mads
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Christrup, Lona Louring
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lund, Trine Meldgaard
    Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen, Denmark..
    Repeated Time-to-event Analysis of Consecutive Analgesic Events in Postoperative Pain2015In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 123, no 6, p. 1411-1419Article in journal (Refereed)
    Abstract [en]

    Background: Reduction in consumption of opioid rescue medication is often used as an endpoint when investigating analgesic efficacy of drugs by adjunct treatment, but appropriate methods are needed to analyze analgesic consumption in time. Repeated time-to-event (RTTE) modeling is proposed as a way to describe analgesic consumption by analyzing the timing of consecutive analgesic events. Methods: Retrospective data were obtained from 63 patients receiving standard analgesic treatment including morphine on request after surgery following hip fracture. Times of analgesic events up to 96 h after surgery were extracted from hospital medical records. Parametric RTTE analysis was performed with exponential, Weibull, or Gompertz distribution of analgesic events using NONMEM (R), version 7.2 (ICON Development Solutions, USA). The potential influences of night versus day, sex, and age were investigated on the probability. Results: A Gompertz distribution RTTE model described the data well. The probability of having one or more analgesic events within 24 h was 80% for the first event, 55% for the second event, 31% for the third event, and 18% for fourth or more events for a typical woman of age 80 yr. The probability of analgesic events decreased in time, was reduced to 50% after 3.3 days after surgery, and was significantly lower (32%) during night compared with day. Conclusions: RTTE modeling described analgesic consumption data well and could account for time-dependent changes in probability of analgesic events. Thus, RTTE modeling of analgesic events is proposed as a valuable tool when investigating new approaches to pain management such as opioid-sparing analgesia.

  • 36.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Davidse, Alistair
    Wilkins, Justin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Van der Walt, Jan-Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Smith, Peter
    McIlleron, Helen
    Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients2011In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 55, no 9, p. 4230-4237Article in journal (Refereed)
    Abstract [en]

    Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.

  • 37.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Miller, Raymond
    Daiichi Sankyo Pharma Dev, Edison, NJ USA..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study2015In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 55, no 11, p. 1268-1279Article in journal (Refereed)
    Abstract [en]

    A model characterizing the population pharmacokinetics (PK) of edoxaban and its major metabolite, M4, following a single oral dose of 15mg administered to subjects with varying kidney function was developed. Thirty-two subjects contributed with edoxaban plasma, edoxaban urine, and M4 plasma concentrations. Edoxaban urine concentrations allowed estimation of renal clearance, and high contribution of renal to total clearance enabled estimation of absolute oral bioavailability. A 2-compartment model with delayed absorption and elimination parameterized as renal clearance linearly related to creatinine clearance (CLcr) and nonrenal clearance forming M4 described edoxaban PK. The PK of M4 was described with a 1-compartment model. For a typical subject (70kg; CLcr, 100mL/min) bioavailability, clearance, and central and peripheral volume of distribution for edoxaban was estimated to 72.3%, 21.0 L/h, 95.4 L, and 54.3 L, respectively. For both edoxaban and M4, the model predicted systemic exposure to increase 57.0%, 35.0%, and 11.6% in a subject having CLcr of 30, 50, and 80mL/min, respectively, compared with a subject having a CLcr of 100mL/min. Concentration ratios (M4 over edoxaban) were predicted to vary with time after dose, but with minor influence of kidney function and body weight. Results were in agreement with previous analyses.

  • 38. Langdon, Grant
    et al.
    Wilkins, Justin
    McFadyen, Lynn
    McIlleron, Helen
    Smith, Peter
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Population pharmacokinetics of rifapentine and its primary desacetyl metabolite in South African tuberculosis patients2005In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 49, no 11, p. 4429-4436Article in journal (Refereed)
    Abstract [en]

    This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.

