Human Pharmacokinetics and Safety of Subcutaneous Collagenase Clostridium Histolyticum in Women

Background: Clostridium collagenase histolyticum (CCH) is being evaluated in women as a cellulite treatment. Objective:To report preclinical safety and human pharmacokinetics (PK) and safety data for CCH. Methods: Across 3 PK studies, 41 women received 12 subcutaneous injections per thigh/buttock in 1 session (up to 3.36 mg/dose). Blood samples were taken at baseline; at 5, 10, 20, and 30 minutes postdose; and at 1, 2, 4, 8, 12, 24, 48, 168, and 504 hours postdose. In a preclinical study, rats received 0, 0.029, 0.13, or 0.29 mg/dose of CCH intravenously (IV) every other day (GOD) for 16 days (total, 8 doses) and were evaluated for histopathologic changes. Results: In human PK studies, no quantifiable plasma concentrations of AUX-I or AUX-II were observed postdose (n= 39 evaluable). Adverse events were injection site related (bruising [97.6%], pain [878%], and edema/swelling [46.3%]). Antidrug antibodies were seen in most women at 504 hours postdose. In rats, plasma concentrations of AUX-I and AUX-II (CCH components) were measurable for 30 minutes and 1-2 hours, respectively, after IV administration. At Z43x proposed human therapeutic dose on a mg/kg basis, rats experienced elevated liver enzyme levels, increased liver weights, and histologic changes that were mostly reversed during a 14-day recovery period. Conclusions: In human studies, no quantifiable circulating CCH levels were observed after a single subcutaneous dose of CCH up to 3.36 mg. Preclinical data indicated that repeat IV dosing (GOD; 8 doses) at z43x proposed human dose on a mg/kg basis for CCH was generally well tolerated.