PubChem compound: 44384985
Collagenases are proteinases that hydrolyze collagen under physiological conditions. Collagenase Clostridium histolyticum is used as a lyophilized product for parenteral administration, which is comprised of two collagenases in a defined mass ratio. These collagenases, referred to as AUX-I and AUX-II, are representative of the two major collagenase classes (Class I and Class II) produced by Clostridium histolyticum.
The two classes of collagenases have similar but complementary substrate specificity. Both collagenases effectively cleave interstitial collagen but at different sites on the molecule; additionally, they prefer different conformations (triple helical versus denatured or cleaved). These differences account for the ability of the two classes of enzymes to digest collagen in a complementary manner.
Class I collagenases (α, β, γ, and η) are the products of the colG gene, they initiate collagen hydrolysis near the amino and carboxy termini of triple helical domains and generate large proteolytic fragments. In contrast, the Class II collagenases (δ, ε, and ζ,) are products of colH gene, their initial cleavage sites are located within the interior of the collagen molecule and generate smaller collagen fragments.
Both classes of collagenases readily hydrolyze gelatin (denatured collagen) and small collagen peptides, whereas Class II has higher affinity for small collagen fragments. Class I cleaves insoluble triple helical collagen with higher affinity than Class II collagenase. Together, these collagenases work to provide broad hydrolytic activity towards collagen.
Injection of collagenase into a Dupuytren’s cord, which is comprised mostly of interstitial collagen types I and III, results in enzymatic disruption of the cord.
The signs and symptoms of Peyronie’s disease are caused by a collagen plaque. Injection of collagenase into a Peyronie’s plaque, which is comprised mostly of collagen, may result in enzymatic disruption of the plaque. Following this disruption of the plaque, penile curvature deformity and patient bother caused by Peyronie’s disease are reduced.
Since collagen accounts for 75% of the dry weight of skin tissue, the ability of collagenase to digest collagen in the physiological pH and temperature range makes it particularly effective in the removal of detritus. Collagenase thus contributes towards the formation of granulation tissue and subsequent epithelization of dermal ulcers and severely burned areas. Collagen in healthy tissue or in newly formed granulation tissue is not attacked.
Following administration of either a single dose of 0.58 mg of collagenase clostridium histolyticum to 16 patients with Dupuytren’s contracture, or two concurrent injections of 0.58 mg of collagenase in the same hand in 12 patients with Dupuytren’s contracture, no quantifiable levels of collagenase were detected in plasma from 5 minutes to 30 days post injection.
Following each of two intralesional administrations, separated by 24 hours, of collagenase 0.58 mg into the penile plaque of 19 patients with Peyronie’s disease, plasma levels of AUX-I and AUX-II in patients with quantifiable levels (82% and 40% for AUX-I and AUX-II, respectively) were minimal and shortlived. The maximal individual plasma concentrations of AUX-I and AUX-II were <29 ng/mL and <71 ng/mL, respectively. All plasma levels were below the limits of quantification within 30 minutes following dosing. There was no evidence of accumulation following two sequential injections of collagenase administered 24 hours apart. No patients had quantifiable plasma levels 15 minutes after modelling of plaque on Day 3 (i.e., 24 hours after Injection 2 on Day 2).
There has been no evidence of systemic toxicity to date in the clinical studies conducted with collagenase administered through localized injection into the Dupuytren’s cord or into the Peyronie’s plaque.
Because collagenase is not a substrate for cytochrome P450 or other medicinal product metabolizing enzyme pathways, and because no active metabolites are expected, no metabolism studies have been performed.
No formal studies on elimination have been performed. There is no quantifiable systemic exposure following a single injection of collagenase in patients with Dupuytren’s contracture and only minimal and short-lived systemic exposure in patients with Peyronie’s disease.
No dose adjustment is necessary in any special patient groups e.g., Elderly, Renally or Hepatically Impaired, by Gender or Race.
Collagenase has not been studied in children and adolescents aged 0-18 years and hence no pharmacokinetic data are available.
There is no information available on collagenase absorption through skin or its concentration in body fluids associated with therapeutic and/or toxic effects, degree of binding to plasma proteins, degree of uptake by a particular organ or in the fetus, and passage across the blood brain barrier.
In a single-dose phase or 61-day repeat-dose phase (3 times a week every 3 weeks for 3 cycles) study of intrapenile administration of collagenase clostridium histolyticum in dogs at exposures lower than or equal to the maximum recommended human dose on a mg/m² basis, there was no evidence of systemic toxicity.
When collagenase was given intravenously every other day to male and female rats before cohabitation and through mating and implantation, no effects on the oestrus cycle, tubal transport, implantation and pre-implantation development and/or on libido or epididymal sperm maturation were noted with intravenous doses up to 0.13 mg/dose (approximately 11 times the human dose on a mg/m² basis). There were no adverse reactions on early embryonic development (indicating no evidence of teratogenicity) in rats. No systemic toxicity was observed in this study at any dose level.
Collagenase clostridium histolyticum was not mutagenic in Salmonella typhimurium (AMES test) and was not clastogenic in both an in vivo mouse micronucleus assay and an in vitro chromosomal aberration assay in human lymphocytes.
Standard two-year rodent bioassays have not been performed with collagenase. Thus, the carcinogenic risk is unknown.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
