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  • 1.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Korth-Bradley, J.
    Pfizer Inc, Collegeville, PA USA..
    Harnisch, L.
    Pfizer Ltd, Global Clin Pharmacol, Sandwich, Kent, England..
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 6, p. 977-988Article in journal (Refereed)
    Abstract [en]

    This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

  • 2. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 470-476Article, review/survey (Refereed)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

  • 3. Amidon, K. S.
    et al.
    Langguth, P.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yu, L.
    Amidon, G. L.
    Bioequivalence of Oral Products and the Biopharmaceutics Classification System: Science, Regulation, and Public Policy2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 3, p. 467-470Article in journal (Refereed)
    Abstract [en]

    The demonstration of bioequivalence (BE) is an essential requirement for ensuring that patients receive a product that performs as indicated by the label. The BE standard for a particular product is set by its innovator, and this standard must subsequently be matched by generic drug products. The Biopharmaceutics Classification System (BCS) sets a scientific basis for an improved BE standard for immediate-release solid oral dosage forms. In this paper, we discuss BE and the BCS, as well as the issues that are currently relevant to BE as a pharmaceutical product standard.

  • 4. Avery, P. J.
    et al.
    Jorgensen, A.
    Hamberg, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Pirmohamed, M.
    Kamali, F.
    A Proposal for an Individualized Pharmacogenetics-Based Warfarin Initiation Dose Regimen for Patients Commencing Anticoagulation Therapy2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 5, p. 701-706Article in journal (Refereed)
    Abstract [en]

    A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)(days 4-7)>4.0 (n = 63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction = 4.2 mg), whereas in those with mean INR(days 4-7) < 2.0 (n = 145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.

  • 5.
    Baverel, Paul G.
    et al.
    MedImmune, Clin Pharmacol Drug Metab & Pharmacokinet, Cambridge, England.
    White, Nicholas
    MedImmune, Clin Pharmacol Drug Metab & Pharmacokinet, Cambridge, England.
    Vicini, Paolo
    MedImmune, Clin Pharmacol Drug Metab & Pharmacokinet, Cambridge, England.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Agoram, Balaji
    MedImmune, Clin Pharmacol Drug Metab & Pharmacokinet, Cambridge, England;FortySeven Inc, Clin Pharmacol & DMPK, Menlo Pk, CA USA.
    Dose-Exposure-Response Relationship of the Investigational Anti-Interleukin-13 Monoclonal Antibody Tralokinumab in Patients With Severe, Uncontrolled Asthma2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 5, p. 826-835Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G(4) monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV1)) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV1 response relationship in patients with asthma. Near-maximal FEV1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.

  • 6.
    Bergstrand, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Söderlind, E.
    Weitschies, W.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release, and pharmacokinetics2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 1, p. 77-83Article in journal (Refereed)
    Abstract [en]

    Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MMM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MMM studies.

  • 7.
    Cars, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Stockholm Cty Council, Publ Healthcare Serv Comm Adm, Stockholm, Sweden..
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Malmström, R. E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Clin Pharmacol, Stockholm, Sweden..
    Neovius, M.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Schwieler, J.
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden..
    Wettermark, B.
    Stockholm Cty Council, Publ Healthcare Serv Comm Adm, Stockholm, Sweden.;Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effectiveness of Drugs in Routine Care: A Model for Sequential Monitoring of New Medicines Using Dronedarone as Example2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 3, p. 493-501Article in journal (Refereed)
    Abstract [en]

    Although there is no doubt about the scientific value of randomized controlled clinical trials, they are usually conducted in selected populations different fromthose treated in clinical practice. Therefore, it is important to optimize real-time post-marketing evaluation of the effectiveness, safety, and cost of new drugs. Using electronic health records and administrative health databases froma well-defined region with universal access to healthcare, we have built a framework for real-time sequential monitoring of the effectiveness of newly marketed drugs in routine care. We chose the antiarrhythmic agent dronedarone as the study drug and flecainide as the comparator drug for illustration of the model. We demonstrate that this model produces consistent results with increasing precision over time as data accumulates in the clinical systems. We believe that use of this model at the introduction of new drugs can provide complementary evidence, especially in settings of adaptive licensing of new drugs.

  • 8. Chu, X.
    et al.
    Korzekwa, K.
    Elsby, R.
    Fenner, K.
    Galetin, A.
    Lai, Y.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Moss, A.
    Nagar, S.
    Rosania, G. R.
    Bai, J. P. F.
    Polli, J. W.
    Sugiyama, Y.
    Brouwer, K. L. R.
    Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 94, no 1, p. 126-141Article, review/survey (Refereed)
    Abstract [en]

    Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.

  • 9.
    Cullberg, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Eriksson, Ulf G.
    Wåhlander, Karin
    Eriksson, Henry
    Schulman, Sam
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetics of ximelagatran and relationship to clinical response in acute vein thrombosis2005In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 77, no 4, p. 279-290Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.

    METHODS:

    A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.

    RESULTS:

    The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.

    CONCLUSIONS:

    The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

  • 10. de Jong, F. A.
    et al.
    Scott-Horton, T. J.
    Kroetz, D. L.
    McLeod, H. L.
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mathijssen, R. H.
    Verweij, J.
    Marsh, S.
    Sparreboom, A.
    Irinotecan-induced diarrhea: functional significance of the polymorphic ABCC2 transporter protein2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 81, no 1, p. 42-49Article in journal (Refereed)
    Abstract [en]

    Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04–0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49–7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.

