Intracellular and plasma measurements of AZT and 3TC and their metabolites in neonates

Neonates receive antiretroviral prophylaxis often involving AZT either alone or in association with 3TC. Since access to intracellular NRTI triphosphate (TP) measurement is limited, pharmacological intracellular data are still lacking.

A poster from L. Durand-Gasselin and coworkers presented findings from a study to measure AZT and 3TC plasma levels, as well as intracellular phosphorylated metabolites concentrations, in HIV exposed babies born to HIV positive mothers.

52 HIV exposed neonates (age range: 0-45 days) received AZT (8mg/kg/24h), either alone (n = 32) or with 3TC (4mg/kg/24h) (n = 20). Plasma and PBMCs were isolated from blood and intracellular NRTI metabolites (AZT-TP, d4T-TP, 3TC-TP) and plasma NRTI (AZT, d4T, 3TC) concentrations were determined using validated LC-MS/MS assays.

The investigators found plasma AZT and intracellular AZT-TP levels in the neonates decreased significantly with age (p<0.0001). The median AZT-TP concentration reached 202.2 fmol/106 cells (CV%=44) between days1 and 8, but only 62.9fmol/106 cells (CV%=65) between days 32 and 40. They suggest that this phenomenon could be explained by the maturation of intestinal, hepatic and renal functions occurring during the first weeks of life.

Therefore, they observed high AZT and AZT-TP levels during the first week as compared to adult historical data. Intracellular levels of d4T-TP closely correlate with those of AZT-TP with an average d4T-TP to AZT-TP ratio of 0.28. Plasma 3TC and intracellular 3TC-TP levels did not differ significantly by age. The median 3TC-TP concentration was 19 pmol/106 cells, which is consistent with adult data.

They noted that babies receiving AZT monotherapy, whose mothers treatment included 3TC, had residual plasma 3TC and intracellular 3TC-TP up to one week after birth. The investigators wrote: We observed high concentration of AZT and related intracellular metabolites (AZT-TP and d4T-TP) during the first week of life. Following the first fortnight, intracellular NRTI-TP measurements showed no major difference with adults in term of 3TC-TP levels and metabolic pathway from AZT to d4T and d4T-TP. They added: These characteristics, in favor of efficacy, could have some drawbacks in terms of mitochondrial toxicity.

Durand-Gasselin L, Pruvost A, Dehée A et al. Intracellular and plasma measurements of AZT and 3TC and their metabolites in newborn babies from HIV infected mothers. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 25.