Martin Beliveau(1), Claudia Jomphe(1), Zoya Gluzman-Poltorak(2), Lena Basile(2), Vladimir Vainstein(2)
(1) Certara Strategic Consulting, Montreal, Canada (2) Neumedicines Inc Los Angeles US
Objectives: Acute radiation syndrome (ARS) is a life-threatening illness caused by whole body or significant partial-body exposure to radiation doses > 1 Gy over a short period of time, as would occur in the event of a nuclear accident or attack. The development program for rHuIL-12 (HemaMax) as a medical countermeasure to lethal radiation exposure follows the FDA’s Animal Rule, where efficacy is determined in appropriate animal models and safety is demonstrated in humans. Because the effective human dose cannot be assessed in controlled clinical efficacy studies due to ethical issues, HemaMax was translated by combining the animal and clinical data into a translational modeling dose scaling approach to address animal rule requirements.
Methods: PK data from HemaMax IV and SC administration in non-human primate and healthy human volunteer trials were analyzed by non-compartmental analysis, as well as by modeling drug disposition in population approach. Absorption of HemaMax following sub-cutaneous (SC) dosing was optimized by including two parallel, first-order absorption processes to account for the absorption via the lymphatic system and blood capillaries. The effect of irradiation on pharmacokinetics was also investigated. Population analysis was used to evaluate exposure in the typical US population in case of radiation disaster.
Results: Data analysis suggested that irradiation had minimal impact on actual exposure metrics and that exposure to HemaMax was similar in irradiated and non-irradiated monkeys. Monte Carlo simulations demonstrated that HemaMax SC doses ranging from 150 to 250 ng/kg in non-irradiated monkeys resulted in more than 90% of exposure being within those observed in non-irradiated humans administered a 12 µg SC dose. As such, due to species differences and variability observed in PK, an efficacious HemaMax dose of 150 ng/kg in non-irradiated monkeys would correspond to a human dose of 12 µg. Analysis of the covariates established that in case of unit dose administration weight contributes only about 20% variability in the systemic exposure.
Conclusions: modeling of non-human primate and human PK data of HemaMax allowed for successful dose translation between the species and establishment of the projected efficacious dose to support the development of the drug under Animal Rule; PK analysis also supports use of a unit dose, which greatly facilitates emergency use of the drug.
Reference: PAGE 25 () Abstr 5833 [www.page-meeting.org/?abstract=5833]
Poster: Methodology - New Modelling Approaches