  • 11.
    de Lange, E. C. M.
    et al.
    Leiden University, the Netherlands.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University.
    Translational Aspects of Blood-Brain Barrier Transport and Central Nervous System Effects of Drugs: From Discovery to Patients2015In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 97, no 4, p. 380-394Article in journal (Refereed)
    Abstract [en]

    The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.

  • 12.
    Deitchman, A. N.
    et al.
    Univ Florida, Gainesville, FL USA..
    Broeker, A.
    Univ Florida, Gainesville, FL USA..
    Kast, J.
    Univ Florida, Gainesville, FL USA..
    Wicha, Sebastian G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Singh, R. S.
    Univ Florida, Gainesville, FL USA..
    Derendorf, H.
    Univ Florida, Gainesville, FL USA..
    Evaluation Of Antibiotic Interactions: A Case Example With Time Kill Curve Experiments2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 101, no S1, p. S26-S26Article in journal (Refereed)
  • 13.
    Dosne, Anne-Gaëlle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bergstrand, M.
    Pharmetheus, Uppsala, Sweden..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An Automated Sampling Importance Resampling Procedure For Estimating Parameter Uncertainty2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 101, no S1, p. S57-S57Article in journal (Other academic)
  • 14.
    Fang, Lanyan
    et al.
    US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Kim, Myong-Jin
    US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Li, Zhichuan
    US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Wang, Yaning
    US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    DiLiberti, Charles E.
    Montclair Bioequivalence Serv LLC, Montclair, NJ USA.
    Au, Jessie
    Optimum Therapeut LLC, Carlsbad, CA USA.
    Hooker, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ducharme, Murray P.
    Learn & Confirm Inc, St Laurent, PQ, Canada.
    Lionberger, Robert
    US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Zhao, Liang
    US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Model-Informed Drug Development and Review for Generic Products: Summary Of FDA Public Workshop2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 1, p. 27-30Article in journal (Refereed)
    Abstract [en]

    On October 2nd and 3rd, 2017, the US Food and Drug Administration (FDA) hosted a public workshop titled “Leveraging Quantitative Methods and Modeling to Modernize Generic Drug Development and Review.”1 This report summarizes Session 2 of the public workshop: “Model Informed Drug Development and Review for Generic Products.” The session focused on the application of quantitative methods and modeling in modernizing the generic drug development and review.

  • 15.
    Friberg, L. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vermeulen, A. M.
    Petersson, K. J. F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, M. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An agonist-antagonist interaction model for prolactin release following risperidone and paliperidone treatment2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 85, no 4, p. 409-417Article in journal (Refereed)
    Abstract [en]

    A mechanistic pharmacokinetic/pharmacodynamic model is presented, characterizing the time course of prolactin in healthy as well as schizophrenic subjects following the administration of various doses and formulations of the antipsychotic drugs risperidone and paliperidone. Prolactin concentrations from nine studies (1,462 subjects) were analyzed in NONMEM. A competitive agonist-antagonist interaction model described the competition between these drugs and dopamine for the D(2) receptors that regulate prolactin release. Tolerance development was explained by a feedback loop with prolactin stimulating dopamine release, whereas models wherein tolerance is described in terms of depletion of a prolactin pool did not explain the data well. The diurnal prolactin rhythm was described by a two-period cosine function. Baseline prolactin was health-status dependent and higher in women than in men, although the drug-induced release was less than proportional to baseline. This quantitative mechanism-based model is the first to describe prolactin release in patients, and it confirms that paliperidone and risperidone have similar potencies for prolactin release.

  • 16.
    Friberg, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    de Greef, R.
    Kerbusch, T.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Modeling and Simulation of the Time Course of Asenapine Exposure Response and Dropout Patterns in Acute Schizophrenia2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 1, p. 84-91Article in journal (Refereed)
    Abstract [en]

    Modeling and simulation were utilized to characterize the efficacy dose response of sublingual asenapine in patients with schizophrenia and to understand the outcomes of six placebo-controlled trials in which placebo responses and dropout rates varied. The time course of total Positive and Negative Syndrome Scale (PANSS) scores was characterized for placebo and asenapine treatments in a pharmacokinetic-pharmacodynamic model in which the asenapine effect was described by an E-max model, increasing linearly over the 6-week study period. A logistic regression model described the time course of dropouts, with previous PANSS value being the most important predictor. The last observation carried forward (LOCF) time courses were well described in simulations from the combined PANSS + dropout model. The observed trial outcomes were successfully predicted for all the placebo arms and the majority of the treatment arms. Although simulations indicated that the post hoc probability of success of the performed trials was low to moderate, these analyses demonstrated that 5 and 10 mg twice-daily (b.i.d.) doses of asenapine have similar efficacy.

