PT-026 - CAN MODEL BASED APPROACHES ACCURATELY IDENTIFY BIO(IN)EQUIVALENCE OF TOPICAL CLOTRIMAZOLE PRODUCTS?

S. RATH¹, D. BAKIR², I. KANFER³, M. DUCHARME²; ¹LESLIE DAN FACULTY OF PHARMACY, UNIVERSITY OF TORONTO, TORONTO, ONTARIO, CANADA, ²Université de Montréal, ³LESLIE DAN FACULTY OF PHARMACY, UNIVERSITY OF TORONTO.

Background: The challenges associated with bioavailability and bioequivalence (BA/BE) assessment of topical dermatological products have resulted in a dearth of generic versions of such products. Therefore, regulatory agencies are urging researchers to develop surrogate approaches to assess the BE of such products to facilitate regulatory approval. Tape stripping (TS), a relatively non-invasive technique used to study the dermatopharmacokinetics (DPK) of topically applied agents within the stratum corneum, involves tedious experimental procedures, complicated calculations, and assumptions. Therefore, our objective was to develop a model-based approach using TS data for a more direct estimation of the rate and extent of “absorption” or input into the skin for BA/BE assessment.

Methods: A compartmental pharmacokinetic (PK) model was developed using TS data from healthy human participants from two studies:
1. A reference cream (R) containing 1% clotrimazole (CLZ), was compared with itself using 13 participants in a fully replicate study design to demonstrate the applicability of the developed model to accurately assess BE
2. 1% CLZ gel (T) was tested alongside two applications of R using 6 participants in a partially replicate study design to assess BE between these two pharmaceutically inequivalent products
A population PK (PPK) analysis was conducted with the maximum likelihood expectation maximization (MLEM) algorithm in ADAPT5®. A 14-compartment model was developed where the DPK parameters of importance for BE assessment were Kin (first-order absorption/input rate constant) and Fs (% of dose delivered into the skin). An average BE (ABE) approach was used for BE assessments.

Results: Multiple PPK models were investigated and the most appropriate one was identified. The final model consisted of 14 compartments. With a minimum of 25 participants, the model will be able to successfully conclude BE in terms of Kin and Fs when R is compared with itself, whereas the gel failed to comply with the BE acceptance criteria (Table 1).

Conclusion: While the conventional TS method provides information about the extent of exposure, the proposed model-based approach can accurately assess BE with respect to the rate of input in addition to the extent of exposure.