Background
Lamivudine is a widely used antiretroviral drug included in first-line HIV treatment regimens and recommended by the WHO.1 Each year, over 1.3 million women living with HIV become pregnant, many of whom breastfeed their infants. While breastfeeding is essential for infant health, it can also serve as a route of drug exposure. This study aimed to develop a mechanistic population pharmacokinetic model to characterise the transfer of lamivudine from maternal plasma to breast milk and estimate infant drug exposure through breastfeeding.2
Methods
Thirty-five HIV-positive, breastfeeding mothers and their infants receiving lamivudine (150 mg BD or 300 mg OD) were enrolled from the Infectious Diseases Institute and affiliated clinics in Kampala, Uganda. Intensive maternal plasma / breast milk pharmacokinetic sampling was conducted at 0, 1, 2, 4, 8, 12, 16, 20 postdose and lamivudine concentrations quantified by LC-MS/MS. Plasma and breast milk concentrations were simultaneoulsly analysed by nonlinear mixed-effects modelling in NONMEM 7.4.3, with assistance of Pirana and R.
Results
Overall 254 plasma and 262 breast milk samples were analysed. A one-compartment model (Ka = 1.81 h-1; CL = 19.6 Lh-1; V = 184 L) adequately described plasma lamivudine disposition, while an effect compartment model best captured the delayed transfer to breast milk. The estimated milk-to-plasma ratio was 1.79, and the plasma-to-milk equilibration rate constant was 0.242. Maternal clearance was associated with weight and CRCL, although covariate estimates lacked precision (%RSE>30). Infant exposure was estimated at a median of 735.9 µg/day representing 0.25% of the maternal dose and well below the 10% threshold considered to pose a risk.3
Conclusion
We developed a mechanistic PK model describing lamivudine transfer into breast milk. Infant exposure was minimal, suggesting low risk. Future works will assess the impact of i) post-partum sampling times and ii) infant feeding frequency, breast milk volume and infant pharmacokinetic attributes on plasma-to-breastmilk transfer.
References
- WHO 2024 Mother-to-child transmission of HIV (https://www.who.int/teams/global-hiv-hepatitis-and-stis-programmes/hiv/prevention/mother-to-child-transmission-of-hiv) Last accessed on 15 March 2024.
- Pertinex H. et al (https://ascpt.onlinelibrary.wiley.com/doi/10.1002/psp4.12497).
- Nishimura A et al. Breastfed Med. 2021; 16(5): 424-431.
