Abstract
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.
Highlights
In vivo drug probe phenotyping is the current gold standard approach to evaluate cytochrome P450 (CYP) phenotype in order to account for sources of between- and within- subject variability in metabolic clearance (Rowland et al, 2016)
Midazolam pharmacokinetics following the administration of a 1 mg oral midazolam dose was assessed in a cohort of healthy males (n = 30; Table 1) at baseline (Day 1), following a 7 day course of rifampin (Induction phase; Day 8) and following a 3 day course of immediate release clarithromycin (Mechanismbased inhibition phase; Day 15) with a four day washout period between the induction and mechanism-based inhibition phases
For the first time, the validation of a 3-h midazolam sampling interval to support the assessment of between-subject variability in CYP3A phenotype across specific sub-populations as well as the evaluation of changes in CYP3A function due to induction and mechanism-based inhibition of this enzyme
Summary
In vivo drug probe phenotyping is the current gold standard approach to evaluate cytochrome P450 (CYP) phenotype in order to account for sources of between- and within- subject variability in metabolic clearance (Rowland et al, 2016). This approach, which is used extensively in academic and industry research, involves the administration of a drug that is a selective substrate for an enzyme of interest and subsequent collection of timed blood samples, typically over 24–48 h, in order to determine the area under the plasma drug concentration time curve (AUC) (Ryu et al, 2007). 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
