Francis W Ojara1,2, Aida N Kawuma1, Catriona Waitt1,3
1. Infectious Diseases Institute, Makerere University College of Health Sciences, Uganda 2. Department of Pharmacology and Therapeutics, Gulu University, Uganda 3. Department of Pharmacology and Therapeutics, University of Liverpool, UK
Introduction
Lamivudine (3TC) is a component of several firstline antiretroviral (ARV) regimens used to treat HIV and is a WHO-listed essential medicine [1]. Over 1.3 million women with HIV become pregnant annually [1], with a significant proportion breastfeeding their infants there after. Breast milk is an acceptable, feasible, affordable, sustainable, and safe form of nutrition – especially in low-resource settings, but it can also be a notable route of drug exposure for breastfed infants. Building on a previously developed population pharmacokinetic model describing plasma-to-breast milk transfer of 3TC [2], this work seeks to explore a mechanistic characterisation of plasma-to-breast milk transfer of 3TC, and subsequent exposure in breastfed infants
Objectives
- To develop a mechanistic population pharmacokinetic model characterising the transfer of 3TC from maternal plasma-to-breast milk
- To evaluate the impact of different maternal demographic and clinical covariates on maternal plasma-to-breast milk transfer of 3TC
- To estimate infant exposure to 3TC through breast milk
Methods
Thirty-five mothers, and their breastfeeding infants receiving firstline ART at the Infectious Diseases Institute and affiliated clinics in Kampala, Uganda were enrolled. The study was approved by the University of Liverpool and the Joint Clinical Research Center (JCRC, Kampala-Uganda) ethics committees, and registered with the Uganda National Council of Science and Technology. The mothers received 3TC 150 mg twice daily (bd) or 300 mg once daily (od), in combination with nevirapine + zidovudine, or efavirenz and tenofovir. Mothers were randomised to attend two visits at either 1-2 weeks; 4-6 week or 10-12 weeks post-partum. Intensive maternal plasma / breast milk pharmacokinetic sampling was conducted at 0, 1, 2, 4, 8, 12, 16, 20 hours post dosing and 3TC concentrations were quantified using a validated LC-MS/MS assay. Longitudinal plasma and breast milk concentration-time data were simultaneoulsly analysed by nonlinear mixed-effects (nlme) modelling. Weight, BMI, creatinine clearance (CRCL) and age were evaluated as covariates. The analysis was undertaken in NONMEM 7.4.3, with assistance of Pirana and R.
Results
Overall 254 plasma- and 262 breastmik samples were assayed. Steady-state concentrations of plasma and breastmilk were comparable in the bd and od dosing schedules. A delay in plasma to breast milk distribution of 3TC was observed. A 1-compartmental disposition model adequately characterised the plasma disposition of 3TC: Ka = 1.81 h-1; CL = 19.6 Lh-1; V = 184 L. Breast milk transfer was characterised by an effect compartment model, with a plasma-to-breast milk equilibration rate constant of 0.242 and milk-to-plasma ratio of 1.79. CL was significantly affected by weight and CRCL and V was affected by weight, however covariate effects were imprecisely estimated (%RSE>30). A daily infant dose of 735.9 µg; range (349.6, 1493.2) was estimated, assuming a daily breast milk intake of 0.150 L/Kg/day [3, 4]. This represents 0.25% of the daily maternal dose, significantly lower than the threshold of >10% [5].
Conclusions / Next steps
A population PK model characterising maternal plasma-to-breastmilk transfer of 3TC was successfully developed, effectively describing the observed delayed distribution, and accumulation of 3TC in breastmilk. Non of the covariates effects for age, weight, CRCL were precisely estimated. The estimated infant exposure is significantly lower the recommended 10% threshold of maternal exposure. Subsequent steps will include i) evaluation of the influence of time post-partum on plasma-to-breastmilk transfer of 3TC and infant exposure and ii) characterisation of infant 3TC exposure accounting for feeding frequency, breast milk volume and infant pharmacokinetic attributes.
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).
- Court R, et al. Br J Clin Pharmacol. 2022; 88(8):3548‐3558. doi:10.1111/bcp.15380
- John T. Wilson, Drug Metabolism Reviews. 1983; 14 (4) 619-652. doi: 10.3109/03602538308991402
- Nishimura A et al. Breastfed Med. 2021; 16(5): 424-431.
Reference: PAGE 32 (2024) Abstr 11201 [www.page-meeting.org/?abstract=11201]
Poster: Drug/Disease Modelling - Infection