Biology subjects

Hermann, D. J.

Publications and source records attributed to Hermann, D. J..

3 recordsLinked to original sources

bioRxiv2025

A modeling-based framework to evaluate forgiveness of TB drug combinations in a BALB/c relapsing mouse model.

Tuberculosis (TB) remains a leading cause of death due to an infectious agent. Adherence to long and complex TB treatments is supported by methods including directly observed therapy. The negative impact of missed drug doses on clinical outcomes is well-established, highlighting both the importance of adherence support and methods to quantify the ability of a regimen to continue exerting a biologic effect, during gaps in dosing known as "forgiveness" property. To explore the value of the BALB/c Relapsing Mouse Model of TB in evaluating treatment forgiveness, we assessed the impact of weekend dose holidays on the bactericidal, including RS ratio(R), and sterilizing efficacy of RHZE/RH and BPaMZ in perspective of each drug exposure. The cure/relapse data from this study plus multiple historical studies were used to identify a nonlinear mixed-effects Emax model that was used to estimate time to cure 50% and derive time to cure 90% mice (T90). Expected time-dependent bactericidal activity and reductions in RS ratio were observed for both treatments, with more rapid decreases for the BPaMZ groups. The weekend dosing holiday significantly decreased reductions in lung CFU and RS ratio earlier in RHZE/RH treatment, but no such effect was observed for BPaMZ. Similarly, the predicted T90 was significantly greater for RHZE/RH (but not BPaMZ), with weekend doses omitted. No major drug exposure difference was observed between the 2 dosing schedules. Our results suggest BPaMZ is more forgiving of missed doses than RHZE/RH and suggests utility of this methodology to support evaluation of TB treatment forgiveness.

pharmacology and toxicology↗

bioRxiv2025

A Stochastic Simulation-Based Approach to Inform Relapsing Mouse Model (RMM) Study Design for Non-Clinical Assessment of Tuberculosis

The development of new regimens to treat tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), is critical to improving patient outcomes and decreasing global infectious disease mortality. Early evaluation of candidate regimens in non-clinical models of TB, such as the relapsing mouse model (RMM), remains an important step in prioritizing the most efficacious regimens for further clinical evaluation. Although RMM studies may be informative, they are also animal-, labor-, and time-intensive to complete and represent significant investment in time and resources during non-clinical development. Given the strong pipeline of regimens in development, identification of "leaner" RMM studies may have a significant impact on resource utilization, and hence we compared alternative study designs with the goal of identifying study attributes that can be modified to improve resource use, particularly animal use. By simulating relapse outcomes from "virtual" studies (i.e., groups mice treated for selected durations with control and hypothetical anti-TB regimens) followed by model-based analysis of the simulated data, we were able to compare the "true" (input) values with model estimates of time to 95% cure probability (T95) and assess bias and precision of competing designs. Using this approach, we demonstrated that 28% fewer mice could be used in RMM studies while maintaining low bias and a precision for T95 estimation within +/- 1-2 weeks for most regimens. Therefore, it is expected that RMM studies based upon the alternative designs evaluated herein may be employed to promote improved animal stewardship while generating informative data for decision making.

pharmacology and toxicology↗

bioRxiv2022

Novel tuberculosis combination regimens of two and three-months therapy duration

The tuberculosis treatment duration is 4-6 months, but can be 18-20 months with multidrug resistance. Ultrashort regimens that cure regardless of resistance status ["pan-tuberculosis regimens"] would be a major step towards global tuberculosis control. Starting with seven drugs [bedaquiline, delamanid, pretomanid, OPC-167832, sutezolid, moxifloxacin, and pyrazinamide] in clinical testing, we calculated that there were thousands of possible novel combinations to evaluate. We used mathematical and pharmacokinetics/pharmacodynamic-based hollow fiber modeling to reduce this complexity to nine combinations, which we tested. Each regimens fast and slow growth bacteria kill-slope trajectories and times-to-extinction were estimated and translated to minimum required therapy duration in patients. Sputum microbial kill trajectories of two combination regimens that have undergone clinical testing were correctly predicted by this approach. Four pan-tuberculosis regimens were predicted to achieve relapse-free cure after 2-3 months therapy in patients. The kill-slopes were used to design expedited clinical trials that minimize patients risks.

pharmacology and toxicology↗