Simone Zannoni (1), Chiara Roversi (1), Denise Federico (1), Marco Pergher (1), Xavier Boulenc (1), Sylvie Sordello (1), Anna Upton (1), Alessia Tagliavini (1)
(1) Evotec SE
Introduction/Objectives:
Tuberculosis (TB) remains a leading infectious disease-related cause of death worldwide. Current treatment options are extremely long and complex, and adherence is supported through programs such as directly observed therapy.
The performance of drug combinations for TB treatment is commonly assessed preclinically using the relapsing mouse model (RMM). This murine model of TB is used to test the overall curative potential of a drug combination by evaluating the proportion of mice exhibiting relapse (defined as the recurrence of mycobacteria growth in cultures of the lung tissue samples after a posttreatment clearance period) following different treatment durations [1].
Since weekend support is not always available, some patients receive TB drugs 5 out of 7 days per week (5/7) instead of 7/7 days; furthermore, recent studies demonstrated the negative impact of missed doses on the efficacy of the standard of care drug regimen [2; 3], resulting in the need to quantitatively evaluate the impact of weekend dosing holiday on sterilization activity.
The main objective of this work was to apply a model-based analysis using a population nonlinear mixed-effects modelling approach on data coming from a Pilot RMM study, to estimate the time to reach 50% and derive 90% of cure (T50 and T90, respectively) for two common control combinations. The combinations were both tested either 5 or 7 days per week, and the performance of the two schedules was compared.
Methods:
In this Pilot study, the two drug combinations comprised the standard of care for drug susceptible TB (Rifampicin, Isoniazid, Ethambutol, Pyrazinamide; RHZE/RH) and the experimental regimen (Bedaquiline, Pretomanid, Moxifloxacin, Pyrazinamide; BPaMZ). BPaMZ and RHZE/RH were tested both with a 5/7 and 7/7 design for 2, 4, 6, 8, 10, 12, 14 or 16 weeks and after each period of treatment, 12 weeks treatment off was used for assessing relapse. Relapse data were treated as a binary endpoint (0 or 1) corresponding to absence or presence of relapse, respectively.
A population logistic Emax model was developed to predict T50 and derive T90 for TB drug combinations, based on observed percentage of cure/relapse data collected in the Pilot study in addition to 4-drug regimens tested across multiple historical studies of TB combinations’ efficacy.
The model is described according to the classical Emax function, which serves to characterize the probability of relapse over time for each combination of a particular study; a Hill coefficient (γ) is included to represent the steepness of the relapse probability curve over treatment time. To account for possible sources of inter-study variability, the inoculum was included as a covariate into the model, as it had been demonstrated to have a meaningful impact on T50 in previous studies [1].
Furthermore, a random effect was associated with T50 to take into account the remaining unexplained variability.
Once T50 and γ were estimated for the tested combinations, and thus T90 could be derived, a specific ranking of the two controls for the two schedules was drawn up to compare their performance. The model was developed using NONMEM® 7.5.1 and data handling was performed through SAS® 9.4.
Results:
Both combinations demonstrated time-dependent sterilization activity with an increased efficacy for the 7/7 design, as expected. The developed model was successfully identified with all T50s and γ parameters estimated with good precision (RSE < 25% for all population parameters). The model was able to describe the relapse-time curves well, by incorporating inter-study variability as a sum of the inoculum effect and remaining unexplained variability.
The predicted T90s were approximately 20% lower for both combinations when the weekend dosing holiday was in place: indeed, for BPaMZ 5/7 and RHZE/RH 5/7, individual T90s for the Pilot study were 1.29 and 4.03 months respectively, similar to values found in literature [1; 4], as opposed to 1.00 and 3.29 months for the same combinations dosed 7/7.
Conclusions:
Comparison of the sterilization activity of both combinations, dosed 5/7 versus 7/7, demonstrated an improved (i.e., reduced) T90 following dosing 7 days per week. Indeed, data suggest that dosing holidays impact time to cure similarly for differentiated drug combinations in this murine TB model, since comparable T90 decrease (in percentage) for both differentiated control combinations was observed.
References:
[1] Berg A, Clary J, Hanna D, Nuermberger E, Lenaerts A, Ammerman N, Ramey M, Hartley D & Hermann D. Model-based meta-analysis of relapsing mouse model studies from the critical path to tuberculosis drug regimens initiative database. Antimicrob Agents Chemother. 2022 Mar;66(3):e01793-21. https://doi.org/10.1128/aac.01793-21 [2] Vernon A, Fielding K, Savic R, Dodd L, Nahid P. The importance of adherence in tuberculosis treatment clinical trials and its relevance in explanatory and pragmatic trials. PLoS Med. 2019 Dec 10;16(12):e1002884. https://doi.org/10.1371/journal.pmed.1002884 [3] Fox WS, Strydom N, Imperial MZ, Jarlsberg L, Savic RM. Examining nonadherence in the treatment of tuberculosis: The patterns that lead to failure. Br J Clin Pharmacol. 2023 Jul;89(7):1965-1977. https://doi.org/10.1111/bcp.15515 [4] Mudde SE, Ayoun Alsoud R, van der Meijden A, Upton AM, Lotlikar MU, Simonsson USH, Bax HI, de Steenwinkel JEM. Predictive Modeling to Study the Treatment-Shortening Potential of Novel Tuberculosis Drug Regimens, Toward Bundling of Preclinical Data.
J Infect Dis. 2022 Jun 1;225(11):1876-1885. https://doi.org/10.1093/infdis/jiab101
Reference: PAGE 32 (2024) Abstr 10902 [www.page-meeting.org/?abstract=10902]
Poster: Drug/Disease Modelling - Oncology