Bedaquiline exposure in pregnancy and breastfeeding in women with rifampicin‐resistant tuberculosis

Abstract

We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics (PK) and describe bedaquiline exposure in the breast milk of mothers treated for rifampicin-resistant tuberculosis (TB), where there are no human data available. Methods:We performed a longitudinal PK study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure.Pharmacokinetic sampling was performed at 4 time-points over 6 hours in the third trimester, and again at approximately 6 weeks postpartum. We obtained serial breast milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and nonbreastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the breast milk and plasma bedaquiline assays, and population PK modelling to interpret the bedaquiline concentrations.Results: We recruited 13 women, 6 of whom completed the ante-and postpartum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante-and postpartum bedaquiline exposures than reported in nonpregnant controls. Bedaquiline concentrations in breast milk were higher than maternal plasma (milk to maternal plasma ratio: 14:1). A single random plasma bedaquiline and M2 concentration was available in 4 infants (median age: 6.5 wk): concentrations in the 1 breastfed infant were similar to maternal plasma concentrations; concentrations in the 3 nonbreastfed infants were detectable but lower than maternal plasma concentrations. Conclusion:We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in breast milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.Richard Court and Kamunkhwala Gausi contributed equally to this study.

A systematic review on maternal-to-infant transfer of drugs through breast milk during the treatment of malaria, tuberculosis, and neglected tropical diseases

“…In the 4 studies that enrolled infants, evaluation of infant blood drug concentrations was performed in 2 studies. In the study by Court and colleagues [ 30 ], limited infant plasma sampling was performed, based on 4 infants from the 13 mother–infant pairs. In the study by Gilder and colleagues [ 29 ], infant capillary blood concentrations were collected only for evaluation of the hematocrit.…”

“…M:P ratios calculated from specific time points do not account for differences between plasma and breast milk concentration-time profiles, unlike those generated from AUCs, and might yield misleading findings. For studies that employed model-based compartmental analysis, the M:P ratio was calculated from model-derived breast milk and plasma AUCs [ 42 , 43 ] or by directly modeling the plasma-to-milk drug transfer kinetics [ 30 , 44 ].…”

“…A longitudinal pharmacokinetic study of this drug was conducted in 13 pregnant women aged 30 years (interquartile range (IQR): 25 to 37) [ 30 ]. During their third trimester of pregnancy, they were dosed with 200 mg of bedaquiline 3 times a week as part of a standard regimen for treating rifampicin-resistant tuberculosis.…”

Validation and application of a quantitative LC-MS/MS assay for the analysis of first-line anti-tuberculosis drugs, rifabutin and their metabolites in human breast milk

“…We used drug-free human breast milk donated by Milk Matters human milk bank, South Africa (HREC number 639/2019) for the preparation of STDs and QCs for method development and validation. For our exploration of isoniazid, acetyl isoniazid, ethambutol, and pyrazinamide in breast milk, we used breast milk samples from women (≥18 years old) on treatment for rifampicin-resistant (RR-) TB at King Dinuzulu-Hospital (KDH) in Durban, South Africa [17] . KDH is a specialist provincial rifampicin-resistant TB hospital where, until recently, all pregnant women with RR-TB in KwaZulu-Natal province were referred for care.…”

Best practices for the care of pregnant people living with TB

“…Regimen construction in pregnant people follows a similar approach as in non-pregnant people: selecting 4–5 drugs that are active against the person’s particular TB strain is desirable. Clinicians should prioritize the use of the WHO Group A medications (bedaquiline [BDQ], linezolid [LZD], and the third-generation FQs) 45 , 46 and the WHO Group B medications (clofazimine [CFZ] and cycloserine [CS}). 47 , 48 The novel nitroimidazole agent, pretomanid, has been associated with testicular toxicity in animal studies and the US Food and Drug Agency has mandated semen studies in humans prior to recommending the drug for broader use.…”