Model-informed once-daily dosing strategy for children, adolescents and adults for bedaquiline and delamanid
Yu-Jou Lin (1), Louvina E. van der Laan (2), Mats O. Karlsson (1), Anthony J. Garcia-Prats (2,3), Anneke C. Hesseling (2), Elin M. Svensson (1,4)
(1) Department of Pharmacy, Uppsala University, Uppsala, Sweden, (2) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa, (3) Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, USA, (4) Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands
Objectives:
The introduction of novel anti-tuberculosis drugs e.g. bedaquiline (BDQ), delamanid (DLM), and pretomanid, has revolutionized the treatment of drug-resistant tuberculosis (TB) across all ages [1]. The complexity of the currently registered dosing schedules for BDQ [2] and DLM [3] is a barrier to uptake. Simpler once-daily dosing schedule is critical to enable evidence-based patient-friendly regimens and improve adherence. We applied modeling and simulation approaches to demonstrate the expected drug exposures with proposed once-daily doses for adults of BDQ and DLM. We then compared new model-informed once-daily dosing regimens for BDQ and DLM in children with current World Health Organization (WHO)-recommended dosing [4].
Methods:
We evaluated the following 3 regimens for BDQ in adults: the regulatory registered dose (400 mg once daily [QD] × 2 weeks + 200 mg thrice weekly [TIW] × 22 weeks) [2], dose used in the ZeNix trial (200 mg QD × 8 weeks + 100 mg QD × 16 weeks) [5] and proposed once-daily dose (400 mg QD × 2 weeks + 100 mg QD × 22 weeks) and 2 regimens for DLM in adults: the 100 mg twice daily (BID) registered dose [3] and proposed 300 mg QD dose for 24 weeks.
To simulate typical adult exposures, a reference individual (32-year-old, non-black race, 56.6 kg and 3.65 g/dL of baseline albumin level) was used. A virtual pediatric population (n = 40,000) with age uniformly distributed from 0 to <15 years, 50/50 male/female ratio and 40% of black race was simulated. The weight-per-age distribution was based on WHO growth curves and data from the National Health and Nutrition Examination Survey [6,7], adjusted by a factor for TB disease [8]. Children < 3 kg or > 80 kg were excluded.
Published population models characterizing the exposure of BDQ and its metabolite M2 [9] and DLM and its metabolite DM-6705 [10] in adults were utilized. For simulation of BDQ and M2 exposures in children, the Svensson adult model [9] served as a base and was adapted to the pediatric population with the following adjustments: 1) the scaling value of 0.75 was used for clearances and 2) the effect of albumin levels on clearances was not included. For DLM and DM-6705, the Sasaki pediatric model [11] was utilized. Given the limited information on bioavailability in children < 1 year of age, two scenarios (constant or linearly decreased bioavailability with age below 1 year) were tested. During simulation for both drugs, child growth along with the maturation of CYP3A4 was accounted for. Exposures with several CYP3A4 ontogeny profiles (Johnson, Salem and Upreti) [12–14] were assessed. The BDQ weekly AUC and M2 Cmax at week 8 and 24, DLM daily AUC at day 14, and DM-6705 Cmax at day 14 and week 8 were selected as pharmacokinetic target metrics. Exposures in children were compared with model-derived adult targets to assess the treatment efficacy and safety in both regimens.
Results:
Proposed BDQ once-daily dosing showed a similar pharmacokinetic profile compared to labeled dosing scheme over 24 weeks in adults, suggesting their exposures were comparable. For DLM and DM-6705, the suggested 300-mg QD dose provided 13-14% lower exposures at steady-state compared to the 100-mg BID dose. The cumulative proportion of children of exposures of BDQ, DLM and their metabolites showed less than 5% difference between the WHO and model-informed once-daily dosing regimens, i.e., exposures were similar. Systematically higher exposures of BDQ (9.1-15%) and M2 (23-40%) and lower exposures of DLM (14-25%) and DM-6705 (5.6-25%) with proposed once-daily doses were observed compared to the WHO-recommended doses. Simulation results indicated that most children < 1 year of age fell within the target range of BDQ and M2 while using Johnson and Salem ontogeny but below the target range using Upreti ontogeny. In the worst-case scenario simulation setting (i.e., constant bioavailability using ontogeny from Salem), up to 59% of those < 3 months of age exceeded DM-6705 target at week 8 regardless of dosing strategy.
Conclusions:
This study demonstrated the use of model-informed approaches to propose a novel daily dosing regimen for BDQ and DLM in adults and children. TB disease correction factor, CYP3A4 ontogeny function along with child growth were incorporated during simulation. The proposed once-daily dosing strategy of BDQ and DLM will be tested in PARADIGM4TB and IMPAACT 2020 trials in adults and children, respectively.
Funding:
The project has received funding from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) 2020 and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101007873. Overall support for the IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA, Deutsches Zentrum für Infektionsforschung e. V. (DZIF), and Ludwig-Maximilians-Universität München (LMU). EFPIA/AP contribute to 50% of funding, whereas the contribution of DZIF and the LMU University Hospital Munich has been granted by the German Federal Ministry of Education and Research.
References:
[1] Dartois VA, Rubin EJ. Nat Rev Microbiol (2022).
[2] U.S. Food and Drug Administration. (2012) [https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/204384s000lbl.pdf].
[3] European Medicines Agency. (2013) [https://www.ema.europa.eu/en/documents/product-information/deltyba-epar-product-information_en.pdf].
[4] World Health Organization. WHO operational handbook on tuberculosis 2022 module 5: Management of tuberculosis in children and adolescents. (2022).
[5] Conradie et al., N Engl J Med (2022).
[6] World Health Organization. (2006) [https://www.who.int/publications/i/item/924154693X].
[7] Kuczmarski et al., Vital Health Stat 11 (2002).
[8] Svensson et al., Clin Pharmacokinet (2018).
[9] Svensson EM, Dosne A, Karlsson MO. CPT Pharmacomet Syst Pharmacol (2016).
[10] Tanneau et al., Clin Pharmacokinet (2022).
[11] Sasaki et al., Antimicrob Agents Chemother (2022).
[12] Johnson TN, Rostami-Hodjegan A, Tucker GT. Clin Pharmacokinet (2006).
[13] Salem et al., Clin Pharmacokinet (2014).
[14] Upreti VV, Wahlstrom JL. J Clin Pharmacol (2016).
