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Brill, Margreke JE
Publications (6 of 6) Show all publications
Kristoffersson, A. N., Rognås, V., Brill, M. J., Dishon-Benattar, Y., Durante-Mangoni, E., Daitch, V., . . . Friberg, L. E. (2020). Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria. Clinical Microbiology and Infection, 26(12), 1644-1650
Open this publication in new window or tab >>Population pharmacokinetics of colistin and the relation to survival in critically ill patients infected with colistin susceptible and carbapenem-resistant bacteria
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2020 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 26, no 12, p. 1644-1650Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: The aim was to analyse the population pharmacokinetics of colistin and to explore the relationship between colistin exposure and time to death.

METHODS: Patients included in the AIDA randomized controlled trial were treated with colistin for severe infections caused by carbapenem-resistant Gram-negative bacteria. All subjects received a 9 million units (MU) loading dose, followed by a 4.5 MU twice daily maintenance dose, with dose reduction if creatinine clearance (CrCL) < 50 mL/min. Individual colistin exposures were estimated from the developed population pharmacokinetic model and an optimized two-sample per patient sampling design. Time to death was evaluated in a parametric survival analysis.

RESULTS: Out of 406 randomized patients, 349 contributed pharmacokinetic data. The median (90% range) colistin plasma concentration was 0.44 (0.14-1.59) mg/L at 15 minutes after the end of first infusion. In samples drawn 10 hr after a maintenance dose, concentrations were >2 mg/L in 94% (195/208) and 44% (38/87) of patients with CrCL ≤120 mL/min, and >120 mL/min, respectively. Colistin methanesulfonate sodium (CMS) and colistin clearances were strongly dependent on CrCL. High colistin exposure to MIC ratio was associated with increased hazard of death in the multivariate analysis (adjusted hazard ratio (95% CI): 1.07 (1.03-1.12)). Other significant predictors included SOFA score at baseline (HR 1.24 (1.19-1.30) per score increase), age and Acinetobacter or Pseudomonas as index pathogen.

DISCUSSION: The population pharmacokinetic model predicted that >90% of the patients had colistin concentrations >2 mg/L at steady state, but only 66% at 4 hr after start of treatment. High colistin exposure was associated with poor kidney function, and was not related to a prolonged survival.

Keywords
Carbapenem resistance, Colistin, Population pharmacokinetics, Renal function, Survival, Survival analysis
National Category
Infectious Medicine Microbiology
Identifiers
urn:nbn:se:uu:diva-429140 (URN)10.1016/j.cmi.2020.03.016 (DOI)000600573300013 ()32213316 (PubMedID)
Available from: 2020-12-20 Created: 2020-12-20 Last updated: 2021-02-09Bibliographically approved
Brussee, J. M., Yu, H., Krekels, E. H. J., Palic, S., Brill, M. J. .., Barrett, J. S., . . . Knibbe, C. A. J. (2018). Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach. Pharmaceutical research, 35(9), Article ID 182.
Open this publication in new window or tab >>Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach
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2018 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 9, article id 182Article in journal (Refereed) Published
Abstract [en]

Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
CYP3A, extraction ratio, absorption, first-pass metabolism, gut wall, liver, pediatrics
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-362025 (URN)10.1007/s11095-018-2458-6 (DOI)000440347600001 ()30062590 (PubMedID)
Available from: 2018-10-17 Created: 2018-10-17 Last updated: 2018-11-12Bibliographically approved
Brussee, J. M., Yu, H., Krekels, E. H. J., de Roos, B., Brill, M. J., van den Anker, J. N., . . . Knibbe, C. A. J. (2018). First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT: Pharmacometrics and Systems Pharmacology (PSP), 7(6), 374-383
Open this publication in new window or tab >>First-Pass CYP3A-Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates
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2018 (English)In: CPT: Pharmacometrics and Systems Pharmacology (PSP), E-ISSN 2163-8306, Vol. 7, no 6, p. 374-383Article in journal (Refereed) Published
Abstract [en]

To predict first-pass and systemic cytochrome P450 (CYP) 3A-mediated metabolism of midazolam in preterm neonates, a physiological population pharmacokinetic model was developed describing intestinal and hepatic midazolam clearance in preterm infants. On the basis of midazolam and 1-OH-midazolam concentrations from 37 preterm neonates (gestational age 26-34 weeks) receiving midazolam orally and/or via a 30-minute intravenous infusion, intrinsic clearance in the gut wall and liver were found to be very low, with lower values in the gut wall (0.0196 and 6.7 L/h, respectively). This results in a highly variable and high total oral bioavailability of 92.1% (range, 67-95%) in preterm neonates, whereas this is around 30% in adults. This approach in which intestinal and hepatic clearance were separately estimated shows that the high bioavailability in preterm neonates is explained by, likely age-related, low CYP3A activity in the liver and even lower CYP3A activity in the gut wall.

