Ruvarashe Joylyne Madzime 1, Lufina Tsirizani 1, Richard Court 1, Louvina van der Laan 2, Buyisile Mkhize 1, Lubbe Wiesner 1, Gary Maartens 1, Francesca Conradie 3, Marian Loveday 4,5, Catriona Waitt 6,7, Paolo Denti 1
1 Division of Clinical Pharmacology, Department of Medicine, University Of Cape Town (Cape Town, South Africa), 2 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University (Cape Town, South Africa), 3 Department of Clinical Medicine, University of the Witwatersrand (Johannesburg, South Africa), 4 HIV and other Infectious Diseases Research Unit, South African Medical Research Council (KwaZulu-Natal, South Africa), 5 CAPRISA-MRC HIV-TB Pathogenesis and Treatment Research Unit (KwaZulu-Natal, South Africa), 6 Infectious Diseases Institute, College of Health Sciences, Makerere University (Kampala, Uganda), 7 Department of Women’s and Children’s Health, University of Liverpool (Liverpool, United Kingdom)
Objectives
Rifampicin-resistant tuberculosis (RR-TB) is a global health concern, with approximately 400 000 incident cases annually1. Linezolid is part of BPaLM, a short regimen recently recommended by the World Health Organization for RR-TB treatment. Linezolid is associated with potential toxicity, including anaemia and peripheral neuropathy2. The effect of pregnancy on the pharmacokinetics of linezolid and its penetration into breastmilk are not well characterised. We aimed to develop a population pharmacokinetic model describing the pharmacokinetics of linezolid in adults, including pregnant women, treated for RR-TB, and to determine the impact of pregnancy on linezolid pharmacokinetics. Additionally, we aimed to quantify the transfer of linezolid from maternal plasma to breastmilk and describe exposure in breastfed infants.
Methods
We pooled data from the BEAT-Tuberculosis trial3 and the King Dinizulu Hospital (KDH) pregnancy study4, both conducted in South Africa. All participants were dosed with 600 mg of linezolid daily. BEAT-Tuberculosis was a phase 3 clinical trial comparing a shorter 6-month RR-TB treatment regimen with standard of care in adults, including pregnant women. We collected plasma samples at pre-dose, 2, 4, 6, 8,10, and 24 hours post-dose in non-pregnant participants; pre-dose, 2, 4, 6, 8, and 24 hours post-dose in the third trimester and at 6 weeks postpartum. At the postpartum visit, breastmilk samples were collected at the same plasma sampling timepoints (except at 24 hours), and a single plasma sample was collected from infants at a convenient timepoint within the mother’s sampling interval. The KDH study is an observational study of pregnant women treated for RR-TB treatment. We collected samples in the third trimester, and at 6 weeks postpartum at pre-dose, 2, 4, and 6 hours post-dose. Matched breastmilk samples and a single infant plasma sample per dosing interval were also collected through collaboration with the Maternal and Infant Lactation pharmacoKinetics (MILK) team. All samples were assayed at the University of Cape Town Clinical Pharmacology laboratory with a lower limit of quantification of 0.1 mg/L for plasma, and 0.191 mg/L for breastmilk. Modelling was performed in NONMEM using FOCE-I. We tested one- versus two-compartment models, lag versus transit absorption models, and allometrically scaled disposition parameters using total body weight versus fat-free mass (FFM). All values below limit of quantification were handled using the M7+ method according to Wijk et al5. We tested the pregnancy effect on clearance and bioavailability. Breastmilk was modelled using a hypothetical effect compartment, estimating the breastmilk-plasma ratio, and the equilibration half-life of linezolid in breastmilk. The daily infant dose and relative infant dose (RID) were estimated from the breastmilk-plasma ratio, assuming the standard assumption that infants ingest 0.15 L/kg/day of breastmilk.
Results
A total of 76 participants provided linezolid samples, with 59 (78%) being women (pregnant and non-pregnant), 40 (53%) pregnant women (13 of whom had matching postpartum plasma and breastmilk samples). There were 9 plasma samples from breastfed infants. The median (range) weight was 60 (37 – 104) kg and FFM 40 (27 – 55) kg. There were 20 (26%) participants with HIV, mostly treated with a dolutegravir-based anti-retroviral regimen. Linezolid plasma pharmacokinetics were best described by a one-compartment model with first-order elimination and absorption using transit compartments. Disposition parameters were best scaled using FFM (ΔOFV = -30 versus ΔOFV = -13 with weight), and clearance was 3.86L/h. While we could not find a significant effect of pregnancy or renal function on clearance (ΔOFV = -1.437 and ΔOFV = -0.256 respectively), we found that pregnant women have ~20% lower bioavailability than non-pregnant individuals (ΔOFV = -28). Linezolid breastmilk-plasma ratio was 1.21, and the RID was 20%. Infant plasma concentrations were detectable in 3 out of 9 (33%) breastfed infants. The maximum observed infant concentration was 4-fold lower than the corresponding maternal plasma concentration.
Conclusions
A one-compartment model with linear elimination and absorption best described linezolid pharmacokinetics in adult RR-TB patients, including pregnant women – in keeping with similar reports in non-pregnant adults6. Linezolid pharmacokinetics data in pregnant or lactating women, especially with RR-TB, are scarce. Reduced bioavailability in pregnant women does not necessarily warrant dose revision. The observed breastmilk-plasma ratio suggests that linezolid breastmilk concentrations were marginally higher than those in plasma. The RID suggests moderate exposure of linezolid in infants, necessitating further safety evaluation in breastfed infants.
References:
1. World Health Organization. Global Tuberculosis Report 2024. 2024. Accessed November 4, 2025. https://iris.who.int/server/api/core/bitstreams/7292c91e-ffb0-4cef-ac39-0200f06961ea/content
2. Wasserman S, Brust JCM, Abdelwahab MT, et al. Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study. J Antimicrob Chemother. 2022;77(4):1146-1154. doi:10.1093/jac/dkac019
3. Conradie F, Badat T, Poswa A, et al. BEAT Tuberculosis: a randomized controlled trial of a 6-month strategy for rifampicin-resistant tuberculosis. medRxiv. Published online January 1, 2025:2025.05.04.25326549. doi:10.1101/2025.05.04.25326549
4. Loveday M, Hughes J, Sunkari B, et al. Maternal and infant outcomes among pregnant women treated for multidrug/rifampicin-resistant tuberculosis in South Africa. Clinical Infectious Diseases. 2021;72(7):1158-1168. doi:10.1093/cid/ciaa189
5. Wijk M, Wasmann RE, Jacobson KR, Svensson EM, Denti P. A pragmatic approach to handling censored data below the lower limit of quantification in pharmacokinetic modeling. CPT Pharmacometrics Syst Pharmacol. 2025;14(6):1042-1049. doi:10.1002/psp4.70015
6. Abdelwahab MT, Wasserman S, Brust JCM, et al. Linezolid population pharmacokinetics in South African adults with drug-resistant tuberculosis. Antimicrob Agents Chemother. 2021;65(12). doi:10.1128/AAC.01381-21
Reference: PAGE 34 (2026) Abstr 11996 [www.page-meeting.org/?abstract=11996]
Poster: Drug/Disease Modelling - Infection