Sharon Jepkorir Sawe (1), Lufina Tsirizani Galileya (1), Richard Court (1), Asanda Poswa (2), Tasnim Badat (2), Lubbe Wiesner (1), Gary Maartens (1), Marian Loveday (3), Francesca Conradie (2), 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 Prevention Research Unit, South African Medical Research Council, KwaZulu-Natal, South Africa
Objectives: Delamanid is a WHO-recommended drug for the treatment of RR-TB [1]. Delamanid has a terminal half-life of 30-38 h and is mainly metabolized by albumin into DM-6705, which exhibits a longer half-life of 5-13 days [2], [3]. The pharmacokinetics (PK) of delamanid and DM-6705 in adults is well described [3]–[5], although no PK information is currently available for pregnant women. We developed a joint model of delamanid and DM-6705 in patients with RR-TB, and evaluated the effect of pregnancy, body size, HIV status, and albumin concentrations on delamanid exposure.
Methods: We pooled data from two studies in South African adults treated for RR-TB with regimens including delamanid 100 mg twice daily, administered orally. Blood samples were drawn pre-dose, and at 2, 4, 6, 8, 10, and 24 h post-dose. Delamanid and DM-6705 concentrations were assayed using HPLC-MS/MS, both with a lower limit of quantification of 0.001 mg/L. In pregnant women, sampling was performed during the third trimester and again approximately 6-weeks postpartum. Albumin concentrations were measured close to the respective pharmacokinetic visits. The data were analysed in NONMEM and the model was developed sequentially, describing first the parent data, and then incorporating the metabolite data. One- and two-compartment disposition models with first-order elimination and absorption, with or without lag or transit absorption compartments were tested. The fraction of delamanid metabolized to DM-6705 was fixed to 1. Model variability was quantified testing between-subject variability on disposition parameters and between-occasion variability on absorption parameters. A combined proportional and additive error model was used to describe the residual unexplained variabilities for both delamanid and DM-6705, and were correlated using the NONMEM level 2 (L2) data item. Allometric scaling of all disposition parameters, including those for the metabolite was tested using either total body weight or fat-free mass (FFM) [6]. Extra variability on the absorption parameters was tested to account for the uncertainty related to unobserved doses. We assessed the effect of covariates on the PK of delamanid and DM-6705 including pregnancy, albumin, HIV status, and morning versus evening dosing.
Results: PK samples were available for 24 participants, contributing 158 delamanid and 162 DM-6705 concentrations with none below the limit of quantification. The median (range) age was 34 (19-60) years, weight 55 (37-104) kg, and albumin concentrations 29 (20-43) g/L. Fifteen (63%) participants had HIV, mostly treated with dolutegravir-based antiretroviral therapy. Of the 16 female participants included, 7 (44%) were pregnant, of whom 4 (57%) contributed matched antepartum and postpartum PK profiles. Albumin concentrations were 3.40% lower in pregnant women compared to non-pregnant participants. Delamanid and DM-6705 PK were best described by a two-compartment disposition model with absorption transit compartments, and by a one-compartment disposition model with delamanid clearance as input, respectively. The typical values for clearances, best allometrically scaled using weight, were 33.9 L/h for delamanid, and 160 L/h for DM-6705. We found an increase of 33.3% in bioavailability of the evening dose compared with the morning dose of delamanid. The model significantly improved when the estimate of the greater variability (2.22-fold) in all the absorption parameters following unobserved doses was allowed. Notably, no statistically significant effect of pregnancy, albumin, or HIV status was found on the PK of delamanid or DM-6705.
Conclusions: We developed a joint model, which adequately described the PK of delamanid and its main metabolite DM-6705. Our findings are in line with previous research [4], [5], highlighting total body weight as a better body size descriptor for drug disposition than FFM. The observed values for clearances were comparable to those reported in adult populations [4], [5]. Similarly, our study aligns with prior reports indicating a higher bioavailability for the evening dose, possibly attributable to variations in absorption of delamanid influenced by food quantity and composition [4], [5]. Reassuringly, no pregnancy effect was found on the PK of delamanid or DM-6705, thus alleviating concerns for dose adjustments in pregnancy – although additional research with a larger sample size of pregnant women is required.
References:
[1] WHO, “WHO consolidated guidelines on tuberculosis Module 4: Treatment Drug-resistant tuberculosis treatment 2022 update,” 2022. Accessed: Mar. 17, 2023. [Online]. Available: https://www.who.int/publications/i/item/9789240063129
[2] 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.
[3] K. Sasahara et al., “Pharmacokinetics and metabolism of delamanid, a novel anti-tuberculosis drug, in animals and humans: Importance of albumin metabolism in vivo,” Drug Metab. Dispos., vol. 43, no. 8, pp. 1267–1276, 2015, doi: 10.1124/dmd.115.064527.
[4] 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.
[5] X. Wang, S. Mallikaarjun, and E. Gibiansky, “Population pharmacokinetic analysis of delamanid in patients with pulmonary multidrug-resistant tuberculosis,” Antimicrob. Agents Chemother., vol. 65, no. 1, 2021, doi: 10.1128/AAC.01202-20.
[6] B. J. Anderson and N. H. G. Holford, “Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics,” Annu. Rev. Pharmacol. Toxicol., vol. 48, no. 1, pp. 303–332, Feb. 2008, doi: 10.1146/annurev.pharmtox.48.113006.094708.
Reference: PAGE 32 (2024) Abstr 11000 [www.page-meeting.org/?abstract=11000]
Poster: Drug/Disease Modelling - Infection