  • 39.
    Larsen, Malte Selch
    et al.
    Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark.;Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark..
    Juul, Rasmus Vestergaard
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
    Groth, Andreas Velsing
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kristensen, Annemarie T.
    Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark..
    Knudsen, Tom
    Novo Nordisk AS, Global Res, Haemophilia Pharmacol, Translat Haemophilia Pharmacol, Malov, Denmark..
    Agersö, Henrik
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
    Kreilgaard, Mads
    Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark..
    Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 115, p. 196-203Article in journal (Refereed)
    Abstract [en]

    Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.

  • 40.
    Larsen, Malte Selch
    et al.
    Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark;Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark.
    Juul, Rasmus Vestergaard
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark.
    Kreilgaard, Mads
    Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark.
    Kristensen, Annemarie T.
    Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Impact of trial design on the estimation of drug potency and power in clinical trials of haemophilia with inhibitors2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 123, p. 531-538Article in journal (Refereed)
    Abstract [en]

    Historically, clinical trials of haemophilia with inhibitors (HwI) have been challenged by the small patient population. New approaches to clinical trial methodology and statistical modelling could potentially be used for study optimization. The aim of this work was to evaluate the impact of different trial designs and study conditions on the estimated drug potency and power, and compare traditional statistical methods with repeated time-to-event (RTTE) modelling in terms of power. Bleeding information from a clinical trial of 23 haemophilia patients with inhibitors treated on-demand was used to develop a baseline RTTE model using NONMEM. Clinical trial simulations for a hypothetical anti-haemophilic drug were performed, by adding a drug effect and a literature-derived placebo effect to the baseline RTTE model, using different trial designs (parallel-group, placebo-controlled parallel-group, crossover and placebo-controlled crossover designs) and study conditions, including sample size, study duration and doses. The precision and accuracy of the estimated drug potency (EC50) and power for different trial designs, study conditions and statistical methods (RTTE modelling, t-test and negative binomial regression) were evaluated. The developed baseline RTTE model accurately described the clinical data. The crossover designs displayed up to four-fold higher precision of the estimated EC50 and three-fold higher power relative to the parallel-group trial designs. Furthermore, RTTE modelling provided a higher power relative to the traditional statistical tests. We found that crossover designs in combination with RTTE modelling can reduce the required sample size and study duration, while ensuring high power and precise estimation of EC50, in clinical trials of HwI.

  • 41.
    Maloney, Alan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Optimal adaptive design in clinical drug development: a simulation example2007In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 10, p. 1231-1243Article in journal (Refereed)
    Abstract [en]

    The objective of this article is to demonstrate optimal adaptive design as a methodology for improving the performance of phase II dose-response studies. Optimal adaptive design uses both information prior to the study and data accrued during the study to continuously update and refine the study design. Dose-response models include linear, log-linear, 4-parameter sigmoidal E-max, and exponential models. Where the response has both a placebo effect and plateau at higher doses, only the 4-parameter sigmoidal E-max model behaves acceptably and hence is used to illustrate the methodology. Across 13 hypothetical dose-response scenarios considered, it was shown that the capability of the adaptive designs to "learn" the true dose response resulted in performances up to 180% more efficient than the best fixed optimal designs, This work exposes the common misconception that adaptive designs are somehow "risky." As shown in this simple simulation example, the converse is true. Adaptive designs perform extremely well both when prior information is accurate and inaccurate. This leads to improved dose-response models and dose selection in phase III. This benefits sponsors, regulators, and subjects alike by reducing sample size, increasing information, and providing better dose guidance.

  • 42.
    Maloney, Alan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schaddelee, Marloes
    Freijer, Jan
    Krauwinkel, Walter
    van Gelderen, Marcel
    Jacqmin, Philippe
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An example of optimal phase II design for exposure response modelling2010In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 37, no 5, p. 475-491Article in journal (Refereed)
    Abstract [en]

