A Clinical Study To Assess The Magnitude, Time‐course And Variability Of CYP3A4 Induction By Rifampin In Healthy Volunteers
Authors: Kapetas Asha 
Published: April 2020

IntroductionConsistent with its important role in human drug metabolism, CYP3A4 has an exceptionally broad substrate specificity. Consequently, CYP3A4 is highly susceptible to metabolic‐drug drug interactions (mDDI’s) that induce activity, which are an important source of between‐subject variability (BSV) in drug exposure. Failure to account for BSV is a common underlying cause of attrition in early clinical drug development. An understanding of CYP3A4 induction will hence improve the accuracy of clinical mDDI prediction. No prescriptive dosing guidance exists for clinical DDI studies that use the prototypical CYP3A4 inducer rifampin to assess the clinical mDDI victim risk of drugs metabolised by CYP3A4. Recent simulation data indicate dosing rifampin for less than 10 days is likely to underestimate the magnitude of induction.AimsThis study sought to assess CYP3A4 activity at baseline (Day 1) and following 7 and 14 days administration of rifampin (600 mg PO/daily) in a cohort of healthy males and females and to assess CYP3A4 activity at baseline and following 7 days administration of rifampin (300 mg PO/daily) in a cohort of healthy males. The impact of rifampin dose (mg) was assessed as a trial characteristic effecting the magnitude of CYP3A4 induction. The performance of a personalised PBPK model with respect to estimating exposure to oral midazolam was also evaluated.MethodsThe study was a single centre, open label, single sequence metabolic phenotyping clinical trial. Healthy volunteers were dosed with midazolam (1 mg PO on Day 1, 8, 15) and timed blood samples (8mL) were collected pre‐dose, and up to 6 hr post‐dose. Participants self‐administered up to a 14‐day course of rifampin (300 or 600 mg PO daily). Midazolam exposure was measured prior the first rifampin dose (Day 1), following seven doses of rifampin (Day 8) and 16 hours after completing the 14‐day course rifampin (Day 15). Baseline CYP3A4 activity was compared with activity following administration of rifampin for 7 and 14 days. A verified Simcyp® model describing rifampin‐mediated CYP3A4 induction was used to compare personalised PBPK simulations to observed oral midazolam exposure at baseline and following rifampin administration.ResultsThe mean observed midazolam AUC ratio following dosing of rifampin (300 mg) for 7 days was 0.32, the mean midazolam AUC ratio following dosing of rifampin (600 mg) for 7 days was 0.21. No significant difference in AUC ratio was observed between 7 and 14 days rifampin dosing (600 mg). Simulated midazolam PK parameters for Day 1 (baseline) was within 2‐fold of the observed parameter (i.e. MFE 0.62 to 1.61) for all participants. Simulated parameters for Day 7 and Day 14 ranged from 3‐fold lower to 6.5‐fold higher than the observed parameter (i.e. MFE 0.33 to 6.40).DiscussionConsistent with prior studies greater CYP3A4 induction was achieved using 600 mg rifampin. Contrary to simulations suggesting a minimum of 10 days rifampin dosing is required to achieve maximal induction of hepatic CYP3A4, data indicate 7 days dosing is sufficient to produce maximal change in midazolam exposure. Robust concordance of individual participant simulated and observed oral midazolam PK parameters at baseline (Day 1) was observed, however concordance was variable and typically poor following rifampicin administration.Support or Funding InformationNHMRC