The results of this study suggest that, based on key AUC-related parameters, lamivudine at 300 mg once daily is pharmacokinetically equivalent to the standard 150-mg twice-daily regimen. This at least partly explains why in comparative clinical trials, the once-daily regimen, in combination with other antiretroviral agents, has reduced plasma HIV RNA levels and elevated CD4 cell counts as well as lamivudine at 150 mg twice daily in HIV-1-infected patients receiving the same concurrent antiretroviral therapy (Sension et al., 8th Conf. Retrovir. Opportunistic Infect., p. 317; Bonwonwatanuwong et al., 1st Int. AIDS Soc. Conf. HIV Pathogenesis Treatment, abstr. 4).
The steady-state plasma lamivudine pharmacokinetic parameters observed in this study were similar to those previously reported in HIV-infected patients (7
). A higher steady-state plasma Cmax
in the absence of a significant change in lamivudine exposure (AUC) occurred following the 300-mg once-daily regimen compared to the 150-mg twice-daily regimen, a pattern that was also seen when these two dosage regimens were compared over a 15-day period in patients with hepatitis B infection (7
). Although lamivudine plasma trough concentrations (C0,ss
, 0.02 to 0.11 μg/ml; C24,ss
, 0.02 to 0.09 μg/ml) were 53% lower with the 300-mg once-daily regimen than the 150-mg twice-daily regimen, they nevertheless remained within the 90% inhibitory concentration (IC90
) range of lamivudine against HIV-1 in various cell lines (0.0087 to 0.464 μg/ml) (4
). In a crossover study of 7-day regimens of lamivudine at 300 mg once daily and 150 mg twice daily in 12 HIV-infected patients, Bruno (R. Bruno, 1st Int. AIDS Soc. Conf. HIV Pathogenesis Treatment, abstr. 342, 2001) reported similarly lower plasma lamivudine trough concentrations (by 56% versus 53% in the present study) and higher Cmax
values (by 67% versus 66%) with the 300-mg once-daily regimen in the absence of significant differences in plasma lamivudine Cave
, AUC, and tmax
. In addition, Bruno noted that the elimination half-life of lamivudine (not evaluated in the present study) following 300 mg once daily did not differ from that observed following 150 mg twice daily.
The AUC24,ss, Cave,ss, and Cmax,ss results of this study indicate that the intracellular lamivudine-TP pharmacokinetics following lamivudine at 300 mg once daily are essentially equivalent to those following 150 mg twice daily. Pharmacokinetic differences between the two lamivudine regimens were less striking intracellularly than in plasma. Thus, in contrast to what occurred in plasma, the intracellular lamivudine-TP Cmax,ss did not differ between the regimens, and trough concentrations, reflected in the C24,ss and C0,ss values, were only 18 to 24% lower with the once-daily regimen. The latter difference is of unknown clinical significance in view of the high interpatient variability in intracellular pharmacokinetics that was seen in this study and the observation that median lamivudine-TP C24,ss and C0,ss concentrations (1.90 and 1.61 pmol/106 cells, respectively) remained within the range reported in lamivudine responders (1.01 to 4.32 pmol/106 cells) (Robbins et al., 40th ICAAC, abstr. 1168). The smaller difference between the 300-mg once-daily and 150-mg twice-daily regimens for intracellular lamivudine-TP trough concentrations compared with plasma lamivudine trough concentrations is probably due to the saturable enzymatic step from intracellular lamivudine-DP to lamivudine-TP and the effect of pooling of intracellular lamivudine-DP. These factors allow continued production of lamivudine-TP despite lower plasma lamivudine concentrations in the 12- to 24-h postdose period for the 300-mg once-daily regimen compared to the 150-mg twice-daily regimen.
The plasma lamivudine and intracellular lamivudine-TP pharmacokinetics observed in our study population of healthy volunteers were comparable to those previously described in HIV-infected patients (7
). We felt that a study population consisting of healthy subjects was appropriate, because earlier studies showed no differences in lamivudine pharmacokinetic parameters in healthy males and females from those reported in patients with HIV infection (11
). Furthermore, because a population pharmacokinetics study showed that lamivudine pharmacokinetics are unaffected by surrogate markers of HIV disease (CD4+
counts, HIV-1 RNA PCR, and Centers for Disease Control and Prevention Classification), it is unlikely that lamivudine biodispositions would differ between healthy and HIV-infected populations (12
Our study showed a high degree of intersubject variability in intracellular lamivudine-TP pharmacokinetics (CV, 48 to 124%). This magnitude of variability is consistent with the CVs generally exceeding 50% that have been found in other studies of intracellular lamivudine-TP pharmacokinetics (10
; Moore et al., Abstr. 7th Conf. Retrovir. Opportunistic Infect., abstr. 96; B. L. Robbins, T. T. Tran, F. H. Pinkerton, Jr., et al., Program Abstr. 5th Conf. Retrovir. Opportunistic Infect., abstr. 361, p. 224, 1998). Variability in nucleoside phosphorylation is likely due to a combination of patient-related factors (immune status, cellular function, phenotype, genetic variation), pharmacokinetic/pharmacodynamic factors (endogenous enzyme activity, competition for enzymes by endogenous substrates, and concomitantly administered nucleoside antiretrovirals), and assay-related factors (e.g., bioanalytical limitations) (1
In this short-term study, the absence of differences in the relative safety profiles of lamivudine at 300 mg once daily and 150 mg twice daily was expected. Two longer-term phase I to phase II studies previously confirmed that the safety profile of lamivudine did not differ over the dose range of 0.5 to 12 mg/kg/day (~37.5 to 900 mg/day), administered for 24 weeks or longer (14
). Moreover, in the NUCA3001 study, which compared lamivudine at 300 mg twice daily (twice the daily dose administered in this study) with 150 mg twice daily in combination with zidovudine over 24 weeks, no differences in type or incidence of adverse events were noted (5
In conclusion, for key AUC-related parameters, lamivudine at 300 mg once daily is pharmacokinetically equivalent to lamivudine at 150 mg twice daily and is equally well tolerated.