2021 FDA Science Forum
Feasibility of In Vitro Permeation Testing for Cleocin T® (Clindamycin Phosphate) Topical Lotion to Support the Demonstration of Bioequivalence
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Background
Cleocin T® (clindamycin phosphate) topical lotion, EQ 1% Base (“Cleocin T®”) is indicated for the treatment of acne vulgaris and contains clindamycin phosphate at a concentration equivalent to 10 mg/mL of clindamycin free base. Clindamycin phosphate is an ester prodrug that hydrolyzes to its pharmacologically active moiety, clindamycin base, potentially both on the skin surface and within the skin. There is no clear understanding of the relative amounts of clindamycin base versus clindamycin phosphate that permeate across the skin. The objective of this study was to evaluate the feasibility of an in vitro permeation test (IVPT) for Cleocin T® and to identify an appropriate clindamycin analyte to monitor to support a demonstration ?of bioequivalence (BE).?
Methods
An IVPT study across dermatomed human cadaver skin was conducted with the Phoenix dry heat diffusion cell system (Teledyne, Hanson, Chatsworth CA). An un-occluded 50 mg/cm2 dose of Cleocin T® was applied to skin samples (six replicates from single donor). The sampling schedule was done over 48 hours. Mass balance of clindamycin and clindamycin phosphate were assessed after the IVPT study to determine the relative distribution of the two moieties in the skin, and in the donor and receiver compartments. Simultaneous quantification of clindamycin phosphate and clindamycin base in IVPT samples was done using an in-house developed and validated ultra-performance liquid chromatography equipped with Ultraviolet detector (UPLC-UV) method.
Results
The UPLC method successfully separated clindamycin phosphate (retention time: 4.3 min) and clindamycin base (retention time: 4.9 min). The average recovery of clindamycin phosphate in the drug product was 112.3% ± 2.6%? (mean ± RSD, N=6); ?however, the content of clindamycin base did not exceed 0.01% w/w in the drug product. The IVPT results showed that both clindamycin phosphate and clindamycin base permeated across the skin. The cumulative amounts (mean ± SEM, n=6) of clindamycin phosphate and clindamycin base permeated to the receptor solution over 48 h were 5.17 ± 2.1 µg/cm2 and 28.7 ± 0.21 µg/cm2, respectively (Figure 1). The results of the mass balance studies indicated that the recovery of clindamycin phosphate and clindamycin base were ~62.5% and ~2645.2%, respectively, suggesting that the conversion of clindamycin phosphate to clindamycin base occurs, potentially in the formulation, on the surface of the skin, and during permeation into or through the skin.
Conclusion
The results of this exploratory IVPT study using skin from a single donor suggests that both clindamycin phosphate and clindamycin base permeate across the skin, and that it may be feasible to utilize one or both analytes to evaluate the cutaneous pharmacokinetics of clindamycin from Cleocin T® lotion.