  • 17. Gaitonde, P.
    et al.
    Trame, M. N.
    Syvanen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lesko, L. J.
    Schmidt, S.
    Mechanism-Based Evaluation of Codeine Toxicity in Children2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 95, p. S42-S43Article in journal (Other academic)
  • 18. Gamazon, E. R.
    et al.
    Daneshjou, R.
    Cavallari, L. H.
    Limdi, N. A.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Johnson, J. A.
    Klein, T. E.
    Scott, S.
    Tsunoda, T.
    Deloukas, P.
    Altman, R.
    Cox, N.
    Perera, M. A.
    Expression Quantitative Trait Loci Analysis of Stable Warfarin Dose Identifies Novel Associations: Finding Signal within the Noise2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 93, no S1, p. S27-S27Article in journal (Other academic)
  • 19.
    Guiastrennec, Benjamin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ramachandran, Geetha
    National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kumar, A.K. Hemanth
    National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
    Bhavani, Perumal Kannabiran
    National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
    Gangadevi, N. Poorana
    National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
    Swaminathan, Soumya
    National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India.
    Gupta, Amita
    Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
    Dooley, Kelly E.
    Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
    Savic, Radojka M.
    University of California San Francisco, San Francisco, California, USA.
    Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 4, p. 733-741Article in journal (Refereed)
    Abstract [en]

    This work aimed to evaluate the once‐daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration–time profiles and treatment outcome were obtained from 161 Indian children with drug‐sensitive tuberculosis undergoing thrice‐weekly dosing as per previous Indian pediatric guidelines. The exposure–response relationships were established using a population pharmacokinetic‐pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4–7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable). Model‐based simulation of optimized (Punfavorable ≤ 5%) rifampin once‐daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose‐exposure–response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.

  • 20.
    Hamberg, Anna Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Barban, M.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Pengo, V.
    Padrini, R.
    Jonsson, E. Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 81, no 4, p. 529-538Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.

  • 21.
    Hamberg, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lindh, J. D.
    Dahl, Marja- Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Padrini, R.
    Deloukas, P.
    Rane, A.
    Jonsson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Pharmacometric Model Describing the Relationship Between Warfarin Dose and INR Response With Respect to Variations in CYP2C9, VKORC1, and Age2010In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 87, no 6, p. 727-734Article in journal (Refereed)
    Abstract [en]

    The objective of the study was to update a previous NONMEM model to describe the relationship between warfarin dose and international normalized ratio (INR) response, to decrease the dependence of the model on pharmacokinetic (PK) data, and to improve the characterization of rare genotype combinations. The effects of age and CYP2C9 genotype on S-warfarin clearance were estimated from high-quality PK data. Thereafter, a temporal dose-response (K-PD) model was developed from information on dose, INR, age, and CYP2C9 and VKORC1 genotype, with drug clearance as a covariate. Two transit compartment chains accounted for the delay between exposure and response. CYP2C9 genotype was identified as the single most important predictor of required dose, causing a difference of up to 4.2-fold in the maintenance dose. VKORC1 accounted for a difference of up to 2.1-fold in dose, and age reduced the dose requirement by ~6% per decade. This reformulated K-PD model decreases dependence on PK data and enables robust assessment of INR response and dose predictions, even in individuals with rare genotype combinations.

  • 22. Hamrén, Bengt
    et al.
    Björk, Elisabeth
    Sunzel, Maria
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment2008In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 84, no 2, p. 228-235Article in journal (Refereed)
    Abstract [en]

    Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was similar to 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

  • 23. Haslemo, T
    et al.
    Loryan, Irena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Institutet, Yerevan State Medical University.
    Ueda, N
    Mannheimer, B
    Bertilsson, L
    Ingelman-Sundberg, M
    Molden, E
    Eliasson, E
    UGT1A4*3 encodes significantly increased glucuronidation of olanzapine in patients on maintenance treatment and in recombinant systems2012In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 92, no 2, p. 221-227Article in journal (Refereed)
    Abstract [en]

    Olanzapine, a world leader in antipsychotic drugs, is used in the treatment of schizophrenia and bipolar disorder. There is considerable interpatient variability in its hepatic clearance. Polymorphic glucuronidation of olanzapine by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4) was investigated retrospectively in patient samples taken for routine therapeutic drug monitoring (TDM) and in recombinant metabolic systems in vitro. Multivariate analyses revealed that patients who were heterozygous as well as those who were homozygous for the UGT1A4*3 allelic variant had significantly higher concentrations of the major metabolite olanzapine 10-N-glucuronide in serum (+38% (P = 0.011) and +246% (P < 0.001), respectively). This finding was in line with the significant increases in glucuronidation activity of olanzapine observed with recombinant UGT1A4.3 (Val-48) as compared with UGT1A4.1 (Leu-48) (1.3-fold difference, P < 0.001). By contrast, serum concentrations of the parent drug were not significantly influenced by UGT1A4 genotype. Our findings therefore indicate that UGT1A4-mediated metabolism is not a major contributor to interpatient variability in olanzapine levels. However, with respect to other drugs for which UGT1A4 has a dominant role in clearance, increased glucuronidation encoded by UGT1A4*3 might impact the risk for subtherapeutic drug exposure.

  • 24.
    Hirsch, Jan M
    et al.
    Departments of Oral Surgery, Clinical Pharmacology, and Pulmonary Medicine, Sahlgrens University Hospital, Göteborg, Sweden.
    Hedner, J
    Wernstedt, L
    Lundberg, J
    Hedner, T
    Hemodynamic effects of the use of oral snuff1992In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 52, no 4, p. 394-401Article in journal (Refereed)
    Abstract [en]

    The hemodynamic effects during rest and exercise of oral snuff were investigated in an open, placebo-controlled study of nine habitual users of oral snuff. Blood pressure, heart rate, and central hemodynamics were measured noninvasively. Plasma concentrations of nicotine, cotinine, norepinephrine, and epinephrine, as well as neuropeptide Y-like immunoreactivity were measured before and after snuff intake during rest and exercise. Snuff intake induced a significant increase in heart rate and blood pressure and a decrease in stroke volume during rest. Hemodynamic changes were unrelated to nicotine or cotinine concentrations. Resting levels of norepinephrine and neuropeptide Y-like immunoreactivity were similar with or without snuff, whereas epinephrine was slightly increased 30 minutes after snuff intake. The exercise-induced increase in norepinephrine and neuropeptide Y-like immunoreactivity did not differ between the days subjects received snuff and the days they received placebo. In contrast, maximum work load was associated with a slight increase in circulating epinephrine after snuff intake. The findings suggest that snuff intake is associated with significant hemodynamic effects during rest but not during exercise. These effects could not be readily explained by activation of the sympathetic nervous system.

