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TFV Levels Far Lower in Milk
Than Plasma With Dried Milk and Blood Spots
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International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020
By Mark Mascolini for NATAP and Virology Education
Dried blood or breast milk spots indicated much lower tenofovir (TFV) concentrations in breast milk than in plasma, according to results of a detailed study in 26 HIV-positive Ugandan women [1]. Maternal weight emerged as a deciding factor in TFV clearance.
Although many postpartum women in resource-poor locales take an antiretroviral regimen including tenofovir disoproxil fumarate (TDF), TFV transfer from mother to infant soon after birth remains poorly characterized. Researchers from Kampala's Infectious Disease Institute and the University of Liverpool performed this study to develop a population pharmacokinetic model for TFV concentrations in maternal blood and breast milk relying on dried blood spots and dried breast milk spots from pregnant and postpartum Ugandan women.
The analysis involved 26 women past 32 weeks gestation or 1 to 2 weeks postpartum taking a regimen containing 300 mg of TDF once daily. All women were at least 18 years old. Researchers conducted intensive pharmacokinetic sampling of maternal dried blood spots and dried breast milk spots collected 5 or 6 times within 12 hours of an observed dose. For each woman, sample collections occurred in 2 of 3 postpartum periods: 1 to 2 weeks, 4 to 6 weeks, and 10 to 12 weeks. The investigators used nonlinear mixed effects modeling to develop a population pharmacokinetic model and to assess the impact of covariates including maternal weight, age, body mass index, and mode of delivery.
The 26 study participants has a median weight of 56 kg (interquartile range [IQR] 53 to 61.5) at the second pharmacokinetic visit, a median age of 29 years (IQR 25 to 32), and a median CD4 count of 598 (IQR 496 to 729). A one-compartment, first-order absorption/elimination model adequately described TFV plasma pharmacokinetics. Parameter estimates were 104 L/h for clearance, 1500 L for volume of distribution, and 5.66/h for maternal blood absorption rate constant.
Modeling breast milk concentration as a constant ratio of plasma concentration, the researchers determined that breast milk levels lay below 10% of plasma concentrations (milk-to-plasma ratio constant [Kbm] 0.0904). Multivariate analysis identified maternal weight as the only independent predictor of TFV clearance.
The researchers are further refining their breast milk model to improve the breast milk profile in the first 8 hours after dosing. They may exclude outlier concentrations at 12 hours from the final analysis.
Reference
1. Najjemba L, Pertinez H, Waitt C, et al. Plasma and breastmilk pharmacokinetics of tenofovir using dried blood and breast milk spots in HIV infected postpartum women in Uganda. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 2.
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