    This paper presents an example of how optimal design methodology was used to help design a phase II clinical study. The planned analysis would relate the clinical endpoint to exposure (measured via the area under the curve (AUC)), rather than dose. Optimal design methodology was used to compare a number of candidate phase II designs, and an algorithm for finding optimal designs was employed. The sigmoidal E-max with baseline (E-0) model was used to relate the clinical endpoint to individual subject AUCs, and the primary metrics were D optimality and the standard error (SE) of the AUC required to yield a clinically relevant change in the clinical endpoint. The performance of the candidate designs were compared across four different 'true' exposure response relationships (determined from the analysis of an earlier proof of concept (PoC) study). The results suggested the total sample size should be increased from the planned 540 individuals, and that the optimal design with 700 individuals would be equivalent to 812 individuals with the reference design (a 16% gain). The performance with this design was considered acceptable, although all designs performed poorly if the true exposure response relationship was very flat. This work allowed a prospective assessment of the likely performance and precision from the exposure response modelling prior to the start of the phase II study, and hence allowed the design to be revised to ensure the subsequent analysis would be of most value.

  • 43.
    Maloney, Alan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schaddelee, Marloes
    Astellas Pharma Europe, Leiderdorp, The Netherlands.
    D Optimal Designs for Three Poisson Dose-Response Models2013In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 40, no 2, p. 201-211Article in journal (Refereed)
    Abstract [en]

    The objective of this paper was to find and investigate the performance of the D optimal designs for three Poisson dose-response models. Phase II dose ranging studies are pivotal in the drug development program, being used to select dose(s) for phase III. Count data is encountered in a number of clinical areas. The Poisson distribution provides an intuitive platform for modelling such data, especially when combined with random effects which allow subjects to differ in their response rates. This work investigated three Poisson dose-response models of increasing complexity. A simple Emax model was used to describe the drug effect, and D optimal designs under a range of different parameter values (scenarios) were found. The relative performances between scenarios were assessed using: the precision of all parameters, the precision of the drug effect parameters, and the percent coefficient of variation (%CV) of the ED50 parameter. The results showed that the D optimal designs were similar across models and scenarios, with the D optimal designs consisting of placebo, the maximum dose, and a dose just below the ED50. However the relative performance of the optimal designs was very different. For example, with 1000 subjects, the %CV of the ED50 parameter ranged from 1.4% to 91%. Performance typically improved with higher baseline counts, smaller random effects, and larger Emax. This work introduces a framework for determining and evaluating the performance of D optimal designs for phase II dose ranging studies with count data as the primary endpoint.

  • 44. Mihara, K
    et al.
    Svensson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Tybring, G
    Hai, T N
    Bertilsson, L
    Ashton, M
    Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C191999In: Fundamental & Clinical Pharmacology, ISSN 0767-3981, E-ISSN 1472-8206, Vol. 13, no 6, p. 671-675Article in journal (Refereed)
    Abstract [en]

    The purpose of the study was to determine the enantiomer pharmacokinetics of omeprazole and 5-hydroxy-omeprazole before and after administration of the antimalarial artemisinin to confirm artemisinin's ability to induce CYP2C19. Nine healthy male Vietnamese subjects were given a single 20 mg dose of omeprazole orally 1 week before (day -7) artemisinin administration. Artemisinin was then given orally (500 mg) for 7 days (days 1-7). On days 1 and 7, a single 20 mg dose of omeprazole was coadministered with artemisinin. After a washout period of 6 days, a single 20 mg dose of omeprazole was again administered together with a single 500 mg of artemisinin (day 14). Stereoselective pharmacokinetics of omeprazole and 5-hydroxyomeprazole was determined on days of omeprazole administration. Seven days of artemisinin administration significantly decreased the AUC of both omeprazole enantiomers (day 7), compared with day 1 (P < 0.001). All values were normalized after the washout period. Artemisinin increased the AUC ratio of R-5-hydroxyomeprazole/R-omeprazole significantly (P < 0.01) on day 7. The AUC ratio of omeprazole sulphone/S-omeprazole did not differ between study days. Artemisinin decreased the AUC of S-omeprazole to the same extent as that of R-omeprazole in extensive CYP2C19 metabolizers, suggesting that artemisinin induces a different enzyme in addition to CYP2C19. These results support and strengthen earlier findings that artemisinin induces CYP2C19 as well as at least one enzyme other than CYP3A4. 

