Population pharmacokinetic meta-analysis with efavirenz

A population-based pharmaco-kinetic (PK) model has been developed for efavirenz based on 16 phase I studies. The combined data set consisted of 334 healthy volunteers, 2,907 efavirenz dose administrations and 9,342 measured plasma concentrations across a range of doses from 100-600 mg. The pharmacokinetic structural model was a 2-compartment model with first-order absorption with differentiation between single- and multiple-dose exposure to account for known hepatic cytochrome P450 induction of efavirenz metabolism. Model-building was performed on the index data set (66% of the total database), as a data-splitting technique was used to validate the final model using NONMEM. The final model confirmed the appropriateness of separate clearance terms for single and multiple dose administration (2.65 versus 10.2 l/h, respectively). Clearance increased with dose and frequency of administration. A lower clearance was predicted in Asians and Blacks relative to Caucasians. A slightly lower clearance was observed in females relative to males (9.08 compared to 10.2 l/h in males) and interactions on clearance due to co-administration of fluconazole, ritonavir, rifampin, indinavir and azithromycin were identified. The magnitudes of these effects were small and did not suggest dose adjustment in the various sub-populations. With little exception, these results agree with the findings from the non-compartmental analyses. The residual variability was 21% CV and the intersubject variation in CL/F and V/F was 48 and 85%, respectively. The phase I meta-analysis was able to substantiate the pharmacokinetic characteristics of efavirenz derived from the composite of individual well-defined studies. The model was deemed adequate for subsequent evaluation in HIV-infected patients. Covariates and outlier classes identified in this phase I meta-analysis were similarly identified in subsequent analyses of patient data

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