  • 25. Holford, N
    et al.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Time for quantitative clinical pharmacology: a proposal for a pharmacometrics curriculum2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 82, no 1, p. 103-105Article in journal (Refereed)
    Abstract [en]

    A formal training program in pharmacometrics is essential to train clinical pharmacology scientists. A proposal is made for a pharmacometrics curriculum. The curriculum has components at the undergraduate, graduate and postgraduate levels.

  • 26.
    Hooker, Andrew C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Ten Tije, A J
    Carducci, M A
    Weber, J
    Garrett-Mayer, E
    Gelderblom, H
    McGuire, W P
    Verweij, J
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Baker, S D
    Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P4503A activity measurements2008In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 84, no 1, p. 111-118Article in journal (Refereed)
    Abstract [en]

    The relationship between cytochrome P4503A4 (CYP3A4) activity and docetaxel clearance in patients with varying degrees of liver function (LF) was evaluated. Docetaxel 40, 50, or 75 mg/m(2) was administered to 85 patients with advanced cancer; 23 of 77 evaluable patients had abnormalities in LF tests. Baseline CYP3A activity was assessed using the erythromycin breath test (ERMBT). Pharmacokinetic studies and toxicity assessments were performed during cycle 1 of therapy and population modeling was performed using NONMEM. Docetaxel unbound clearance was lower (317 vs. 470 l/h) and more variable in patients with LF abnormalities compared to patients with normal LF. Covariates evaluated accounted for 83% of variability on clearance in patients with liver dysfunction, with CYP3A4 activity accounting for 47% of variation; covariates accounted for only 23% of variability in patients with normal LF. The clinical utility of the ERMBT may lie in identifying safe docetaxel doses for patients with LF abnormalities.

  • 27. Isbister, G. K.
    et al.
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hackett, L. P.
    Duffull, S. B.
    Pharmacokinetics of quetiapine in overdose and the effect of activated charcoal2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 81, no 6, p. 821-827Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate the pharmacokinetics of quetiapine overdose and the effect of charcoal. The data set included 204 concentration-time points from 54 quetiapine overdose events (median dose 2,700 mg (300-24,000 mg)). Charcoal was administered 0.5-6 h after 19 overdoses. A fully Bayesian methodology for population pharmacokinetic analysis was used and data were modelled using WinBUGS. Uncertainty in the dose history was considered in model building by estimating dose amount and dose time within a possible range. Inclusion of informative priors stabilized the model and population parameter values could be estimated well. A one-compartment model with first-order input and first-order elimination described the data. The final model included uncertainty in dose time. The median and interquartile range of the half-life for individual patients was 6.6 h (4.9-8.4 h). Charcoal was estimated to reduce fraction absorbed by 35%. Co-ingested CYP3A4 inhibitors appeared to decrease clearance and CYP3A4 inducers increase clearance. Charcoal administration may be beneficial after quetiapine overdose.

  • 28.
    Itkonen, Matti K.
    et al.
    Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Tornio, Aleksi
    Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Filppula, Anne M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland .
    Neuvonen, Mikko
    Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Neuvonen, Pertti J.
    Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Niemi, Mikko
    Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Backman, Janne T.
    Univ Helsinki, Dept Clin Pharmacol, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland.
    Clopidogrel but Not Prasugrel Significantly Inhibits the CYP2C8-Mediated Metabolism of Montelukast in Humans2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 3, p. 495-504Article in journal (Refereed)
    Abstract [en]

    The oxidation of montelukast is mainly mediated by cytochrome P450 (CYP) 2C8, but other mechanisms may contribute to its disposition. In healthy volunteers, we investigated the effects of two widely used P2Y(12) inhibitors on montelukast pharmacokinetics. Clopidogrel (300mg on day 1 and 75mg on day 2) increased the area under the plasma concentration-time curve (AUC) of montelukast 2.0-fold (90% confidence interval (CI) 1.72-2.28, P < 0.001) and decreased the M6:montelukast AUC(0-7h) ratio to 45% of control (90% CI 40-50%, P < 0.001). Prasugrel (60mg on day 1 and 10mg on day 2) had no clinically meaningful effect on montelukast pharmacokinetics. Our results imply that clopidogrel is at least a moderate inhibitor of CYP2C8, but prasugrel is not a clinically relevant CYP2C8 inhibitor. The different interaction potentials of clopidogrel and prasugrel are important to consider when antiplatelet therapy is planned for patients at risk for polypharmacy with CYP2C8 substrates.

  • 29. Johnson, J. A.
    et al.
    Gong, L.
    Whirl-Carrillo, M.
    Gage, B. F.
    Scott, S. A.
    Stein, C. M.
    Anderson, J. L.
    Kimmel, S. E.
    Lee, M. T. M.
    Pirmohamed, M.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Klein, T. E.
    Altman, R. B.
    Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 4, p. 625-629Article, review/survey (Refereed)
    Abstract [en]

    Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for similar to 50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.

