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.



A different formulation, collagenase clostridium histolyticumaaes (Qwo™, Endo Aesthetics LLC, Malvern, PA), using a higher dose and volume and lower concentration, was approved by the US Food and Drug Administration in July 2020 for the treatment of moderate to severe cellulite in the buttocks of adult women. When injected, it causes enzymatic disruption of the fibrous septae. In one phase 2 (ClinicalTrials.gov identifier: NCT02724644) and two phase 3 (ClinicalTrials.gov identifiers: NCT03428750 [Randomized Evaluation of Cellulite Reduction by Collagenase Clostridium Histolyticum (RELEASE-1)]; NCT03446781 [RELEASE-2]), randomized, double-blind, placebo-controlled studies of women (n=1218; total for 3 studies) with moderate to severe cellulite on the buttocks and/or posterolateral thighs, SC CCH significantly improved the appearance of cellulite compared with placebo based on both clinicians’ and patients’ ratings and was generally well tolerated.13,14 Although CCH acts locally when injected SC to target the collagenase structural matrix (eg, septae), additional data would be valuable to help understand the systemic exposure profile of CCH administration for cellulite and to provide insight regarding the potential systemic impact if CCH were inadvertently administered intravenously (IV). The objective of the manuscript is to discuss the pharmacokinetics (PK) and safety of a single SC dose of CCH in women with cellulite and to summarize preclinical animal toxicity data to further understand the safety profile of a potential inadvertent IV systemic CCH exposure.

METHODS

Human Pharmacokinetics and Safety
Three PK studies were conducted in healthy adult women with cellulite on the thighs or buttocks. All 3 studies used the same CCH injection technique (Figure). In study 1 (EN3835- 102), a single overall CCH dose of 0.84 mg was administered as 12 SC injections in 1 area (thigh/buttock) with cellulite. In study 2 (EN3835-104), a single overall CCH dose of 1.68 mg was administered as 0.84 mg (12 SC injections) in each of 2 areas (thigh/buttock) with cellulite. In study 3 (EN3835-103; ClinicalTrials.gov identifier: NCT03675685), a single overall CCH dose of 3.36 mg was administered as 0.84 mg (12 SC injections) in each of 4 areas (right and left thigh; right and left buttock) with cellulite. A CCH dose of 3.36 mg is twice the proposed maximum human total dose to treat cellulite in women. If a cellulite dimple required >1 SC injection, the injection sites were to be spaced approximately 2 cm apart.

Blood samples to measure plasma AUX-I and AUX-II concentrations were collected at baseline (predose) and 5, 10, 20, and 30 minutes postdose, and at 1, 2, 4, 8, 12, 24, 48, 168, and 504 hours (day 22) postdose in all 3 studies. Pharmacokinetic variables were estimated using a noncompartmental approach (Phoenix® WinNonlin® 6.4, Certara L.P., Princeton, NJ). Serum anti—AUX-I, anti—AUX-II antibodies, and neutralizing antibodies to AUX-I and AUX-II were measured at baseline and 504 hours postdose. AUX-I and AUX-II concentrations and antibody levels were determined using validated enzyme-linked immunosorbent assay methods. Safety was assessed through 504 hours (day 22) post-dose for the 3 studies.

The safety population included all women enrolled in the studies who received ≥1 injection of CCH. The PK population was defined as all women enrolled who received the full CCH dose and had sufficient 24-hour data to determine key PK parameters (eg, observed maximum concentration, elapsed time to maximum concentration, and area under the curve).

Preclinical Safety
For the general toxicology study, Sprague-Dawley rats (10- 30 per sex, per dose level) received 0, 0.029, 0.13, or 0.29 mg/ dose of IV CCH every other day (QOD) for 16 days (total of 8 doses, each dose separated by ~48 hours). Histopathologic evaluation was performed at the end of the treatment or after a 14-day recovery period. Toxicity and toxicokinetic profiles were assessed, as was reversibility of any changes during the 14-day recovery period. The dose/kg in rats at the highest dose (on a mg/kg basis) was 1.16 mg/kg (which is 97-fold higher than the proposed therapeutic treatment dose for a human with the average body weight of 70 kg [ie, 0.012 mg/kg of body weight]).

A fertility reproductive toxicology study evaluated fertility and embryo-fetal development. Male and female Sprague-Dawley rats (25 per sex, per dose) received 0, 0.0145, 0.0435, or 0.13 mg/