Population Pharmacokinetics and Exposure‐response Relationship of Enfuvirtide in Treatment‐experienced Human Immunodeficiency Virus Type 1—infected Patients

Objective Our objective was to characterize population pharmacokinetics of enfuvirtide, 90 mg twice daily injected subcutaneously, in treatment-experienced human immunodeficiency virus type 1 (HIV-1)–infected patients, as well as the relationship between exposure and antiviral effect. Methods Plasma concentrations of enfuvirtide and HIV-1 ribonucleic acid were obtained from 628 patients in 2 phase III studies. NONMEM software was used for population pharmacokinetic analysis and to assess the effects of age, gender, body weight, anti-gp41 antibodies, and concomitant drugs. Enfuvirtide exposure (area under the plasma concentration-12-hour time curve or steady-state trough concentration) was calculated from individual parameter estimates derived from the model. The decline in HIV-1 ribonucleic acid from baseline at week 2 or 24 was regressed against estimates of enfuvirtide exposure by a maximum effect model. The exposure-response relationship was examined in functional monotherapy (phenotypic sensitivity score of 0) and combination therapy (phenotypic sensitivity score ≥1). Results Enfuvirtide population pharmacokinetics was well described by a 1-compartment model with first-order absorption and elimination. Body weight and female gender were identified as affecting apparent clearance but not efficacy and safety. Concomitant medications had no significant effect on enfuvirtide pharmacokinetics. Antiviral response to enfuvirtide was independent of drug exposure, suggesting that the approved 90-mg twice-daily dose was in the plateau portion of the dose-response curve. For functional monotherapy (phenotypic sensitivity score of 0), approximately 66% of estimated maximal effect was achieved at week 2 and 73% at week 24, and for combination therapy, more than 92% was achieved at both weeks 2 and 24. Conclusions Body weight and gender affected enfuvirtide clearance, but changes in exposure did not affect efficacy or safety. Efficacy reached a plateau at the 90-mg twice-daily dosage in the exposure-response curve. Clinical Pharmacology & Therapeutics (2005) 77, 515–528; doi: 10.1016/j.clpt.2005.02.005