Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine

Abstract

Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.

FIG. 1.

Efavirenz plasma concentration-time profiles after dosing with efavirenz alone and with coadministration of carbamazepine. Subjects received 600 mg efavirenz (EFV) QD for 14 days, followed by coadministration with carbamazepine (CBZ) for 21 days. Plasma samples were collected during day 14 and day 35 and at predose between days 1 and 14 and days 15 and 35.

FIG. 2.

Efavirenz oral clearance (CL/F) in the absence and in the presence of carbamazepine according to model-based simulation. Subjects received 600 mg efavirenz (EFV) QD for 14 days, followed by coadministration with carbamazepine (CBZ) for 21 days.

FIG. 3.

Model-projected daily exposures to 600 mg efavirenz in the absence (day 14) and in the presence (day 35 and day 90) of 400 mg/day carbamazepine. Horizontal lines represent the 5th and 95th percentiles of the simulated day 90 AUC values for monotherapy with 600 mg efavirenz per day. The line in the middle of the box represents the 50th percentile, and the margins of box represent the 25th and 75th percentiles of the simulated AUC. The vertical bars represent the whiskers. The data for day 14 represent the efavirenz AUC after 14 doses of monotherapy. The data for day 35 and day 90 represent the efavirenz AUC following coadministration with 400 mg/day carbamazepine for 3 and 11 weeks, respectively.

FIG. 4.

Predictive check plot representing model-predicted and actual measured efavirenz plasma concentrations. Subjects received 600 mg efavirenz (EFV) QD for 14 days, followed by coadministration with carbamazepine (CBZ) for 21 days. The solid line represents the model-predicted median (50th percentile) efavirenz concentration, and the gray area represents the 5th and 95th percentiles of model-predicted efavirenz concentrations. The circles represent observed efavirenz concentrations.

FIG. 5.

Observed and simulated efavirenz plasma concentration-time profiles in a subject with a lack of enzyme induction (outlier). The subject received 600 mg efavirenz QD for 14 days, followed by coadministration with carbamazepine for 21 days.