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Population Pharmacokinetics and Effects of Efavirenz in HIV Patients

C. Csajka(1), C. Marzolini(1), K. Fattinger(2), L.A. Décosterd(1), J. Fellay(3), A. Telenti(3), J. Biollaz(1), T. Buclin(1)

(1)Divison of Clinical Pharmacology, University Hospital CHUV, Lausanne, Switzerland; (2)Division of Clinical Pharmacology, University of Zürich, Switzerland; (3)Division of Infections Diseases, University Hospital CHUV, Lausanne, Switzerland

Objectives: The reverse transcriptase inhibitor efavirenz is currently used at a fixed dose of 600 mg qd. Dosage individualisation based on plasma concentration monitoring might however be indicated. This study aimed to assess efavirenz pharmacokinetic profile and interpatient versus intrapatient variability in HIV positive patients to explore the relationship between drug exposure, efficacy and CNS toxicity and to build up a Bayesian approach for dosage adaptation.

Methods: The population pharmacokinetic analysis was performed using NONMEM based on plasma samples from a cohort of unselected patients receiving efavirenz. With the use of a one-compartment model with first order absorption, the influence of demographic and clinical characteristics on oral clearance and oral volume of distribution were examined. The average drug exposure over one dosing interval was estimated for each patient and correlated with markers of efficacy and toxicity. The population kinetic parameters and the variabilities were integrated into a Bayesian equation for dosage adaptation based on a single plasma sample.

Results: 235 patients contributed to 719 efavirenz concentrations. Oral clearance was 9.4 L/h, oral volume of distribution was 252 L and the absorption rate constant was 0.3 h-1. Of the covariates evaluated, the African ethnicity and drugs inhibiting the cytochrome P4503A4 showed an influence on efavirenz pharmacokinetics. A large interpatient variability was found to affect efavirenz relative bioavailability (CV 54.6%), while the intrapatient variability was small (CV 26%). An inverse correlation between average drug exposure and viral load and a trend with CNS toxicity were detected. This enabled the derivation of a dosing adaptation strategy suitable to bring the average concentration into a therapeutic target of 1000-4000 mg/L, to optimise viral load suppression and minimise CNS toxicity.

Conclusion: The high interpatient and low intrapatient variability, along with the relationship with markers of efficacy and toxicity, make efavirenz a drug suitable for therapeutic drug monitoring. Individualisation of efavirenz dosage regimen based on routine drug level monitoring appears suitable for its optimal management.