  • 45.
    Mourik, Bas C.
    et al.
    Erasmus Univ, Dept Med Microbiol & Infect Dis, Med Ctr, Rotterdam, Netherlands..
    Svensson, Robin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Knegt, Gerjo J.
    Erasmus Univ, Dept Med Microbiol & Infect Dis, Med Ctr, Rotterdam, Netherlands..
    Bax, Hannelore I.
    Erasmus Univ, Sect Infect Dis, Dept Internal Med, Med Ctr, Rotterdam, Netherlands..
    Verbon, Annelies
    Erasmus Univ, Sect Infect Dis, Dept Internal Med, Med Ctr, Rotterdam, Netherlands..
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Steenwinkel, Jurriaan E. M.
    Erasmus Univ, Dept Med Microbiol & Infect Dis, Med Ctr, Rotterdam, Netherlands..
    Improving treatment outcome assessment in a mouse tuberculosis model2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5714Article in journal (Refereed)
    Abstract [en]

    Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (R(p)ZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide-moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2-6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal E-max model in favor over linear or conventional E-max models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and R(p)ZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use.

  • 46.
    Muliaditan, Morris
    et al.
    UCL, Sch Life & Med Sci, London, England..
    Davies, Geraint R.
    Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool, Merseyside, England..
    Simonsson, Ulrika S.H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gillespie, Stephen H.
    Univ St Andrews, Sch Med, St Andrews, Fife, Scotland..
    Della Pasqua, Oscar
    UCL, Sch Life & Med Sci, London, England.;GlaxoSmithKline, London, England..
    The implications of model-informed drug discovery and development for tuberculosis2017In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 22, no 3, p. 481-486Article, review/survey (Refereed)
    Abstract [en]

    Despite promising advances in the field and highly efficacious first-line treatment, an estimated 9.6 million people are still infected with tuberculosis (TB). Innovative methods are required to effectively transition the growing number of compounds into novel combination regimens. However, progression of compounds into patients occurs despite the lack of clear understanding of the pharmacokineticpharmacodynamic (PKPD) relationships. The PreDiCT-TB consortium was established in response to the existing gaps in TB drug development. The aim of the consortium is to develop new preclinical tools in concert with an in silico model-based approach, grounded in PKPD principles. Here, we highlight the potential impact of such an integrated framework on the various stages of TB drug development and on the dose rationale for drug combinations.

  • 47.
    Niebecker, Ronald
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Miller, Raymond
    Nyberg, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Krekels, Elke H J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism-the Hokusai-VTE phase 3 study2015In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 80, no 6, p. 1374-1387Article in journal (Refereed)
    Abstract [en]

    AIMS: This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CLcr ) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations.

    METHODS: The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.

    RESULTS: A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CLcr . Compared with healthy volunteers, inter-compartmental clearance and the CLcr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients.

    CONCLUSIONS: The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.

  • 48.
    Niward, Katarina
    et al.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Univ Hosp Linkoping, Dept Infect Dis, S-58185 Linkoping, Sweden.
    Forsman, Lina Davies
    Karolinska Inst, Dept Med Solna, Unit Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Infect Dis, Stockholm, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Dept Med Solna, Unit Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp Solna, Dept Infect Dis, Stockholm, Sweden.
    Chryssanthou, Erja
    Karolinska Univ Hosp Solna, Dept Clin Microbiol, Stockholm, Sweden;Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Carlstrom, Oskar
    Univ Hosp Linkoping, Dept Infect Dis, S-58185 Linkoping, Sweden.
    Alomari, Teba
    Univ Hosp Linkoping, Dept Infect Dis, S-58185 Linkoping, Sweden.
    Carlsson, Bjorn
    Linkoping Univ, Dept Clin Pharmacol, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Pohanka, Anton
    Karolinska Univ Hosp Huddinge, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden.
    Mansjo, Mikael
    Publ Hlth Agcy Sweden, Dept Microbiol, Stockholm, Sweden.
    Nordvall, Michaela Jonsson
    Univ Hosp Linkoping, Dept Clin Microbiol, Linkoping, Sweden.
    Johansson, Anders G.
    Univ Hosp Linkoping, Dept Clin Microbiol, Linkoping, Sweden.
    Eliasson, Erik
    Karolinska Univ Hosp Huddinge, Div Clin Pharmacol, Dept Lab Med, Stockholm, Sweden.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Dept Microbiol, Stockholm, Sweden.
    Paues, Jakob
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Univ Hosp Linkoping, Dept Infect Dis, S-58185 Linkoping, Sweden.
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schon, Thomas
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Kalmar Cty Hosp, Dept Clin Microbiol & Infect Dis, Kalmar, Sweden.
    Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 10, p. 2838-2845Article in journal (Refereed)
    Abstract [en]

    Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (<8 mg/L), 19% for isoniazid (<3 mg/L), 27% for pyrazinamide (<35 mg/L) and 16% for ethambutol (<2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

  • 49.
    Nyberg, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Kristin E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yin, O. Q. P.
    Daiichi Sankyo Pharma Dev, Translat Med & Clin Pharmacol, Modeling & Simulat, Edison, NJ USA..
    Miller, R.
    Daiichi Sankyo Pharma Dev, Translat Med & Clin Pharmacol, Modeling & Simulat, Edison, NJ USA..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Edoxaban Exposure-Response Analysis and Clinical Utility Index Assessment in Patients With Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism2016In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 5, no 4, p. 222-232Article in journal (Refereed)
    Abstract [en]

    Edoxaban exposure-response relationships from the phase III study evaluating edoxaban for prevention and treatment of venous thromboembolism (VTE) in patients with acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were assessed by parametric time-to-event analysis. Statistical significant exposure-response relationships were recurrent VTE with hazard ratio (HR) based on average edoxaban concentration at steady state (C-av) (HRCav) 50.98 (i.e., change in the HR with every 1 ng/mL increase of C-av); the composite of recurrent DVT and nonfatal PE with HRC(av)50.99; and the composite of recurrent DVT, nonfatal PE, and all-cause mortality HRC(av)50.98, and all death using maximal edoxaban concentration (C-max) with HR (C-max) 50.99. No statistical significant exposure-response relationships were found for clinically relevant bleeding or major adverse cardiovascular event. Results support the recommendation of once-daily edoxaban 60 mg, and a reduced 30 mg dose in patients with moderate renal impairment, body weight <= 60 kg, or use of P-glycoprotein inhibitors verapamil or quinidine.

  • 50. Rekic, Dinko
    et al.
    Roshammar, Daniel
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Model based design and analysis of phase II HIV-1 trials2013In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 40, no 4, p. 487-496Article in journal (Refereed)
    Abstract [en]

    This work explores the advantages of a model based drug development (MBDD) approach for the design and analysis of antiretroviral phase II trials. Two different study settings were investigated: (1) a 5-arm placebo-controlled parallel group dose-finding/proof of concept (POC) study and (2) a comparison of investigational drug and competitor. Studies were simulated using a HIV-1 dynamics model in NONMEM. The Monte-Carlo Mapped Power method determined the sample size required for detecting a dose-response relationship and a significant difference in effect compared to the competitor using a MBDD approach. Stochastic simulation and re-estimation were used for evaluation of model parameter precision and bias given different sample sizes. Results were compared to those from an unpaired, two-sided t test and ANOVA (p a parts per thousand currency sign 0.05). In all scenarios, the MBDD approach resulted in smaller study sizes and more precisely estimated treatment effect than conventional statistical analysis. Using a MBDD approach, a sample size of 15 patients could be used to show POC and estimate ED50 with a good precision (relative standard error, 25.7 %). A sample size of 10 patients per arm was needed using the MBDD approach for detecting a difference in treatment effect of a parts per thousand yen20 % at 80 % power, a 3.4-fold reduction in sample size compared to a t test. The MBDD approach can be used to achieve more precise dose-response characterization facilitating decision making and dose selection. If necessitated, the sample size needed to reach a desired power can potentially be reduced compared to traditional statistical analyses. This may allow for comparison against competitors already in early clinical studies.

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