Yuanxi Zou (1), Veronique de Jager (2), Andreas Diacon (2), Anneke Hesseling (3), Anthony Garcia-Prats (3,4), Elin M. Svensson (1,5)
(1) Department of Pharmacy, Uppsala University, Uppsala, Sweden (2) TASK Applied Science, TASK Clinical Research Centre, Cape Town, South Africa (3) Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Tygerberg, South Africa (4) Department of Pediatrics, University of Wisconsin, Madison, WI, USA (5) Department of Pharmacy, Radboud university medical center, Nijmegen, The Netherlands
Objectives: Delamanid is a nitro-dihydro-imidazooxazole antibiotic which derives its antimycobacterial activity from inhibiting mycolic acid synthesis. A delamanid tablet of 50 mg was approved for treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB) in adults and a dispersible tablet of 25 mg was approved in children above 10 kg by European Medicines Agency in 2021 (EMA). However, the dispersible tablets are not yet widely available in programmatic settings. Administering the 50 mg tablet in crushed or dispersed form could be an option for children who cannot swallow whole tablets, however the bioavailability may be affected by such formulation manipulation. We evaluated the effects of manipulating the 50 mg tablet formulation to inform its practical use in the field for children where dispersible tablets are unavailable.
Methods: The pharmacokinetics (PK) and relative bioavailability of delamanid 50 mg tablets when administered in dispersed form versus swallowed whole, was investigated in a phase I single-dose, open-label, randomized, four-period, cross-over study, conducted in Cape Town, South Africa. Healthy adult participants were randomly assigned 1:1:1 to separately receive 2 of 3 dose strengths of delamanid after a meal, both whole and dispersed. The doses were 25mg (½ x 50mg), 50mg and 100mg (2 x 50mg). Participants received either first the dispersed form and secondly the whole tablets, or vice versa. The dispersed form was prepared by allowing the tablet(s) to disperse over 5-6 mins in 5 mL water, after which 5-15 mL of sugar syrup was added. Each volunteer received a single dose at the specified dose strength and form (dispersed or whole), on days 1, 8, 15, and 22. Blood samples were drawn pre-dose, 1, 2, 4, 6, 8, 24 and 48 hours after each dose, with an additional sample 168 hours after the fourth dose. Both delamanid and metabolite DM-6705 concentrations were measured. The sampling schedules and sample size of the study were selected based on clinical trial simulations in which a population PK model built on a pediatric clinical trial (ClinicalTrials.gov: NCT01856634) was used. The simulation model was a pre-final version of the later published model [1].
The PK data were analyzed by nonlinear-mixed-effects modeling in NONMEM® 7.5 with FOCE-I estimation. The model used for this clinical trial simulations was revised and updated. Effects of dose and formulation on bioavailability and absorption parameters were tested for significance at level α = 0.05. The updated model was evaluated through visual predictive checks. The 90% confidence interval (CI) of the effect of formulation on bioavailability was determined with log-likelihood profiling, which is a function available in PsN [2]. For other parameters, the 90% CIs were determined with SIR method [3] using PsN.
Results: A total of 21 male and 5 female participants were enrolled; two withdrew before completion of the study and were replaced. In total, 763 and 714 observations of delamanid and DM-6705 were included in the analysis. Two-compartment models jointly described both delamanid and DM-6705, with an absorption model including four transit compartments and first-order elimination. Inter-individual variabilities were added on clearance and volume of distribution of both delamanid and DM-6705, and fraction transferred to DM-6705, while inter-occasion variabilities were included on bioavailability, absorption rate, and mean transit time of delamanid. All the variabilities were estimated less than 25% represented by coefficient of variation. The mean absorption time differed between formulations and was typically 2.64 (CI 2.29-3.04) hours for whole tablets and 1.93 (CI 1.56-2.40) hours for dispersed tablets. Importantly from a clinical perspective, the two methods of administration were not significantly different in either bioavailability or the variability in bioavailability. The bioavailability of the dispersed tablets was estimated to be 107% of the whole tablets, with a 90% CI of 99.7-114%, fulfilling the standard 80%-125% criterion for bioequivalence.
Conclusions: We conclude that dispersing the 50mg delamanid tablets in water before administration is feasible and results in similar bioavailability as whole tablets. This supports use of the manipulated 50 mg tablet in children or other patients who cannot swallow whole tablets in settings where the 25 mg dispersible tablet is not available.
References:
[1] Sasaki T, Svensson EM, Wang X, Wang Y, Hafkin J, Karlsson MO, Mallikaarjun S. Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis. Antimicrob Agents Chemother. 2022 Feb 15;66(2):e0160821. doi: 10.1128/AAC.01608-21.
[2] Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005 Sep;79(3):241-57.
[3] Dosne, AG., Bergstrand, M. & Karlsson, M.O. An automated sampling importance resampling procedure for estimating parameter uncertainty. J Pharmacokinet Pharmacodyn 2017 Sep;44:509-520. https://doi.org/10.1007/s10928-017-9542-0
Reference: PAGE 30 (2022) Abstr 10075 [www.page-meeting.org/?abstract=10075]
Poster: Drug/Disease Modelling - Infection