  • 30. Johnson, JA
    et al.
    Caudle, KE
    Gong, L
    Whirl-Carrillo, M
    Stein, CM
    Scott, SA
    Lee, MT
    Gage, BF
    Kimmel, SE
    Perera, MA
    Anderson, JL
    Pirmohamed, M
    Klein, TE
    Limdi, NA
    Cavallari, LH
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 3, p. 397-404Article, review/survey (Refereed)
    Abstract [en]

    This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.

  • 31.
    Jönsson, Siv
    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.
    A rational approach for selection of optimal covariate-based dosing strategies2003In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 73, no 1, p. 7-19Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified.

    METHODS

    The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance.

    RESULTS

    The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug.

    CONCLUSIONS

    The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.

  • 32.
    Jönsson, Siv
    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.
    A rational approach for selection of optimal covariate-based dosing strategies2003In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 73, no 1, p. 7-19Article in journal (Other academic)
    Abstract [en]

    BACKGROUND: At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified. METHODS: The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance. RESULTS: The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug. CONCLUSIONS: The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.

  • 33.
    Karlsson, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Savic, Radojka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Diagnosing Model Diagnostics2007In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 82, p. 17-20Article in journal (Refereed)
    Abstract [en]

    Conclusions from clinical trial results that are derived from model-based analyses rely on the model adequately describing the underlying system. The traditionally used diagnostics intended to provide information about model adequacy have seldom discussed shortcomings. Without an understanding of the properties of these diagnostics, development and use of new diagnostics, and additional information pertaining to the diagnostics, there is risk that adequate models will be rejected and inadequate models accepted. Thus, a diagnosis of available diagnostics is desirable.

  • 34.
    Korell, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Model Answers Pty Ltd, Brisbane, Qld, Australia..
    Martin, S. W.
    Pfizer Inc, Cambridge, MA USA..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Ribbing, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pfizer AB, Global Res & Dev, Sollentuna, Sweden.;Pharmetheus AB, Uppsala, Sweden..
    A Model-Based Longitudinal Meta-Analysis of FEV1 in Randomized COPD Trials2016In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 99, no 3, p. 315-324Article in journal (Refereed)
    Abstract [en]

    A model-based, longitudinal meta-analysis of the efficacy on morning trough forced expiratory volume in 1 second (FEV1) in chronic obstructive pulmonary disease (COPD) is presented. Literature data from 142 randomized maintenance trials were included, comprising 106,422 patients who received 19 compounds. 1982 morning trough FEV1 observations were available, each representing the mean FEV1 for a study arm at a specific timepoint. The final model for absolute FEV1 included baseline, disease progression, placebo effect, and drug effect estimates for all compounds, with interstudy variability on all model components and additional interarm variability on baseline. A dose-response relationship was identifiable for 10 of the 19 compounds. Drug-drug interactions among direct bronchodilators and the effect of concomitant background COPD treatment were included. Covariates were identified on baseline. Disease progression was proportional to the baseline FEV1, and a mean baseline of <1.2 L resulted in a lower efficacy, in particular for antiinflammatory treatments.

  • 35. Kumar, V V P
    et al.
    Oscarsson, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, L .E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Isbister, G K
    Hackett, L P
    Duffull, S B
    The effect of decontamination procedures on the pharmacokinetics of venlafaxine in overdose2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 4, p. 403-410Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to investigate the pharmacokinetics (PK) of venlafaxine in overdose and the effects of single-dose activated charcoal (SDAC) and whole-bowel irrigation (WBI), alone or in combination, as methods of decontamination. The data included 339 concentration-time points from 76 venlafaxine overdose events (median dose 2,625 (150-13,500 mg)); 69 were slow-release doses. SDAC, WBI, a combination of both, or no decontamination were administered to patients as decided by the treating clinician. The data were modeled using WinBUGS (Windows Bayesian Inference Using Gibbs Sampling). A one-compartment model with first-order input and elimination provided an adequate description of the data. SDAC increased clearance (CL) of venlafaxine by 35%, and SDAC and WBI combined reduced the fraction absorbed by 29%. However, the latter produced a greater reduction in maximum plasma concentration (C(max)) for a similar drop in area under the plasma concentration-time curve (AUC). Both SDAC alone, and a combination of SDAC and WBI, decreased the AUC after venlafaxine overdose, but the combination may be more beneficial because it reduces peak concentrations to a greater extent.

  • 36.
    Lacroix, B. D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lovern, M R
    Stockis, A
    Sargentini-Maier, M L
    Karlsson, M .O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, L. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A pharmacodynamic Markov mixed-effects model for determining the effect of exposure to certolizumab pegol on the ACR20 score in patients with rheumatoid arthritis2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 4, p. 387-395Article in journal (Refereed)
    Abstract [en]

    The American College of Rheumatology (ACR) 20% preliminary definition of improvement in rheumatoid arthritis (RA) (ACR20) is widely used in clinical trials to assess response to treatment. The objectives of this analysis were to develop an exposure-response model of ACR20 in subjects receiving treatment with certolizumab pegol and to predict clinical outcomes following various treatment schedules. At each visit, subjects were classified as being ACR20 responders or ACR20 nonresponders or as having dropped out. A Markov mixed-effects model was developed to investigate the effects of the drug on the transitions between the three defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Data from simulations of the ACR20 response rate support the use of dosing regimens of 400 mg at weeks 0, 2, and 4 followed by 200 mg every 2 weeks, or an alternative maintenance regimen of 400 mg every 4 weeks.

