Protocol optimization for the evaluation of pharmacokinetics, biomarkers and efficacy of antitubercular drugs in a novel tuberculosis infection model in marmosets
Silvia Grandoni (1, 2), Peter Velickovic (1, 2), Fatima Rahman (1, 2), Umberto Villani (1, 2), Salvatore D’Agate (1, 2), Candie Joly (5), Julien Lemaitre (5), Laura Via (3,4), Oscar Della Pasqua (1,2)
(1) Consiglio Nazionale Delle Ricerche (CNR), Rome, Italy, (2) Clinical Pharmacology and Therapeutics Group, University College London (UCL), London, United Kingdom, (3) Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, and (4) Tuberculosis Imaging Program, Division of Intramural Research, National Institute for Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA (5) Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses, France.
Objectives: The development of more efficacious drug regimens against M. tb requires predictive preclinical animal models encompassing the same pathological substrates of tuberculosis (TB) presentation in humans [1]. Currently used rodent TB models rarely develop cavitary disease, a distinctive feature of TB in humans [2]. Recently, an infection model in marmosets was developed, which could be used to better understand treatment performance in the presence of granulomas [3]. In order to demonstrate its predictive value in drug development, an initial validation step was proposed with standard of care (SoC) drugs using a protocol that mimics dosing regimens and exposure observed in TB patients. As the PK of SoC drugs and relevant biomarkers have not been fully characterised in marmosets, it is unclear which dose and sampling scheme should be selected for a truly informative prospective study to support translational efforts upholding 3Rs principles for animal research. This investigation aimed 1) to establish the dose of SoC drugs that yields systemic exposure comparable to that observed in humans, and 2) to assess the feasibility of an optimized sampling schedule which minimises the number of samples required per animal while maintaining the precision and accuracy of the PK and PD parameters of interest in a prospective efficacy study.
Methods: Rifampicin (RIF), ethambutol (EMB), pyrazinamide (PZA) and isoniazid (INH) PK data
were obtained after single oral administration in uninfected marmosets and multiple dose in infected animals (RIF 15 mg/kg, EMB 50 mg/kg, PZA 125 mg/kg, INH 30 mg/kg) from studies conducted by the NIAID. All experiments were approved by the NIAID Animal Care and Use Committee. PK models were developed for each drug. One and two compartment models were tested. In order to establish the dose recommendation, simulations were implemented to generate concentration vs. time profiles at steady-state (SS) according to a qd dosing regimen [4]. Predicted exposure at SS, expressed as AUCss, was compared with that in TB patients [4]. If discrepancies were observed between observed and predicted exposure, doses were adjusted and simulated exposures compared with human ones in an iterative manner.
In order to optimize the sampling schedule a stochastic simulation and (re)estimation approach (SSE) was implemented [5]. The impact of different sampling times and animals number on parameter estimates was evaluated in terms of relative bias (rBIAS) and imprecision expressed as relative root mean square error (rRMSE) as suggested by [6]. Simulated scenarios included frequent and sparse blood sampling schemes, in which sampling frequency and interval were iteratively reassessed, whilst maintaining one sample at trough levels (i.e., Cmin). A sampling scheme was deemed acceptable if rBIAS and rRMSE estimates were similar or lower than those observed in the reference scenario. PK data were subsequently used to describe the antibacterial activity assuming similar potency and maximum killing rates as previously observed in humans [7]. Parameter estimation, simulations and SSE were implemented using NONMEM and PsN.
Results: RIF, EMB, PZA and INH PK was described by two-compartment models. RIF clearance (CL) autoinduction was introduced. Model diagnostics revealed that the PK was described in a satisfactory manner. Model-derived exposure estimates show that the doses recommended initially yielded exposures comparable to those obtained in humans [4], except for PZA, for which a dose of 75 mg/kg is needed to ensure achievement of target exposure. In addition, SSE results show that reducing the number of animals leads to an increase in the rBIAS and rRMSE for CL and IIV. Decreasing the sampling frequency to four time points maintained precision as long as sampling times included the absorption and distribution phases.
Conclusions: Characterisation of PK and PD in non-human primates offers an opportunity to improving the translation and prediction of human dose prior to progression to the clinic. Informative protocols are therefore critical for efficient data integration and accurate dose selection. Our analysis has shown that a satellite PK group and the use of priors is required for the assessment of drug disposition characteristics, and should precede the evaluation of antibacterial activity in vivo.
This work has received support from the Innovative Medicines Initiatives 2 Joint Undertaking (grant No 853989).
References:
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