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A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug–Drug Interaction Studies
Open AccessArticle

Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates

1
Department of Clinical Pharmacy, Saarland University, 66123 Saarbrücken, Germany
2
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, Germany
3
Fraunhofer Institute for Biomedical Engineering IBMT, 66280 Sulzbach, Germany
4
Department of Internal Medicine V, Saarland University, 66421 Homburg, Germany
5
Departments of Clinical Pharmacology, and Pharmacy and Biochemistry, University Tübingen, 72076 Tübingen, Germany
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(6), 578; https://doi.org/10.3390/pharmaceutics12060578
Received: 5 June 2020 / Revised: 18 June 2020 / Accepted: 21 June 2020 / Published: 23 June 2020
(This article belongs to the Special Issue Applications of Physiologically-Based Pharmacokinetic (PBPK) Modeling)
Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups. View Full-Text
Keywords: physiologically based pharmacokinetic (PBPK) modeling; buprenorphine; drug-drug interaction (DDI); norbuprenorphine; pediatric scaling; pharmacokinetics physiologically based pharmacokinetic (PBPK) modeling; buprenorphine; drug-drug interaction (DDI); norbuprenorphine; pediatric scaling; pharmacokinetics
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Kovar, L.; Schräpel, C.; Selzer, D.; Kohl, Y.; Bals, R.; Schwab, M.; Lehr, T. Physiologically-Based Pharmacokinetic (PBPK) Modeling of Buprenorphine in Adults, Children and Preterm Neonates. Pharmaceutics 2020, 12, 578.

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