Population pharmacokinetic analysis of enfuvirtide in HIV‐1 infected patients

Objective Enfuvirtide (Fuzeon, T‐20, ENF) is a 36‐amino acid synthetic peptide and the first of a novel class of HIV drugs which block gp41‐mediated viral fusion to host cells. It was recently approved by the FDA, European Union and other countries for treatment of HIV‐1 infection in treatment experienced patients. The objective of this analysis was to evaluate patient factors and concomitant medications influencing the pharmacokinetics (PK) of ENF. Methods Sparse PK data were obtained from two almost identically designed phase 3 studies assessing the efficacy and safety of 90 mg of ENF administered twice daily (BID), subcutaneously (SC) in combination with an optimized anti‐HIV background regimen for 24 weeks. Two plasma samples per visit were collected on three different occasions taken at least 1–2 h apart during one of the following intervals: 5–6 h post‐dose (wk 1 or 2) ‐3 h to pre‐dose (wk 8); and 1 to 4 h post dose (wk 24). Plasma ENF was analyzed by a validated LC/MS/MS method. Results and conclusions One‐compartment model with first order input and elimination described data. Body weight and female gender were identified as covariates affecting apparent clearance (CL/F=0.99+ (BW/70)*0.833)*(1–0.2 GF), where GF =0 for male and 1 for female). However, the PK changes associated with body weight and gender did not affect the efficacy and/or safety of ENF and no dose adjustment is required. As generally expected for a peptide drug, the effect of concomitant medications (analyzed individually and collectively as enzyme inducers or enzyme inhibitors) on the clearance was low (<15 %) and clinically insignificant. Clinical Pharmacology & Therapeutics (2004) 75 , P89–P89; doi: 10.1016/j.clpt.2003.11.340