Validation of a 3-h Sampling Interval to Assess Variability in Cytochrome P450 3A Phenotype and the Impact of Induction and Mechanism-Based Inhibition Using Midazolam as a Probe Substrate
| Autor: | Michael J. Sorich, A. David Rodrigues, Andrew Rowland, Madelé van Dyk, Asha J Kapetas, Manoli Vourvahis, Ashley M. Hopkins |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CYP3A Concordance Pharmacology 03 medical and health sciences 0302 clinical medicine Clarithromycin Linear regression medicine Pharmacology (medical) Bland–Altman plot induction mechanism-based inhibition cytochrome P450 3A4 CYP3A4 business.industry lcsh:RM1-950 Area under the curve clarithromycin Clinical Trial phenotyping studies 030104 developmental biology lcsh:Therapeutics. Pharmacology midazolam 030220 oncology & carcinogenesis Midazolam business rifampin medicine.drug |
| Zdroj: | Frontiers in Pharmacology, Vol 10 (2019) Frontiers in Pharmacology |
| ISSN: | 1663-9812 |
| Popis: | Background: Drug probe phenotyping is used extensively in academic and industry research to evaluate cytochrome P450 (CYP) phenotype in order to account for sources of between- and within- subject variability in metabolic clearance. In terms of application, CYP3A is the most important drug metabolizing enzyme the most frequently studied. Currently, phenotyping studies for CYP3A involve the administration of midazolam and collection of timed blood samples up to 24-48 hours in order to determine an area under the plasma concentration time curve (AUC). The key challenge that limits the use of midazolam-based phenotyping for CYP3A in academic research settings and preclude the use of this approach in a clinical setting is the logistical burden of collecting frequent blood samples for up to 48 h post dose following the administration of a probe drug ± an interacting drug. Aim: The current study sought to validate if a reduced sampling interval could be used to accurately define both between-subject variability in CYP3A phenotype and the magnitude of changes in CYP3A activity due to either induction or mechanism-based inhibition. Methods: The area under the curve (AUC) for midazolam was assessed under baseline, induction (7 days rifampin, 300 mg daily) and, following a washout period of 4 days, mechanism based inhibition (3 days clarithromycin, 250 mg daily) conditions in a cohort of 30 health males. The capacity of normalized reduced sampling interval AUCs measured over 0 to 1, 0 to 2, 0 to 3, and 0 to 4 h to accurately define the AUC0-6 was evaluated with respect to precision (R2 for correlation), bias (slope of normalized correlation), agreement (Bland Altman analysis) and proportional bias (linear regression of Bland Altman parameters). Results: Robust concordance was observed between the AUC calculated from PK collection intervals of 0 to 3 and 0 to 6 h in terms of both the measurement of between-subject variability in midazolam AUC and changes in midazolam AUC due to induction and mechanism-based inhibition of CYP3A4. Conclusion: On this basis, it is proposed that a 3-h assessment of midazolam AUC (AUC0-3) represents a viable strategy to reduce the logistical burden associated with the assessment of CYP3A phenotype. |
| Databáze: | OpenAIRE |
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