Lamivudine disposition after intravenous and oral administration in children with HIV infection was well described by a two-compartment pharmacokinetic model with first-order absorption and elimination. The drug was rapidly eliminated (t1/2β = 2.2 h) and had excellent oral bioavailability (Tmax = 1.5 h; F = 0.66). Over the 20-fold dosage range (0.5 to 10 mg/kg), the clearance and absorption of lamivudine were dose independent, such that drug exposure (AUC) increased in proportion to dose for both the intravenous and oral routes.
The every-12-h dosing interval of lamivudine is considerably longer than the half-life of the parent prodrug, and trough concentrations of the parent drug in serum are well below 1 μM, the concentration that inhibits viral replication by 50% in vitro. However, the intracellular half-life of the active, triphosphate form of the drug is 10.5 to 15.5 h in vitro in phytohemagglutinin-stimulated, HIV-infected peripheral blood lymphocytes. If prolonged intracellular retention of drug in triphosphate form also occurs in vivo, we would expect a prolonged terminal elimination phase of parent drug in serum as the drug is slowly degraded to its nucleoside form and released from cells. However, the concentrations of trough samples, drawn 12 h after the last dose, were below the limit of detection of the assay at all dose levels including the highest dose level. The fact that a prolonged terminal phase was not detected in our study could be because the amount of drug in triphosphate form is small and slow release of the parent drug from this compartment results in a serum drug concentration that is below the level of detection of the assay used in this study.
The extent of absorption (F
= 0.66) and degree of variability (CV = 38%) after oral lamivudine administration in children is comparable to that observed with zidovudine (F
= 0.68; CV = 37%) (3
). In contrast, the absorption of didanosine in children is more limited (F
= 0.19) and more variable (CV = 90%) (2
Lamivudine, like zalcitabine (dideoxycytidine), is eliminated primarily by renal excretion (14
), whereas cytidine and other cytidine analogs (e.g., cytarabine) are rapidly eliminated by deamination to uridine or uridine analogs. The deaminated form of lamivudine was not detected in the sera of patients treated in our trial, indicating that lamivudine is not a substrate for cytidine deaminase. The pharmacokinetic behavior of lamivudine in children is similar to that of zalcitabine (6
), which had a clearance of 150 ml/min/m2
, a t1/2
of 0.8 to 1.4 h, and oral bioavailability of 0.54.
The pharmacokinetics of lamivudine in children (CL = 229 ml/min/m2
= 2.2 h
) is similar to that reported in adults (CL = 230 ml/min/m2
= 2.5 h
). In two other adult studies, in which pharmacokinetic sampling was performed at 24 and 32 h after the dose, a longer estimated terminal t1/2
of approximately 8 h (range, 6.8 to 12.45 h) was reported (17
). However, lamivudine was not measurable 12 h after the dose in our pediatric patients who were treated at comparable dose levels. It is therefore not likely that a prolonged terminal elimination phase would have been detected even with a longer sampling schedule. The mean absolute bioavailability of lamivudine in adults (F
= 0.86) (24
) appears to be slightly higher than that in children. We also evaluated the relationship of age to pharmacokinetic parameters within the pediatric population and found a significant correlation between age and clearance when clearance was normalized to body weight, whereas clearance normalized to body surface area was age independent. Lamivudine dose in this trial was based on body weight rather than body surface area. However, lamivudine is eliminated primarily by renal excretion (14
), and renal blood flow and glomerular filtration rate after the neonatal period are more closely related to body surface area than to body weight (10
). Given the safety profile for lamivudine and lack of a clear relationship between dose or AUC and response, the currently recommended dosing in milligrams per kilogram appears to be adequate for the majority of pediatric patients. Further dosing adjustment based on body surface area or body weight may be required for patients less than 1 year of age once an adequate number of these patients have been studied.
The CSF penetration of lamivudine in children was limited. The percent CSF to serum drug concentration 2 to 4 h after a dose was 12%, which is similar to the percentage of 8% that we previously reported for a nonhuman primate model in which multiple ventricular CSF samples were obtained after an intravenous dose and the ratio (percent) was derived from the AUCs in CSF and plasma (4
). Although the value of single time-point measurements is limited, the concordance of the preclinical data with the clinical data is reassuring. The CSF penetration of pyrimidine nucleoside analogs appears to be a function of the nucleobase rather than the degree of lipophilicity. The thymidine analogs zidovudine and dideoxythymidine had percents CSF to plasma of 21% and 30%, respectively, whereas the percentages for the cytidine analogs azidocytidine and dideoxycytidine were only 1 and 3, respectively (9
). The CSF lamivudine penetration appears to exceed the penetration of the dideoxycytidine compounds. Encephalopathy was an exclusion criterion for our pediatric trial of lamivudine; thus, we were unable to evaluate the relationship between CSF lamivudine concentrations and improvement in neuropsychometric test results.
Side effects thought to be related to the study drug were uncommon and consisted of elevated serum transaminase levels, hyperactivity, and pancreatitis (16
). All the cases of pancreatitis occurred during the expansion phase of the study, and pharmacokinetic parameter values were not available for the affected patients.
The limited-sampling strategy developed in this study allows for accurate estimation of the AUC of lamivudine from two serum samples, drawn 2 and 6 h after an oral dose. The AUC is a better measure of drug exposure than are the peak and trough concentrations given the short half-life and long dosing interval of lamivudine. Results from this trial do not support a role for therapeutic drug monitoring in the management of children receiving lamivudine, because we failed to identify a relationship between pharmacokinetic parameters and measures of toxicity (16
) and response. However, the limited-sampling strategy presented here would be useful for larger scale studies of patients treated at a single dose level to define therapeutic and toxic levels.