Given its safety profile and clinical success record, lamivudine is widely used for infants and children as an integral part of the nucleoside backbone of combination antiretroviral therapy (13
). In the PACTG 300 study, zidovudine-plus-lamivudine therapy was found to decrease the progression of HIV disease from that with didanosine monotherapy and was safe for children older than 1 month (14
). In a number of trials, lamivudine has been used in combination with zidovudine and/or nevirapine during the first 1 to 6 weeks of life to reduce transmission and limit the development of resistance (13
). In the Petra Study, oral lamivudine and zidovudine administered at 36 weeks gestation, intrapartum, and 1 week postpartum to African breastfeeding women and their infants reduced the HIV-1 transmission rate from that with a placebo (5.7% versus 15.3%) (20
). Given the growing concerns about resistance with single-dose nevirapine, the World Health Organization recommends that lamivudine and zidovudine be used in combination with single-dose nevirapine administered to the mother at the time of delivery (24
). Longer administration of lamivudine-containing regimens to reduce transmission due to breastfeeding is being studied; an understanding of lamivudine pharmacokinetics beyond the first few weeks of life is required. Maintenance of adequate lamivudine concentrations is essential to prevent the development of resistance, since one mutation to valine in the reverse transcriptase at position 184 can lead to a >50-fold decrease in sensitivity to lamivudine (21
). Despite the widespread use of lamivudine in pediatrics worldwide, limited pharmacokinetic data exist to ensure that the optimal dose is currently being used for infants.
For adults, the pharmacokinetics of lamivudine in normal, HIV-infected, and hepatitis B-infected subjects have been well studied. The drug is rapidly absorbed after oral administration, with an absolute bioavailability of 86 to 88% for the oral solution, capsule, and tablet (26
). Lamivudine exhibits low protein binding, and its pharmacokinetic parameters can be reasonably well described by a one-compartment model. Because lamivudine is primarily renally excreted, CL/F and Vd/F decrease while the half-life and area under the curve increase with increasing renal impairment in adults (9
). Extrapolating this finding to the immature renal function of infants, one would predict a lower CL/F and Vd/F in infants than in older children and adults with normal renal function. As renal function matures, it would be predicted that CL/F would also increase, requiring a dose adjustment during this time.
Overall, our pharmacokinetic parameters are consistent with the findings of previous, smaller pediatric studies and with expected maturational changes in renal function. Our post hoc data from the current model are compared to previous mean lamivudine pharmacokinetic estimates for various age groups in Table . From neonatal data, oral clearance is seen rapidly increasing between days 1 and 7 of life to a value similar to that for our youngest infants. Previous pediatric studies have reported apparent clearance means from 0.39 to 0.83 liter/h/kg (8
). While previous studies indicate that infant clearance increases during the first week of life, our study shows that rapid maturation continues during the subsequent few weeks of life. Our findings are supported by a recent study published by Burger et al., which showed the age-dependent oral clearance of lamivudine in a group of 51 HIV-infected children from the ages of 1.7 to 17 years (5
). Though tested in different cohorts, the lower oral clearance of lamivudine in our 29-day- to 3-year-old group compared to their 1.7- to 6-year-old group (0.66 versus 1.03 liters/h/kg) demonstrates age-dependent renal function maturation. This suggests that early infancy and childhood are critical periods for renal development, which may lead to the need for dosing modifications to maintain adequate drug exposure of renally excreted drugs.
