A framework for assessing the safety of degraded pharmaceuticals for long-duration space missions - Part 2: framework application in four case studies.

Spaceflight environmental conditions can alter the rate of degradation for some drug products; however, only a limited number of drugs have been tested after prolonged exposure to spaceflight. Existing ground-based drug stability studies do not include key factors associated with spaceflight, such as levels of carbon dioxide (CO2) and ionizing radiation that are significantly higher than on Earth. The National Aeronautics and Space Administration (NASA) has recognized the use of expired or degraded drugs as a risk for space crews because the loss of active pharmaceutical ingredient (API) decreases the therapeutic efficacy of the drug product and increases exposures to potentially hazardous degradation products. A risk assessment framework to systematically evaluate the toxicological risk of drug degradants was described in Part 1. The framework consists of five steps: (1) defining the use scenario of the drug, (2) identifying the API degradants, (3) assessing hazards and dose-response of the degradation products, (4) assessing the dose of degradation products, and (5) characterizing the risk for adverse health effects. Herein, four case studies are presented to illustrate the use of the framework for evaluating degradants for adverse health effects. Four representative medications that are candidates for the NASA's exploration drug formulary are evaluated: azithromycin 250 and 500 mg tablets, diclofenac 1% topical gel, gabapentin 300 mg capsule, and an oral contraceptive tablet consisting of a combination of ethinyl estradiol (0.035 mg tablet) and norethindrone (1 mg tablet). For the drug products evaluated herein, the results show that diclofenac, gabapentin, and ethinyl estradiol degradants are unlikely to present health risks within the range of degradant doses estimated under the framework. However, the results suggest that there may be risks for azithromycin and norethindrone degradants, which may need to be considered in NASA's risk management program. The case studies demonstrate that the framework can accommodate many use scenarios and enables risk classification for API degradants.