Peter Velickovic1, Salvatore D'Agate1, Sally Babiker1, Elsa Smith1, Andrew White2, Sally Sharpe2, Oscar Della Pasqua1
1Consiglio Nazionale Delle Ricerche, 2UK Health Security Agency
Introduction: The tuberculosis (TB) drug development pipeline is being re-populated with drugs, like nitroimidazoles, shortening TB therapy and having efficacy against non-replicating Mycobacterium tuberculosis (Mtb). Prior studies depict treatment-shortening efficacy of a four-drug combination of bedaquiline (B), pretomanid (Pa), moxifloxacin (M), and pyrazinamide (Z) (BPaMZ), relative to the standard isoniazid, rifampicin, pyrazinamide, and ethambutol containing regimen (HRZE)[1]. Translating preclinical findings relies on the integration of pharmacokinetic-pharmacodynamic (PKPD) data and on experimental models that reflect the complex pathophysiology of TB infection in humans [2]. Macaques and other non-human primates (NHP) are susceptible to infection with different Mtb strains, producing the full spectrum of disease conditions [2]. We characterised the pharmacokinetics of HRZE and BPaMZ to support an efficacy study in cynomolgus macaques. These regimens contribute as positive controls to evaluate this infection model as a tool for predicting the performance of novel antitubercular regimens before progression to the clinic. To meet high ethical requirements of using NHPs in preclinical research [3], PKPD modelling and D-optimal design were employed to select appropriate doses and optimize sampling schedule and sample sizes for PKPD assessments for future experimental protocols [4-6]. Objectives: This work aimed at characterising the PK of BPaMZ and HRZE regimens in macaques, integrating data from a satellite PK study with historical data to guide the dose selection and sampling optimization of these antitubercular drugs in a subsequent efficacy study in macaques. Methods: Model building and evaluation: Historical PK data was combined with data of obtained after a one-week q.d. oral administration in uninfected macaques with a rich sampling scheme. Model building was conducted with NONMEM v7.5. Evaluation of the models was performed through the assessment of the objective function, parameter estimates precision, goodness of fit plots and visual predictive checks. Dose optimization: Simulations were implemented with the final PK models to generate concentration vs. time profiles at steady-state for each drug, assuming a q.d. dosing regimen. Doses were selected to ensure comparable systemic exposure across macaques and humans. Predicted exposure at steady-state were summarized in terms of AUCss [7-10]. Sampling optimization: A D-optimal design method was implemented [5] to optimise the collection of sparse blood samples. Scenarios involving different time points, number of samples and number of animals per protocol were tested. For each scenario, PK parameters were re-estimated and the relative standard error (RSE) was used to assess the best performing sampling schedule. Results: Model structures and estimates: 3-compartment model structure with mean time of transit (MTT) parameter was selected for B; for Pa, Z and M 1-compartment model with linear absorption and clearance were selected. Dose recommendation: Doses resulting in comparable exposure in macaques as seen in humans were determined. BPaMZ: B (20 mg/Kg), Pa (50 mg/Kg), M (60 mg/Kg), and Z (200 mg/Kg). Group B: B (10 mg/Kg), Pa (25mg/Kg), M (30mg/Kg), and Z (30mg/Kg). HRZE: H (50mg/kg), R (10mg/kg), Z (30mg/kg), E (25mg/kg). Doses yielded AUCss0-24 (95% C.I.) (mg*h/L): B (22.2 (17.6 – 26.5)), Pa (62.9), M (50.8 (41.1 – 63.3)), Z (347 (267 – 429)), H (28.2 (16.9-47.7)), R (52.4 (12.1-242.7)), E (36.6 (13.2-97.1)). Sampling Optimization: 3 sampling windows, each 30 minutes in length with 3 samples taken in each window was suggested. Weekly sampling times over a 4-week period were suggested to capture bedaquline clearance. Conclusions: A key aspect of the design of experimental protocols aimed at the characterisation of PKPD relationships is the selection of doses and dosing regimens, and collection of informative data through a suitable sampling scheme. Using historical data to develop PK models adequately describing drug disposition characteristics in macaques provided a basis for selection of regimens yielding comparable exposure to humans. The 3R principles [4] were upheld, ensuring refinement and reducing animals whilst maintaining adequate precision in parameter estimates to support the selection of combination regimens prior to progression into humans. This work has received support from the Innovative Medicines Initiatives 2 Joint Undertaking (grant No 853989)
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Reference: PAGE 33 (2025) Abstr 11731 [www.page-meeting.org/?abstract=11731]
Poster: Drug/Disease Modelling - Infection