  • 37.
    Lacroix, Brigitte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    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.
    A Pharmacodynamic Markov Mixed-Effects Model for Determining the Effect of Exposure to Certolizumab Pegol on the ACR20 Score in Patients With Rheumatoid Arthritis2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 4, p. 387-395Article in journal (Refereed)
    Abstract [en]

    The American College of Rheumatology 20% preliminary definition of improvement of rheumatoid arthritis (ACR20) is widely used in clinical trials to assess response to treatment. The objective of this analysis was to develop an exposure-response model of ACR20 in subjects treated with certolizumab pegol, and to predict clinical outcome following various treatment schedules. At each visit, subjects were classified as being ACR20 responders, ACR20 non-responders, or having dropped out. A Markov mixed-effect model was developed to investigate the drug effect on the transitions between the 3 defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Simulations of the ACR20 response rate support dosing regimens of 400 mg at weeks 0, 2 and 4 followed by 200 mg every 2 weeks, or alternative maintenance regimen of 400 mg every 4 weeks.

  • 38. Lenzini, P.
    et al.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Kimmel, S.
    Anderson, J. L.
    Jorgensen, A. L.
    Pirmohamed, M.
    Caldwell, M. D.
    Limdi, N.
    Burmester, J. K.
    Dowd, M. B.
    Angchaisuksiri, P.
    Bass, A. R.
    Chen, J.
    Eriksson, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Rane, A.
    Lindh, J. D.
    Carlquist, J. F.
    Horne, B. D.
    Grice, G.
    Milligan, P. E.
    Eby, C.
    Shin, J.
    Kim, H.
    Kurnik, D.
    Stein, C. M.
    McMillin, G.
    Pendleton, R. C.
    Berg, R. L.
    Deloukas, P.
    Gage, B. F.
    Integration of genetic, clinical, and INR data to refine warfarin dosing2010In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 87, no 5, p. 572-578Article in journal (Refereed)
    Abstract [en]

    Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.

  • 39.
    Lledó-García, R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hennig, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, M. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Comparison of dose-finding designs for narrow-therapeutic-index drugs: concentration-controlled vs. dose-controlled trials2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 1, p. 62-69Article in journal (Refereed)
    Abstract [en]

    This study compared the performances of randomized dose-controlled trials (DCTs) with those of concentration-controlled trials (CCTs) in dose finding for drugs with narrow therapeutic indexes. A simulation-based study was performed for a hypothetical immunosuppressant agent with two clinical end points. Different scenarios were simulated and analyzed, and three designs were compared: one DCT and two CCTs (a target-equivalent CCT and a variability-equivalent CCT). The DCT was consistently superior to the CCTs in the following aspects: (i) precision and bias reduction in parameter estimates, (ii) precision and bias reduction in the estimate of optimal exposure, (iii) bias reduction in prediction of the estimated therapeutic benefit at estimated optimal exposure, and (iv) bias reduction in prediction of the estimated benefit of therapeutic drug monitoring as compared with fixed dosing. DCT designs are more informative when describing the exposure-response relationship for drugs with narrow therapeutic indexes and provide a better basis for decision making with regard to dosing strategy.

  • 40.
    Lledó-García, R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hennig, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, M. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The influence of underlying assumptions on evaluating the relative merits of concentration-controlled and dose-controlled trials2009In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 86, no 1, p. 70-76Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to assess the relative performances of concentration-controlled trial (CCT) and dose-controlled clinical trial (DCT) designs with varying (i) interindividual variability (IIV) in clearance (CL), (ii) relative clinical importance of rejection and infection episodes, (iii) parameter values for the concentration-effect relationships, (iv) interindividual covariance between exposure and effect relationships, and (v) nonlinearity of the concentration-effect relationship. Different scenarios were simulated and analyzed for DCT and CCT designs, and these were compared with respect to bias, prediction, and power. The DCT design showed superiority across all the scenarios studied, with regard to precision and bias in parameter estimates, precision and bias in the estimate of optimal exposure, and bias in prediction of the therapeutic benefit at estimated optimal exposure. However, when a pharmacokinetic-pharmacodynamic (PKPD) covariance in the parameters was considered, either the variance-equivalent concentration-controlled trial (VCCT) or the DCT was the more useful design. Across a number of scenarios, the DCT design is the more informative one.

  • 41.
    Magnusson, M O
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dahl, M-L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cederberg, J
    Karlsson, M O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sandström, R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacodynamics of carbamazepine-mediated induction of CYP3A4, CYP1A2, and Pgp as assessed by probe substrates midazolam, caffeine, and digoxin2008In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 84, no 1, p. 52-62Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop a model describing the carbamazepine autoinduction and the carbamazepine-mediated induction of CYP3A4, CYP1A2, and P-glycoprotein. Seven healthy volunteers were dosed with carbamazepine over 16 consecutive days. The CYP3A4, CYP1A2, and P-glycoprotein activities were assessed, using midazolam, caffeine, and digoxin as probe substrates, on 12 occasions, covering the preinduced state and the onset and termination of the induction process. The data were evaluated using a mechanistic pharmacokinetic approach in NONMEM. The induction processes were described using turnover models, with carbamazepine and carbamazepine-10,11-epoxide as the driving force of the induction. The half-lives of CYP3A4 and CYP1A2 were estimated to be 70 and 105 h, respectively. P-glycoprotein was not affected by the carbamazepine treatment. The possibility of modeling the pharmacodynamics of enzyme induction using a turnover model was illustrated, and the time course of the process was estimated with good precision.

