Human Pharmacokinetics and Safety of Subcutaneous Collagenase Clostridium Histolyticum in Women

September 2020 | Volume 19 | Issue 9 | Original Article | 852 | Copyright © September 2020


Published online August 24, 2020

Ashish C. Bhatia MDa, Michael P. McLane PhDb, Tony Priestley PhDb, Saji Vljyan MBBSb, Martin K. Gelbard MDc

aDepartment of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL; Dermatologic, Laser, & Cosmetic Surgery at Oak Dermatology, Naperville, IL bEndo Pharmaceuticals Inc., Malvern, PA cUCLA School of Medicine, Los Angeles, CA *At the time the studies were conducted.

Abstract
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 (QOD) 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 [87.8%], 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 ≥43× 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 (QOD; 8 doses) at ≥43× proposed human dose on a mg/kg basis for CCH was generally well tolerated.

J Drugs Dermatol
. 2020;19(9):852-856. doi:10.36849/JDD.2020.5048

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INTRODUCTION

Cellulite is a localized alteration of skin topography (eg, dimpling) and affects 80% to 98% of postpubertal women of all ages and ethnicities.1,2 Although the pathophysiology of cellulite has not been fully elucidated, data suggest the number, type, and orientation of the collagen-rich (fibrous) septae play a primary structural role.1,3 Other factors may include subcutaneous (SC) edema and fibrogenesis; SC adipose protrusion; and decreased dermal thickness with age.1-3 Several procedures and technologies that target the dermis and adipose tissue, in addition to fibrous septae, have shown improvements in skin texture and the dermal-SC interface; however, these improvements could be secondary to the effects of releasing the fibrous septae.4-7

Collagenase clostridium histolyticum (CCH) for injection is composed of 2 purified bacterial collagenases (AUX-I and AUX-II [clostridial class I and II collagenases]) that hydrolyze Types I and III collagen under physiologic conditions, resulting in disruption of collagen structures.8 CCH (0.58 mg; Xiaflex®, Endo Pharmaceuticals Inc., Malvern, PA) is currently indicated in the United States for the treatment of collagen-associated disorders (ie, adults with Dupuytren contracture [DC] with palpable cord or Peyronie’s disease [PD] in adult men with a palpable plaque and penile curvature deformity of ≥30 degrees at the start of therapy).8 Safety and immunogenicity data reported in patients with DC or PD demonstrated that CCH treatment is safe and generally well tolerated.9-12 Clinical trial and postmarketing surveillance data indicate that the most common adverse events (AEs) associated with CCH administration for the treatment of DC and PD were localized to the injection site, mostly mild to moderate in intensity, and transient.9-11 In 5-year posttreatment follow-up studies of patients with DC (n=644) or PD (n=280), no long-term safety issues with CCH therapy were identified.9,12 At 5 years posttreatment, >90% of patients treated with CCH for DC and PD were seropositive for anti—AUX-I and anti—AUX-II antibodies.9,12 Patients with DC or PD treated with CCH produced serum neutralizing antibodies; however, the presence of neutralizing antibodies in patients with PD or DC had no apparent effect on the clinical response or the frequency of adverse reactions.8,9