Background:
Current oral lamivudine (3TC) dosing guidance for preterm neonates exposed to HIV is based on limited evidence and no pharmacokinetic (PK) studies in neonates <36 weeks gestational age (GA). As 3TC is one of only three antiretrovirals available for preterm neonates, our aim was to develop a pragmatic 3TC twice daily preterm dosing strategy stratified by GA bands: ≥27 to <30 weeks; and ≥30 to <36 weeks
Methods:
3TC plasma concentration data were pooled from 8 neonatal and infant PK studies receiving 3TC liquid formulation (10 mg/mL); 3 for HIV prevention (PACTG 353, 358, and 386), and 5 for HIV treatment (PACTG 300, 356, IMPAACT P1069, P1106, and the Early Infant HIV Treatment in Botswana study). A population PK model was developed using non-linear mixed effects regression. Different dosing simulations were assessed in a virtual population of preterm neonates (0-6 months of life) to achieve 3TC (AUC0-12) exposures ranging from 3.15 to 13.24 µg∙hr/mL. The model incorporated standard WHO weight-band 3TC dosing of 30 mg twice daily for weights ≥3 to <6 kg and ≥4 weeks of life.
Results:
One-hundred fifty-four infants contributed 858 3TC concentrations; 34 (22%) were born preterm. At first PK sampling, median and range postnatal age (PNA) was 6.3 (0.52-26.6) weeks, body weight 3.8 (1.9-7.8) kg, and plasma serum creatinine 0.4 (0.1-1.2) mg/dL, respectively. 3TC concentrations were best described by a 1 compartment PK model. 3TC clearance (CL/F) and volume of distribution (Vd/F) were allometrically scaled to body weight. Maturation of CL/F was described using an Emax model based on PNA, which also influenced Vd/F. Simulations included GA as a covariate on birth CL/F to account for the impact of developmental changes in renal function expected in preterm neonates. The simulations predict that the optimal 3TC dosing regimen for preterm neonates for GA ≥27 to <30 weeks is 2 mg/kg twice daily from birth, and for GA ≥30 to <36 weeks is 2 mg/kg twice daily for the first 4 weeks of life, followed by 4 mg/kg twice daily. Dosing is adjusted to 30 mg twice daily per WHO weight-band dosing once infants reach ≥ 3kg and aged ≥4 weeks (Figure 1).
Conclusions:
This analysis provides the first pragmatic and evidence based 3TC dosing for preterm neonates where immature renal function undergoes rapid maturation. This proposed preterm 3TC dosing guidance has been endorsed by the WHO-Pediatric Antiretroviral Working Group but should be clinically validated to provide reassurance of model predictions.