  • 42. Maitland-van der Zee, A. H.
    et al.
    Daly, A. K.
    Kamali, F.
    Manolopoulous, V. G.
    Verhoef, T. I.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    de Boer, A.
    Pirmohamed, M.
    Patients Benefit From Genetics-Guided Coumarin Anticoagulant Therapy2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 1, p. 15-17Article in journal (Other academic)
  • 43.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Computational Prospecting for Drug-Transporter Interactions2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 94, no 1, p. 30-32Article in journal (Refereed)
    Abstract [en]

    Membrane transporters are recognized as important determinants of drug disposition, action, and adverse events, yet our understanding of the molecular determinants of drug-transporter interactions is limited. Here, we discuss how computational analysis of transporter amino acid sequence, transporter structure, and ligand chemistry can be used to explore transporter function at the molecular level and to predict interactions with drug molecules.

  • 44. Mölsä, Melissa
    et al.
    Heikkinen, Tuija
    Hakkola, Jukka
    Hakala, Kristo
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Medicinsk genetik.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Medicinsk genetik.
    Laine, Kari
    Functional role of P-glycoprotein in the human blood-placental barrier2005In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 78, no 2, p. 123-31Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: In vitro and animal experiments suggest that P-glycoprotein forms a functional barrier between maternal and fetal blood circulation in the placenta, thus protecting the fetus from exposure to xenobiotics during pregnancy. In this study we aimed to characterize the role of P-glycoprotein in the blood-placental barrier by use of dually perfused human placenta. METHODS: Twenty-eight human placentas were obtained after delivery, and both the maternal side and the fetal side were perfused for 2 hours. Saquinavir was used as a probe drug for P-glycoprotein-dependent active transfer, and PSC833 (valspodar) or GG918 was used as an inhibitor of P-glycoprotein function in a maternal-to-fetal and fetal-to-maternal perfusion setting. Genotyping for ABCB1 (C3435T and G2677A/T) polymorphism and quantification of P-glycoprotein expression were done for each placenta. RESULTS: The fetal-to-maternal transfer of saquinavir was 108-fold higher (P = .003) compared with transfer from the maternal to the fetal direction. Preperfusion with PSC833 increased the placental transfer of saquinavir by 7.9-fold (P < .001), and preperfusion with GG918 increased it by 6.2-fold (P < .001). The end-perfusion transfer (percentage) of saquinavir at 120 minutes was 11-fold (P < .001) and 6-fold (P < .001) higher in placentas preperfused with PSC833 and GG918, respectively, compared with control. However, PSC833 had no effect on the transfer of saquinavir from the fetal to the maternal direction (P = .79). P-glycoprotein expression was correlated with the PSC833-induced change in the saquinavir transfer (r = 0.75, P = .086). ABCB1 polymorphism did not affect the PSC833- or GG918-induced change in the saquinavir transfer. CONCLUSIONS: P-glycoprotein has a major functional role in the human blood-placental barrier but a negligible role in the removal of substances from the fetal circulation to maternal blood. Pharmacologic blockade of P-glycoprotein function can lead to disruption of the blood-placental barrier and increase the transfer of P-glycoprotein substrates to the fetal side by several-fold, which may be a noteworthy mechanism for teratogenicity.

  • 45.
    Plan, Elodie L
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elshoff, Jan-Peer
    Stockis, Armel
    Sargentini-Maier, Laura
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Likert Pain Scores Modeling: A Markov Integer Model and an Autoregressive Continuous Model2012In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 91, no 5, p. 820-828Article in journal (Refereed)
    Abstract [en]

    Pain intensity is principally assessed using rating scales such as the 11-point Likert scale. In general, frequent pain assessments are serially correlated and underdispersed. The aim of this investigation was to develop population models adapted to fit the 11-point pain scale. Daily Likert scores were recorded over 18 weeks by 231 patients with neuropathic pain from a clinical trial placebo group. An integer model consisting of a truncated generalized Poisson (GP) distribution with Markovian transition probability inflation was implemented in NONMEM 7.1.0. It was compared to a logit-transformed autoregressive continuous model with correlated residual errors. In both models, the score baseline was estimated to be 6.2 and the placebo effect to be 19%. Developed models similarly retrieved consistent underlying features of the data and therefore correspond to platform models for drug effect detection. The integer model was complex but flexible, whereas the continuous model can more easily be developed, although requires longer runtimes.

     

  • 46.
    Plan, Elodie L.
    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.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Approaches to simultaneous analysis of frequency and severity of symptoms2010In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 88, no 2, p. 255-259Article in journal (Refereed)
    Abstract [en]

    Mechanistic models that synthesize pharmacological and (patho) physiological process information provide a rich basis for the characterization of drug action. However, the underlying clinical data are often simplified in a manner that does not allow models to fully elucidate the structure of the drug effect. In this article, we describe data-simplification strategies that are in routine use to describe disease symptoms and compare them with a model developed for handling the true complexities of the data.