Comparison of mean lamivudine pharmacokinetic values for HIV-exposed and -infected infants, children, and adults
In our study, after scaling for weight, the univariate analysis demonstrated that gender, serum creatinine levels, elevated bilirubin levels, age, and HIV infection had an impact on clearance. However, only age was found to affect the model, and was consequently retained, in the multivariate analysis. In infant populations, several clinical characteristics can be highly correlated and can lead to a high number of covariates being excluded during the multivariate analysis. Therefore, one must be cautious in constructing only mechanistically plausible models to prevent erroneous inferences from significant covariates. Our data support the observation that lamivudine clearance increases in parallel with the maturation of renal function, as expected in view of the predominantly renal elimination of lamivudine. In adults, impaired renal function demonstrates a significant relationship with lamivudine disposition after a single oral dose of 300 mg (9
). In an adult population pharmacokinetic model, creatinine clearance and weight were significant covariates (18
). Although serum creatinine did not improve our model's clearance predictability in the multivariate analysis, this finding may be confounded by the correlation between age and serum creatinine levels. Our evaluation may also be limited by the fact that we measured only serum creatinine levels and did not measure creatinine clearance. Also, there were no subjects with significant renal dysfunction, and the granularity of the serum creatinine results was limited (rounded to the nearest 0.1 mg/dl, with a median of 0.4 mg/dl). The lack of an association may be due to lamivudine's substantial renal excretion, which may not be predicted by serum creatinine levels or glomerular filtration. In addition, the transporter(s) responsible for lamivudine secretion may mature at a different rate than the glomerulus. Finally, in our population, while one would expect serum creatinine levels to stay stable, the serum creatinine samples in which the reported values were measured and the lamivudine pharmacokinetic samples were not always collected at the same time, possibly explaining the discordance between serum creatinine and clearance.
In our model, accounting for interoccasion variability in bioavailability improved the individual subject clearance prediction over the span of the study. This could reflect differences in absorption based on diet or other physiological processes that affect absorption and other pharmacokinetic parameters. Clinical adverse event reporting from these four PACTG trials found no associated gastrointestinal illness that could have accounted for the differences in absorption. The intervals between pharmacokinetic evaluations were long enough for significant changes in lamivudine disposition to occur. Thus, this study represents not only day-to-day variability but variability in maturation as well. For infants, accounting for interoccasion variability is especially important, since renal maturation and changes in clearance and volume of distribution are occurring as the individual ages. Given the importance of maintaining consistent lamivudine levels to prevent the emergence of resistance, it is important to recognize the variability within a single subject as well as between subjects.
Given the changes in clearance in infants and children within the first 2 years of life, it is important that dosing reflect these changes. Through our simulation we found that transitioning children from 2 mg/kg q12 h to 4 mg/kg q12 h at the age of 4 weeks maintains lamivudine concentrations near adult concentrations. While exact lamivudine levels necessary to optimize therapy are not known, it is clear that the risk of HIV progression is inversely related to age (23
). With such a risk of progression and the good safety profile of lamivudine in children, a dosing regimen that maintains plasma drug concentrations equal to or higher than those for adults would be reasonable given the potential benefit of decreasing viremia more rapidly in this susceptible population.
While it is the intracellular triphosphate anabolite of lamivudine that is the active moiety, we are currently limited to measuring lamivudine plasma concentrations and extrapolating the clinical effects from these measurements. The volume of blood needed to measure intracellular lamivudine triphosphate concentrations with current technology makes serial evaluations impractical for infants and children. While newer technologies are currently being developed to measure intracellular concentrations, these methodologies, which include the use of a radiolabeled drug in microdosing quantities, have not yet been evaluated for antiretrovirals in pediatrics.
Lamivudine is a widely used, well-tolerated, effective medication for the interruption of mother-to-child transmission of HIV and the treatment of HIV-infected children worldwide. This pharmacokinetic analysis indicates early increases in lamivudine clearance during infancy, requiring a dose increase to maintain adequate lamivudine exposure. Using a population pharmacokinetic analysis, this study has demonstrated that the variability in infant lamivudine pharmacokinetics requires a dose transition from 2 mg/kg q12 h to 4 mg/kg q12 h at the age of 28 days for infants with normal maturation of renal function in order to provide adequate lamivudine exposure for the majority of infants. As future studies help define sources of lamivudine pharmacokinetic variability and its exposure-response surface, further refinement of lamivudine use will be possible to ensure optimal drug concentrations and improve the control of viremia in pediatric HIV worldwide.