Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials

Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodefi ciency virus(HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA30 01 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determina tions showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 Liters) were similar t o values previously reported for HIV-infected patients in phase I pharmacok inetic studies. Lamivudine CL/F was significantly influenced by the covaria tes creatinine clearance and weight and not affected by age, Centers for Di sease Control and Prevention (CDC) classification, CD4(+) cell count, HN ty pe 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differ ences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, rena l function, HIV-1 RNA PCR, or CDC classification and CD4(+) cell count when creatinine clearance was included with CL/F in the model, Lamivudine dispo sition was significantly influenced by renal function. However, as only thr ee patients had an estimated creatinine clearance of <60 ml/min, dosage adj ustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.