  • 47. Raje, S
    et al.
    Patat, AA
    Parks, V
    Schechter, L
    Plotka, A
    Paul, J
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    A Positron Emission Tomography Study to Assess Binding of Lecozotan, a Novel 5-Hydroxytryptamine-1A Silent Antagonist, to Brain 5-HT 1A Receptors in Healthy Young and Elderly Subjects, and in Patients With Alzheimer's Disease2008In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 83, no 1, p. 86-96Article in journal (Refereed)
    Abstract [en]

    This positron emission tomography (PET) study was conducted to assess binding of lecozotan, a new potent and silent 5-hydroxytryptamine-1A (5-HT1A) antagonist being developed for the treatment of Alzheimer's disease (AD), to 5-HT1A receptors in the human brain using C-11-labeled WAY-100635. Lecozotan was administered as a single dose of 0.5, 1, or 5 mg to young subjects and 5 mg to elderly subjects and AD patients. PET measurements were performed at 3-4 time points over a 25-h period. Mean peak 5-HT1A receptor occupancy (RO) in young subjects (seen at 1 h) was 10%, 18%, and 44% for the three doses, respectively. Mean peak RO was slightly higher in elderly (63%) and AD patients (55%). An E-max pharmacokinetic/pharmacodynamic model adequately described the lecozotan plasma concentration-RO relationship. Steady-state peak RO is predicted to be approximately 70% for 5 mg q12 h (twice-daily). Results demonstrate that lecozotan binds to the human brain 5-HT1A receptors and has a maximum observed RO of 50-60% following a single dose of 5 mg in elderly subjects/AD patients.

  • 48. Ramsey, L. B.
    et al.
    Johnson, S. G.
    Caudle, K. E.
    Haidar, C. E.
    Voora, D.
    Wilke, R. A.
    Maxwell, W. D.
    McLeod, L.
    Krauss, R. M.
    Roden, D. M.
    Feng, Q.
    Cooper-DeHoff, R. M.
    Gong, L.
    Klein, T. E.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Niemi, M.
    The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 Update2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 423-428Article in journal (Refereed)
    Abstract [en]

    Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.

  • 49. Russu, A.
    et al.
    Marostica, E.
    De Nicolao, G.
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Poggesi, I.
    Gomeni, R.
    Zamuner, S.
    Joint Modeling of Efficacy, Dropout, and Tolerability in Flexible-Dose Trials: A Case Study in Depression2012In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 91, no 5, p. 863-871Article in journal (Refereed)
    Abstract [en]

    Many difficulties may arise during the modeling of the time course of Hamilton Rating Scale for Depression (HAM D) scores in clinical trials for the evaluation of antidepressant drugs: (i) flexible designs, used to increase the chance of selecting more efficacious doses, (ii) dropout events, and (iii) adverse effects related to the experimental compound. It is crucial to take into account all these factors when designing an appropriate model of the HAM D time course and to obtain a realistic description of the dropout process. In this work, we propose an integrated approach to the modeling of a double-blind, flexible-dose, placebo-controlled, phase II depression trial that comprises response, tolerability, and dropout. We investigate three different dropout mechanisms in terms of informativeness. Goodness of fit is quantitatively assessed with respect to response (HAM D score) and dropout data. We show that dropout is a complex phenomenon that may be influenced by HAM D evolution, dose changes, and occurrence of drug-related adverse effects.

  • 50.
    Simonsson, Ulrika S H
    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.
    Hai, Trinh Ngoc
    Huong, Dinh Xuan
    Tybring, Gunnel
    Ashton, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C92003In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 74, no 1, p. 32-43Article in journal (Other academic)
    Abstract [en]

    AIM: Our goal was to investigate whether artemisinin autoinduction is caused by an increase in cytochrome P450 (CYP) 2B6 or CYP2C9 activities, we evaluated the effects of multiple-dose artemisinin administration on S-mephenytoin N-demethylation in healthy subjects. METHODS: Fourteen subjects, 6 poor metabolizers of CYP2C19 and 8 extensive metabolizers, received a single oral dose of 200 mg racemic mephenytoin (CYP2B6 in vivo marker) before (day -28) and during multiple-dose artemisinin administration (250 mg/d orally for 9 days and 500 mg on the tenth day). A 500-mg single dose of artemisinin was administered on day -28. The CYP2C9 in vivo marker tolbutamide was administered on day -28 and on days 7, 12, and 17 to monitor the minor involvement of CYP2C9 in S-mephenytoin N-demethylation. RESULTS: Artemisinin oral clearance increased 5.3-fold (P <.001) by the tenth day of administration. Its pharmacokinetics was not different in the 2 CYP2C19 phenotypes. The oral clearance of R-mephenytoin increased 1.7-fold (P <.05) in both phenotypes during the period of artemisinin administration. The area under the concentration-time curve ratio of S-nirvanol/S-mephenytoin, an index of CYP2B6 activity, increased 1.9-fold (P <.05) in CYP2C19 poor metabolizers during artemisinin multiple-dose administration, whereas the urinary excretion ratio of hydroxytolbutamide plus carboxytolbutamide/tolbutamide remained constant during the study period. CONCLUSIONS: These results indicate that artemisinin induces the N-demethylation of S-mephenytoin probably by an increased capacity of CYP2B6. The autoinduction phenomenon of artemisinin may, therefore, be attributed, at least in part, to induction of CYP2B6, because this is the isozyme primarily involved in its metabolism. In addition, artemisinin alters the disposition of R-mephenytoin by an unidentified isozyme.

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