Place, publisher, year, edition, pages
WILEY, 2018
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-360495 (URN)10.1002/psp4.12295 (DOI)000436934400003 ()29745466 (PubMedID)
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2020-12-17Bibliographically approved
van Rongen, A., Brill, M. J., Vaughns, J. D., Valitalo, P. A. J., van Dongen, E. P. A., van Ramshorst, B., . . . Knibbe, C. A. J. (2018). Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults. Clinical Pharmacokinetics, 57(5), 601-611
Open this publication in new window or tab >>Higher Midazolam Clearance in Obese Adolescents Compared with Morbidly Obese Adults
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2018 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 57, no 5, p. 601-611Article in journal (Refereed) Published
Abstract [en]

Background

The clearance of cytochrome P450 (CYP) 3A substrates is reported to be reduced with lower age, inflammation and obesity. As it is unknown what the overall influence is of these factors in the case of obese adolescents vs. morbidly obese adults, we studied covariates influencing the clearance of the CYP3A substrate midazolam in a combined analysis of data from obese adolescents and morbidly obese adults.

Methods

Data from 19 obese adolescents [102.7 kg (62-149.5 kg)] and 20 morbidly obese adults [144 kg (112-186 kg)] receiving intravenous midazolam were analysed, using population pharmacokinetic modelling (NONMEM 7.2). In the covariate analysis, the influence of study group, age, total body weight (TBW), developmental weight (WTfor age and length) and excess body weight (WTexcess = TBW - WTfor age and length) was evaluated.

Results

The population mean midazolam clearance was significantly higher in obese adolescents than in morbidly obese adults [0.71 (7%) vs. 0.44 (11%) L/min; p < 0.01]. Moreover, clearance in obese adolescents increased with TBW (p < 0.01), which seemed mainly explained by WTexcess, and for which a so-called 'excess weight' model scaling WTfor age and length to the power of 0.75 and a separate function for WTexcess was proposed.

Discussion

We hypothesise that higher midazolam clearance in obese adolescents is explained by less obesity-induced suppression of CYP3A activity, while the increase with WTexcess is explained by increased liver blood flow. The approach characterising the influence of obesity in the paediatric population we propose here may be of value for use in future studies in obese adolescents.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-354103 (URN)10.1007/s40262-017-0579-4 (DOI)000430321100006 ()28785981 (PubMedID)
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Brill, M. J. E., Kristoffersson, A., Zhao, C., Nielsen, E. I. & Friberg, L. E. (2018). Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations. Clinical Microbiology and Infection, 24(7), 697-706
Open this publication in new window or tab >>Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations
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2018 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 24, no 7, p. 697-706Article, review/survey (Refereed) Published
Abstract [en]

Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.

Keywords
Antibiotics, Drug combinations, Interaction, Semi-mechanistic pharmacokinetic-pharmacodynamic modelling, Simulations
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-366616 (URN)10.1016/j.cmi.2017.11.023 (DOI)000436640800008 ()29229429 (PubMedID)
Funder
Swedish Research Council, 2015-06826EU, FP7, Seventh Framework Programme, Health-F3-2011-278348
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved
Brill, M. J., Svensson, E. M., Pandie, M., Maartens, G. & Karlsson, M. O. (2017). Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis. International Journal of Antimicrobial Agents, 49, 212-217
Open this publication in new window or tab >>Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis
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2017 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, p. 212-217Article in journal (Refereed) Published
Abstract [en]

Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug–drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67–99%) and M2 clearance to 119% (92–156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17–35%) and M2 clearance to 59% (44–69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.

National Category
Pharmacology and Toxicology
Research subject
Pharmaceutical Pharmacology
Identifiers
urn:nbn:se:uu:diva-281726 (URN)10.1016/j.ijantimicag.2016.10.020 (DOI)000397144300011 ()28038962 (PubMedID)
Funder
Swedish Research Council, 521-20113442
Available from: 2016-03-30 Created: 2016-03-30 Last updated: 2018-09-05Bibliographically approved
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