title: Population pharmacokinetics of lamivudine in adult human immunodeficiency virus-infected patients enrolled in two phase III clinical trials.
abstract: Lamivudine population pharmacokinetics were investigated by using nonlinear mixed-effect modelling (NONMEM) analysis of data from 394 human immunodeficiency virus (HIV)-infected patients treated with lamivudine (150 to 300 mg every 12 h) in two large, phase III clinical efficacy-safety trials, NUCA3001 and NUCA3002. Analyses of 1,477 serum lamivudine concentration determinations showed that population estimates for lamivudine oral clearance (CL/F; 25.1 liters/h) and volume of distribution (V/F; 128 liters) were similar to values previously reported for HIV-infected patients in phase I pharmacokinetic studies. Lamivudine CL/F was significantly influenced by the covariates creatinine clearance and weight and not affected by age, Centers for Disease Control and Prevention (CDC) classification, CD4(+) cell count, HIV type 1 (HIV-1) RNA PCR, or gender and race when CL/F was corrected for differences in patient weight. The population estimate for lamivudine V/F was not significantly influenced by the covariates gender, race, age, weight, renal function, HIV-1 RNA PCR, or CDC classification and CD4(+) cell count when creatinine clearance was included with CL/F in the model. Lamivudine disposition was significantly influenced by renal function. However, as only three patients had an estimated creatinine clearance of <60 ml/min, dosage adjustments for patients with impaired renal function should not be determined based on the population parameters derived in this analysis.
authors.affiliation: Glaxo Wellcome Inc., Research Triangle Park, University of North Carolina at Chapel Hill, Chapel Hill, Durham, North Carolina 27709, USA. km10993@glaxowellcome.com
authors.forename: K H
authors.initials: KH
authors.lastname: Moore
authors.forename: G J
authors.initials: GJ
authors.lastname: Yuen
authors.forename: E K
authors.initials: EK
authors.lastname: Hussey
authors.forename: G E
authors.initials: GE
authors.lastname: Pakes
authors.forename: J J
authors.initials: JJ
authors.lastname: Eron
authors.forename: J A
authors.initials: JA
authors.lastname: Bartlett
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D019259:Lamivudine / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D011153:Population; D012044:Regression Analysis
chemical_list: D019380:Anti-HIV Agents; D019259:Lamivudine