Translational Pharmacology Consulting Supports Combination Therapy for Treating Pulmonary Mycobacterium Avium Complex Disease

• In Vitro Hollow Fiber Study. In collaboration with Dr. Tawanda Gumbo from Praedicare Inc, Certara scientists supported the design and interpretation of an in vitro lung infection hollow fiber study (HFS) to evaluate the pharmacokinetics and behavior of a drug in a controlled and reproducible manner. This assay can be used to help optimize dosing regimens, reducing the number of animal and human trials required to evaluate a drug’s safety and efficacy.⁴

図 1. In vitro hollow fiber study.

The HFS-MAC was used to assess the contribution of each individual drug component of RHB-204 (CFZ, CLR, and RFB) when administered individually and as part of a two or three-drug combination. The study was also instrumental in determining anti-mycobacterial effects and understanding how the drugs react when used as part of a combination regimen.

• Translational Model of NTM Disease. A translation model of NTM infection in mice was designed and analyzed in collaboration with Dr. Luiz Bermudez of Oregon State University. The model included pharmacokinetic (PK) analysis and histopathology to determine the reduction of bacterial counts in the lung and spleen. Pharmacokinetic modeling was then used to estimate the systemic drug exposure of each drug component alone and in combination which resulted in a reduction in bacterial counts and histopathologic improvement in lung tissue.
• In Vitro Biofilm Model. Mycobacteria can form biofilms–a thin layer of microorganisms within the body– and can serve as a protective shield, allowing the bacteria to survive antibiotic treatment. Certara experts, in conjunction with Dr. Bermudez, designed and analyzed the complexities of mycobacterial biofilm formation using an in vitro model of biofilm. An in vitro model of biofilm recreates the physical and biological characteristics of biofilms in a controlled environment. The in vitro biofilm model of MAC infection showed that CFZ, CLR, and RFB, at physiologically relevant concentrations, have greater efficacy when given in combination as opposed to being given separately.⁵
• Pharmacokinetic (PK) Modeling. PK modeling can provide important information about a drug’s absorption, distribution, metabolism, and elimination processes in the body. This information can be used to optimize a dosing regimen and demonstrate a drug’s safety and efficacy, which are crucial factors in obtaining regulatory approval and securing patent protection. Modeling of the drug components administered in combination to humans, followed by simulations, were performed to estimate the human dose and regimen which provided for comparable systemic exposure profiles of each drug component, to the effective concentrations in the HFS, mouse disease models of MAC infection, and biofilm experiments. Predicted human exposure supported the Phase 3 regimen of two divided doses three times per week, currently being studied in the CleaR-MAC trial (NCT04616924).
• Integrated Analysis. Certara experts performed integrated analyses of all available human, non-clinical, and literature data to support dose rationale for the combination doses and frequency of administration. This analysis was then used to gain the FDA and other regulatory bodies’ acceptance of the protocol for the Phase 3 trial. The selection of doses for RHB-204, along with the dosing schedule, was made through combining pre-clinical evaluations, PK modeling, and clinical information. This was done to maximize efficacy against MAC while minimizing potential drug side effects.