Pharmacokinetics of nevirapine and lamivudine in patients with HIV-1 infection

Abstract

The purpose of this parallel treatment group, double-blind, multicenter study was to characterize the pharmacokinetics of nevirapine and lamivudine when coadministered to patients with the HIV -1 infection. This pharmacokinetic interaction study was nested within a larger Phase III clinical trial conducted to characterize the safety and efficacy of coadministered nevirapine and lamivudine. One hundred HIV -1 infected patients with CD4+ lymphocyte counts = 200 cells/mm 3 and who were on a background of) therapy were randomly assigned to be treated with either nucleoside + lamivudine + nevirapine or nucleoside + lamivudine + placebo. Each patient underwent blood sampling at defined times for the purpose of determining the concentration of nevirapine in plasma and lamivudine in serum under steady-state conditions. Each patient was also monitored closely for concomitant administration of other drugs, including ZDV, ddI, ddC, d4T and cotrimoxazole. The pharmacokinetics of nevirapine and lamivudine were characterized using nonlinear mixedeffects modeling. There were no reported serious adverse events during the 40-day pharmacokinetic study. The results of the modeling analysis revealed that nevirapine had no effect on the pharmacokinetics of lamivudine. Estimates of the apparent clearance for nevirapine (CL/F = 3.3 L/hour; 95% confidence interval [CI] 2.9 to 3.7 L/hour) and lamivudine (CL/F 27.6 L/hour; 95% CI 22 to 33.2 L/hour) were consistent with the values reported in earlier trials. However, the results also showed that concomitant administration of lamivudine with cotrimoxazole resulted in a 31% reduction in the apparent clearance of lamivudine, resulting in a 43% increase in the average steady-state lamivudine serum concentrations. These results indicate that chronic concurrent administration of cotrimoxazole with lamivudine may significantly affect the steady-state pharmacokinetics of lamivudine.

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

“…The estimates from the final population pharmacokinetic model of CL/F, V/F and k a are consistent with previous reports of nevirapine population pharmacokinetics in other populations [24][25][26]. In our study, rifampicin induced the metabolism of nevirapine, seen as an increase in its CL/F by 37.4%, which is in agreement with previous reports of rifampicin altering the pharmacokinetics of nevirapine [4,9,10,12,13].…”

“…Weight was therefore not included in the final model as a predictor of variability in CL/F. A lack of relationship between weight and nevirapine pharmacokinetics has also been seen in other studies [13,24,26,43]. Age was also found to be a predictor of variability in CL/F, where CL/F increased by 1.56% with every 1-year increase in age relative to the population median age of 34.6 years.…”

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

“…Interestingly, the effect of nevirapine induction on CYP2B6 activity leads to an increased concentration of 3-hydroxynevirapine and a lower concentration of the 2-hydroxynevirapine metabolite formed through the CYP3A pathway. The pharmacokinetic characteristics of parent nevirapine in the present study agree with those of previous studies conducted in patients or volunteers after a single dose or at steady state, a finding which clearly demonstrates the autoinducing properties of nevirapine (10,(19)(20)(21)(22)(23)(24)(25)(26)(27). Indeed, the two populations studied herein differ by their ethnicity, demographics, and HIV infection status; the CYP2B6 *1*6 genetic polymorphism frequency is very close, but the significant difference remains when clearances are weight normalized (0.83 ml/ min/kg versus 0.29 ml/min/kg).…”

Effects of Trimethoprim on the Clearance of Apricitabine, a Deoxycytidine Analog Reverse Transcriptase Inhibitor, and Lamivudine in the Isolated Perfused Rat Kidney

“…A previous study with lamivudine in the IPK model showed that the renal excretion of this agent was reduced in the presence of trimethoprim (Sweeney et al, 1995), and subsequent clinical trials confirmed that this interaction might be clinically relevant (Moore et al, 1996;Sabo et al, 2002), although no dose adjustment is recommended (Epivir SmPC). Given the structural similarities between ATC and lamivudine, it is possible that ATC might be subject to a similar interaction with trimethoprim.…”