Population pharmacokinetics of macozinone (PBTZ-169) and active metabolites in healthy volunteers after different oral formulations

Budi O Susanto (1), Haithem Chtioui (2), Lorenzo Ciullini (2), Sylvain Prod’Hom (2), Pascal André (2), Dany Spaggiari (2), Vincent Desfontaine (2), Laura E Rothuizen (2), Laurent A Decosterd (2), Thierry Buclin (2), Alfonso Mendoza-Losana (3), Santiago Ferrer-Bazaga (3), Antonia Wolff (4), Claudia Antoni (4), Stewart T Cole (4,5,6), Ulrika SH Simonsson (1)

(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Service of Clinical Pharmacology, University Hospital of Lausanne and University of Lausanne, Lausanne, Switzerland; (3) Department of Bioengineering, Universidad Carlos III de Madrid, Madrid, Spain; (4) Innovative Medicines for Tuberculosis (iM4TB), Lausanne, Switzerland; (5) Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; (6) Institut Pasteur, Paris, France.

Introduction/Objectives: Macozinone (PBTZ-169) is a new benzothiazinone anti-tuberculosis drug candidate that selectively and irreversibly inhibits the DprE1 enzyme of Mycobacterium tuberculosis (1). With this novel mechanism of action, macozinone is intended for the treatment of drug-susceptible and drug-resistant tuberculosis. The compound was discovered through the FP6 “NM4TB” and FP7 “MM4TB” programs of the European Commission and optimized by medicinal chemistry from the lead BTZ043. Macozinone has shown good efficacy and safety in several preclinical studies (2–7) and has been shown to form five human metabolites, some retaining in vitro anti-TB activity (8,9). The aim of this analysis was to characterize the population PK of macozinone and metabolites in healthy volunteers and to evaluate the impact of different formulations.

Methods: Macozinone was given as a salt form (PBTZ-169 HCl) in different formulations in one phase 1a (NCT03423030) and one phase 1b (NCT03423030) studies. In total, 1761 plasma concentration samples of macozinone from 54 healthy volunteers were included in the analysis. In the phase 1a trial, a spray-dried dispersion (SDD) formulation (10, 20, 40, 80, 160 and 320 mg) and a native crystal powder (NCP) formulation (160 and 320 mg), both given as water suspension were evaluated as single doses using a cross-over study design. Blood samples were drawn and macozinone concentrations were quantified at pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24- and 48-hours post-dose. In the phase 1b trial, NCP formulation suspended in water (300 mg once daily and 300 mg twice daily) and NCP formulation suspended in syrup (150 mg twice daily, 300 mg twice daily and 600 mg once daily) were evaluated for 14 days. Macozinone concentrations were quantified from blood samples drawn  at pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24- and 48-hours post-dose at days 1 and 14. In addition, trough concentrations were also collected between days 1 and 14. Macozinone concentrations were quantified using a validated LC-MS/MS assay in both phase 1a (lower limit of quantification [LLOQ]= 0.1 ng/ml) and phase 1b (LLOQ= 0.5 ng/ml) trials. First Order Conditional Estimation with Interaction (FOCE-I) method with log transform-both-sides was used and the modelling was performed using NONMEM version 7.4.3. Different structural and absorption models were evaluated acknowledging the different PK properties of the formulations. Once the structural model was developed, covariate analysis was conducted for both the parent and metabolite PK parameters. Model performance was evaluated based on likelihood ratio test, goodness of fit plots, individual plots and visual predictive check (VPC) obtained from PsN and ‘xpose4’ package in R.

Results: The PK of macozinone were best described by a 2-compartment model with dual first-order parallel absorption model with linear elimination. Lag time was identified for the slower absorption process for the NCP and syrup formulation. The reverse was seen for the SDD formulation where the faster process was associated with an absorption lag time.  Allometric scaling using body weight was applied to all clearance and volume parameters. The relative bioavailability of the SDD formulation was approximately 2 times higher compared to the NCP formulation whereas the syrup formulation showed 3 times lower relative bioavailability compared to the NCP formulation. In terms of metabolite abundance, the H2-macozinone metabolite was found to be the most abundant metabolite at day 1 and 14 with molar concentrations exceeding the parent compound. Furthermore, 3OH-macozinone and amino-macozinone were the second most abundant metabolites at day 1 and day 14, respectively.

Conclusions:  Population PK model for macozinone in different formulation from Phase 1a and Phase 1b trial in healthy volunteers was successfully developed. Different formulations of macozinone impacted significantly the absorption process and bioavailability of the compound.

Funding: This work has received support from the Innovative Medicines Initiatives 2 Joint Undertaking (grant No 853989). http://www.imi.europa.eu

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Reference: PAGE 31 (2023) Abstr 10652 [www.page-meeting.org/?abstract=10652]

Poster: Drug/Disease Modelling - Infection