Novel Approach for the Bioequivalence Assessment of Topical Cream Formulations: Model-Based Analysis of Tape Stripping Data Correctly Concludes BE and BIE

The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

“…A minimum of 12 subjects should be used for demonstration of equivalence [ 14 ]. Since it was previously shown that duplicate application of each formulation reduces the magnitude of variability in tape stripping data and improves its reproducibility [ 59 , 62 ], according to EMA draft guideline, at least two application sites per product (test, comparator and negative controls) per forearm (one for uptake and one for elimination phase) should be involved [ 14 ]. Investigating the potential of tape stripping in humans to assess bioequivalence of topical acyclovir cream products (the site of action of acyclovir is beyond the SC, in the basal epidermis), Pensado et al [ 57 ] observed high within-subject standard deviation in the obtained mass per unit area of drug in the SC from the selected reference product.…”

“…Since the protocol proposed in EMA draft guideline is quite cumbersome, Ozdin et al [ 62 ] suggested novel dermatopharmocokinetic approach based on only one dose duration during the uptake phase to generate drug content in SC versus time profiles, whereby each time point corresponds to one stripped layer. Population pharmacokinetics modeling, applying ADAPT ® 5 software (Biomedical Simulations Resource, Los Angeles, CA., USA) with maximum likelihood expectation maximization (MLEM) algorithm, was used to fit the obtained data and to estimate the rate and extent of drug absorption or input into the skin.…”

“…The proposed approach based on population pharmacokinetic modeling was deemed successful for topical semisolids, using the approved generic and reference acyclovir creams that were shown to be bioequivalent in an appropriate clinical endpoint study. Although the estimates of the rate and extent of drug absorption with population pharmacokinetic modeling were associated with less inter-individual variability, despite the highly variable tape stripping data, further studies are required to investigate feasibility and the discriminatory power of this approach [ 62 ]. Finally, it is interesting to note that recently FDA approved a generic diclofenac sodium topical gel (1%), based on the collective evidence including (i) Q1 and Q2 sameness and physical and structural similarity to the reference product, (ii) an in vivo bioequivalence study with pharmacokinetic endpoints, and (iii) a virtual bioequivalence assessment leveraging dermal physiologically-based pharmacokinetic (PBPK) modeling and simulation instead of a comparative clinical endpoint study in patients.…”

Application of a dermatopharmacokinetic (DPK) method for bioequivalence assessment of topical metronidazole creams

“…The PK parameters, area under the curve (AUC), peak plasma drug concentration (Cmax) and/or maximum drug quantity per unit area (ng/cm 2 ) in the SC (Qmax) and thermodynamic parameters, SC-vehicle partition coefficient of the drug and diffusivity (D) of the drug across the SC of thickness (L) i.e. D/L 2 have been employed for topical BA and BE assessment (21,24,(39)(40)(41) whereas recently, Ozdin et al (42) proposed a refined strategy that eliminated some of the limitations and complexities in DPK approaches used thus far using the TS procedure described by Nallagundla et al (23) As a result, a DPK profile that consisted of the SC drug quantity (μg) as a function of time was generated using a novel method by attributing one time point to each stripped layer (i.e. DD of 8 min + each TS procedure lasting 30 s).…”

“…This approach obviates the need to tape strip at many DDs and simplifies the DPK procedure by eliminating the need for gravimetric analysis of the tape strips. In view of the fact that the percentage of the dose absorbed after topical application is very small and since topical dermatological products are not intended to deliver the drug into the systemic circulation, PK parameters such as clearance and volume of distribution are not relevant using this method (42).…”