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

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Abstract

Purpose

The purpose of this study was (a) to suggest a novel dermatopharmacokinetic (DPK) approach from which pharmacokinetic parameters relevant to the bioequivalence (BE) assessment of a topical formulation can be deduced while circumventing the need for numerous measurements and assumptions, and (b) to investigate whether this approach enables the correct conclusion of BE and bioinequivalence (BIE).

Methods

Bioequivalent and bioinequivalent formulations of acyclovir were compared versus a reference product (Zovirax®). Tape Stripping was conducted at only one dose duration during the uptake phase to generate drug content in stratum corneum versus time profiles, each time point corresponding to one stripped layer. Nonlinear mixed effect modeling (ADAPT5®) (MLEM algorithm) was used to fit the DPK data and to estimate the rate (Kin) and extent (FS) of drug absorption/input into the skin. Results were evaluated using the average BE approach.

Results

Estimated exposure metrics were within the usual BE limits for the bioequivalent formulation (FS: 102.4 [90%CI: 97.5–107.7]; Kin: 94.2 [90%CI: 83.7–106.0]), but outside those limits for the bioinequivalent formulation (FS: 43.4 [90%CI: 27.9–67.6]; Kin: 54.5 [90%CI: 36.6–81.1]).

Conclusions

The proposed novel DPK approach was shown to be successful, robust and applicable to assess BE and BIE correctly between topical formulations.

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Notes

  1. Studied ACV creams are locally effective topical formulations; therefore, input into the skin should be preferred over absorption which is rather reflective of systemic exposure. For the purpose of simplicity, however, absorption and input into the skin may interchangeably be used throughout this text.

Abbreviations

ACV:

Acyclovir

API:

Active pharmaceutical ingredient

AUC:

Area Under Curve

BA:

Bioavailability

BE:

Bioequivalence/Bioequivalent

BIE:

Bioinequivalence/Bioinequivalent

Cmax :

Maximum concentration

CPT:

Compartment

CV:

Coefficient of variation

DD:

Dose Duration

DPK:

Dermatopharmacokinetics

ED 50 :

The dose duration at which 50% of Emax is obtained

E max :

Maximum effect

FDA:

Food and Drug Administration

FS :

Extent of absorption/input into the skin

GMR:

Geometric Mean Ratio

GOF:

Goodness-of-Fit

HV:

Healthy volunteers

IOV:

Inter-Occasion Variability

IPRED:

Individual-level predictions

Kdiff :

Diffusion rate constant

Kin :

First-order absorption/input rate constant into the skin

Kout :

Diffusion rate constant out from the last compartment

Max:

Maximum

Min:

Minimum

ML:

Maximum Likelihood

MLEM:

Maximum Likelihood Expectation Maximization

MOF:

Minimum Value of the Objective Function

PK:

Pharmacokinetics

Pop:

Population

PRED:

Population-level predictions

Qmax :

Maximum amount

Ref:

Reference

RLD:

Reference Listed Drug

RP:

Reference Product

SC:

Stratum Corneum

STS:

Standard 2-Stage

TOST:

Two One-Sided Tests

TS:

Tape Stripping

VPC:

Visual Predictive Check

WRES:

Weighted residuals

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Author information

Authors and Affiliations

  1. Faculté de pharmacie, Université de Montréal, Pavillon Jean Coutu, 2940 Chemin de la polytechnique, Montréal, Quebec, Canada

    Deniz Ozdin & Murray P. Ducharme

  2. Learn and Confirm Inc., 750 Marcel-Laurin Suite 235, St-Laurent, Quebec, Canada

    Deniz Ozdin & Murray P. Ducharme

  3. Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario, Canada

    Isadore Kanfer

  4. Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa

    Isadore Kanfer

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  1. Deniz Ozdin
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Correspondence to Murray P. Ducharme.

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Ozdin, D., Kanfer, I. & Ducharme, M.P. Novel Approach for the Bioequivalence Assessment of Topical Cream Formulations: Model-Based Analysis of Tape Stripping Data Correctly Concludes BE and BIE. Pharm Res 37, 20 (2020). https://doi.org/10.1007/s11095-019-2724-2

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  • DOI: https://doi.org/10.1007/s11095-019-2724-2

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