Developmental Pharmacokinetic Changes of Lamivudine in Infants and Children

Abstract

Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in infants and children in combination antiretroviral therapy to treat human immunodeficiency virus (HIV) infection. Developmental changes in lamivudine pharmacokinetic disposition were assessed by combining data from 7 studies of lamivudine (Pediatric AIDS Clinical Trials Group 300, 353, 356, 358, 386, 1056, and 1069) representing subjects across the pediatric age continuum. A population pharmacokinetic model was developed to identify factors that influence lamivudine disposition. Age and Thai race were independent predictors of apparent clearance (CL/F), whereas the use of a fixed drug combination formulation (GPO-VIR) was an independent predictor of bioavailability, with CL/F more than doubling from birth to adolescence. Serum creatinine was not associated with CL/F. Monte Carlo simulations were used to compare the lamivudine exposure achieved with World Health Organization (WHO) weight band and Food and Drug Administration (FDA) label dosing recommendations. WHO dosing yielded higher exposure during the first few months of life, but this difference was less pronounced between 6 months and 14 years of age. Overall, both FDA and WHO dosing provided similar AUC values to those previously reported in HIV-infected adults. Lamivudine WHO weight band dosing results in therapeutic exposure in infants and children and may improve drug dosing in resource-limited countries.

Population pharmacokinetics of abacavir and lamivudine in severely malnourished human immunodeficiency virus‐infected children in relation to treatment outcomes

“…Overall, PK parameters for lamivudine presented here are consistent with the findings of previous paediatric studies, which reported mean CL/F ranging from 0.39 to 1.03 L/h/kg . Here we report CL/F of 1.5 L/h/kg, which may indicate a reduced bioavailability in this malnutrition cohort rather than an increased elimination of the drug .…”

“…Analysis of lamivudine PK in paediatric patients in the CHAPAS1 trial identified only bodyweight as a significant covariant; however, the average age of the cohort was 7.2 years compared to a much younger cohort (1.2 years) in the present study . The inclusion of patients younger than 5 months in the current study provided important information to describe this change in these very young infants, identifying that CL/F of lamivudine reached half of expected adult CL/F at age 4 months, similar to the findings of Tremoulet et al . Implementation of early infant diagnostic strategies globally has resulted in earlier identification of newly diagnosed HIV‐infected children, necessitating the initiation of ART in very young infants in treatment programmes.…”

“…The population modelling was conducted using NONMEM version 7.4.1, Intel FORTRAN compiler and PsN version 4.7.0 . Structural model parameter estimates, interindividual variability (IIV) and residual unexplained variability (RUV) were obtained by first‐order conditional estimation with interaction.…”

“…While the population PK of abacavir and lamivudine have been investigated, little is known about the effect of malnutrition on it . The most extensively studied antiretroviral drugs in malnourished children are nevirapine and lopinavir (LPV) .…”

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open‐Label, Randomized Study

“…In some studies, children also received nevirapine suspension (162 mg of sorbitol/mL) or the prophylactic antibiotic trimethoprim‐sulfamethoxazole as a suspension (sorbitol amounts vary depending on the manufacturer). This interaction between lamivudine and sorbitol may also explain previous reports of lower exposures in younger/lower‐weight children compared with older/higher‐weight children17, 18, 19, 20 because younger children are more likely to be prescribed liquid medications for ease of swallowing.…”