Sharon Sawe 1, Lufina Tsirizani 1, Richard Court 1, Buyisile Mkhize 1, Lubbe Wiesner 1, Gary Maartens 1, Francesca Conradie 2, Marian Loveday 3,4, Catriona Waitt 5,6, Paolo Denti 1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town (Cape Town, South Africa), 2 Department of Clinical Medicine, University of the Witwatersrand (Johannesburg, South Africa), 3 HIV and other Infectious Diseases Research Unit, South African Medical Research Council (KwaZulu-Natal, South Africa), 4 CAPRISA-MRC HIV-TB Pathogenesis and Treatment Research Unit (Cape Town, South Africa), 5 Infectious Diseases Institute, Makerere University College of Health Sciences (Kampala, Uganda), 6 Department of Women’s and Children’s Health, University of Liverpool (Liverpool, UK)
Objectives:
Delamanid, a nitroimidazole drug used in the treatment of rifampicin-resistant tuberculosis (RR-TB),[1] has limited pharmacokinetic data describing its distribution into breastmilk and subsequent exposure in breastfed infants. Delamanid has a half-life of 30-38 hours, while its primary metabolite DM-6705 exhibits a prolonged half-life of 121-322 hours.[2] We developed a population pharmacokinetic model to jointly characterize delamanid and DM-6705 in the plasma and breastmilk of lactating women with RR-TB, and assessed infant exposure through measured infant plasma concentrations and estimated infant dose via breastfeeding.
Methods:
We pooled data from two South African studies including postpartum women treated for RR-TB receiving oral delamanid 100 mg twice daily.[3],[4] Paired plasma and breastmilk samples were collected at 4-8 weeks postpartum (predose and 2, 4, 6, 8, and 24 hours post-dose). A single plasma sample was obtained from breastfed infants at a convenient timepoint within the maternal sampling interval. Total concentrations of delamanid and DM-6705 were quantified using validated HPLC-MS/MS assays (lower limit of quantification of 0.001 mg/L in plasma and 0.01 mg/L in breastmilk for both analytes). Data were analyzed in NONMEM (FOCEI). Maternal plasma pharmacokinetics were described using a joint parent-metabolite model informed by prior data from our previously reported cohort, which included non-pregnant women, men, and antepartum observations.[5] One- and two- compartment disposition models with first-order elimination and different absorption models were evaluated. Allometric scaling using total body weight, fat-free mass, or fat mass was tested on disposition parameters. Breastmilk concentrations were incorporated using an effect-compartment approach [6] to estimate the equilibration half-life (describing the delay in transfer of drug from plasma to breastmilk) and breastmilk-to-plasma ratios. We first fixed the plasma parameters and finally estimated both plasma and breastmilk simultaneously. Between subject variability (BSV) was evaluated on disposition and breastmilk parameters, and between-occasion variability on absorption. Residual unexplained variability in plasma and breastmilk concentrations was described using combined proportional and additive error models. Observations below the limit of quantification (BLQ) were handled using the M6+ method.[7] Infant concentrations were assessed descriptively compared to maternal concentrations. We estimated infant dose relative to recommended maternal dose assuming a milk intake of 150 mL/kg/day.[8]
Results:
Paired plasma and breastmilk data from 10 lactating women (median [range] age 30 [19-40] years; weight 56.8 [49.8-86.5] kg), and plasma samples from seven breastfed infants; median (range) weight 5.32 (3.73-6.00) kg were available. In total, 46 maternal plasma concentrations of delamanid (0.40% BLQ) and 46 of DM-6705 (1.26% BLQ) were available. In breastmilk, 46 delamanid (4.35% BLQ) and 46 DM-6705 (17.4% BLQ) concentrations were collected. Plasma pharmacokinetics of delamanid and DM-6705 were adequately described by two-compartment disposition models with linear elimination, with delamanid clearance as input to DM-6705. Absorption was best described by sequential zero- and first-order kinetics. Total body weight best described central disposition parameters, while peripheral distribution was described using normal fat mass,[9] with the fat fraction fixed to 10, indicating dominant adipose contribution. Typical values (95% CI) for clearance and central volume of distribution were 29 (25.6–32.9) L/h and 302 (214–379) L for delamanid, and 118 (97.8–149) L/h and 158 (40.3–279) L for DM-6705. Breastmilk concentrations were described using effect compartments with a fast equilibration half-life between plasma and breastmilk for both the parent and metabolite, and the value was fixed to 10 minutes (after a sensitivity analysis with likelihood profiling) to ensure model stability. The breastmilk-to-plasma ratios were 0.877 (95% CI: 0.707-1.06) for delamanid and 1.25 (95% CI: 0.950-1.67) for DM-6705. Including BSV on breastmilk-to-plasma ratios improved the model fit with the metabolite exhibiting 1.84-fold (95% CI: 1.17-2.88) greater variability than the parent compound. Relative infant doses via breastfeeding were 1.83% (delamanid) and 0.93% (DM-6705) of the maternal weight-adjusted dose (~ 3 mg/kg/day), consistent with low infant plasma concentrations that we observed.
