Age-dependent pharmacokinetics of 3TC in children
The antiretroviral 3TC is licensed for treatment of HIV positive children from 3 months to 16 years. The recommended paediatric dose is 4mg/kg BD compared to the adult dose of 150mg BD (equivalent to 2mg/kg BD). The prescribing information from the originator company states: Total exposure to lamivudine, as reflected by mean AUC values, was compatible between paediatric patients receiving an 8mg/kg/day dose and adults receiving a 4mg/kg/dose.
In an oral presentation David Burger from Radboud University Medical Centre Nijmegen, presented findings from a study to investigate an age effect on 3TC PK and whether systematic clearance is increased in younger children.
Data were selected from children who participated in various PK studies undertaken by the group. Children were receiving 3TC 4mg/kg BD for at least 2 weeks before a full 8-12h PK curve was recorded. Data from HIV positive adults from the study of Bruno et al. (Clin Pharmacokinet 2001; 40: 695-700) were used as adult controls for comparison.
The study included a total of 40 children: 16 boys and 24 girls with a median age of 7.3 years (range: 1.7 to 18 years). The investigators found AUC, Cmax, CL/kg and Vd/kg were significantly related to age with younger children having lower exposure to 3TC. Half-life and Cmin were not influenced significantly by age. They noted: The age of 6 years appeared to be a cut-off for a change in pharmacokinetic parameters of lamivudine in this dataset, with younger children (n=17) having an AUC 42% lower and a Cmax 51% lower (both p=0.001) than older children (n=23).
Additionally, CL/kg and Vd/kg were 74% and 109% higher in children 6 years and below vs. in children aged 7 years and older. They found body surface area (BSA) was less strongly related with age, suggesting that a BSA adjusted dose would have resulted in less variability exposure across the different age groups.
Polly Clayden, HIV i-Base
The mean Cmax and AUC in children aged 7 years and older were similar to historical adult controls adult controls: Cmax 1.93 vs. 2.08 mg/L, AUC 7.05 vs. 8.54 mg/L.h, respectively. There was no sex difference in exposure. There was no difference in children aged 7-12 and >12 years; AUC 7.1 vs. 6.9mg/L.h respectively.
They reported that although a dose of 4mg/kg BD achieves adequate exposure in children aged >7 years (a child of 10 years weighing 35kg will receive an adult dose of 150mg BD) this is not the case for children 6 years and younger.
Dr Burger suggested various explanations: Lower bioavailability? Increased renal clearance? Larger volume of distribution? Oral solution bioequivalent with tablets? He explained that there was no evidence of suboptimal response in younger vs. older children in previous studies and that plasma concentrations are a surrogate marker; intracellular triphosphate is pharmacologically active. Additionally, age dependent variability of 3TC AUC may fall within the range of exposure needed for optimal efficacy, so perhaps targeting adult AUC is unnecessary.
He raised the question: How have paediatric doses been determined? Adult AUC target? Clinical study with PK/PD analysis? He added: Most young children live in developing countries and are treated with generics, often containing lamivudine, there is an urgent need for operational research.
Burger D, Verweel G, Verwey-Van Wissen C et al. Age-dependent pharmacokinetics of lamivudine in HIV-infected children. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 20.