Conclusions:
We developed a joint population pharmacokinetic model describing delamanid and DM-6705 concentrations in plasma and breastmilk of lactating women with RR-TB and assessed exposure in their breastfed infants. Breastmilk concentrations were similar to plasma, while estimated daily infant doses represented a small fraction of recommended mg/kg adult doses, indicating minimal exposure through breastfeeding. These low infant exposures are unlikely to pose a clinically meaningful risk. These findings support continued delamanid use during breastfeeding, with appropriate maternal and infant safety monitoring.
References:
[1] Y. Liu et al., “Delamanid: From discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB),” Tuberculosis, vol. 111, no. April, pp. 20–30, 2018, doi: 10.1016/j.tube.2018.04.008.
[2] L. Tanneau et al., “Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline,” Clin. Pharmacokinet., vol. 61, no. 8, pp. 1177–1185, 2022, doi: 10.1007/s40262-022-01133-2.
[3] F. Conradie, “Building Evidence for Advancing New Treatment for Rifampicin Resistant Tuberculosis (RR-TB) Comparing a Short Course of Treatment (Containing Bedaquiline, Delamanid and Linezolid) With the Current South African Standard of Care.” Accessed: Mar. 17, 2023. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04062201
[4] M. Loveday et al., “Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug / Rifampicin-Resistant Tuberculosis in South Africa,” vol. 72, 2021, doi: 10.1093/cid/ciaa189.
[5] S. Sawe et al., “Population pharmacokinetics of delamanid in adults treated for rifampicin-resistant tuberculosis: effect of pregnancy,” 2024, Population Approach Group Europe (PAGE). [Online]. Available: https://www.page-meeting.org/Abstracts/population-pharmacokinetics-of-delamanid-in-adults-treated-for-rifampicin-resistant-tuberculosis-effect-of-pregnancy/
[6] R. M. Savic et al., “Pediatric Tuberculous Meningitis: Model-Based Approach to Determining Optimal Doses of the Anti-Tuberculosis Drugs Rifampin and Levofloxacin for Children,” Clin. Pharmacol. Ther., vol. 98, no. 6, pp. 622–629, 2015, doi: 10.1002/cpt.202.
[7] M. Wijk, R. E. Wasmann, K. R. Jacobson, E. M. Svensson, and P. Denti, “A Pragmatic Approach to Handling Censored Data Below the Lower Limit of Quantification in Pharmacokinetic Modeling,” CPT Pharmacometrics Syst. Pharmacol., pp. 1–8, 2025, doi: 10.1002/psp4.70015.
[8] J. T. Wilson, Determinants and consequences of drug excretion in breast milk, vol. 14, no. 4. 1983. doi: 10.3109/03602538308991402.
[9] Holford NHG, Anderson BJ. Allometric size: The scientific theory and extension to normal fat mass. Eur J Pharm Sci. 2017 Nov 15;109S:S59-S64. doi: 10.1016/j.ejps.2017.05.056. Epub 2017 May 25. PMID: 28552478.
Reference: PAGE 34 (2026) Abstr 12046 [www.page-meeting.org/?abstract=12046]
Poster: Drug/Disease Modelling - Infection