Current challenges in bioequivalence, quality, and novel assessment technologies for topical products.

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.

Population Pharmacokinetics of MYL-1402O, a Proposed Biosimilar to Bevacizumab and Reference Product (Avastin®) in Patients with Non-squamous Non-small Cell Lung Cancer.

BACKGROUND AND OBJECTIVES: MYL-1402O is a bevacizumab (Avastin®) biosimilar. Pharmacokinetic and safety similarity of MYL-1402O and reference Avastin® authorized in the European Union (EU-Avastin®) and the US (US-Avastin®) was demonstrated in healthy subjects (phase I, NCT02469987). The key objectives of this study were to establish a population pharmacokinetic (PopPK) model on pooled data from the phase I and phase III clinical studies to assess pharmacokinetic linearity of MYL-1402O and Avastin® across dose ranges, to assess the pharmacokinetic similarity of MYL-1402O and Avastin® in patients with non-squamous non-small cell lung cancer (nsNSCLC), and to explore potential covariates to account for systematic sources of variability in bevacizumab exposure. METHODS: Efficacy and safety of MYL-1402O compared with EU-Avastin® was investigated in a multicenter, double-blind, randomized, parallel-group study in patients with stage IV nsNSCLC (phase III, NCT04633564). PopPK models were developed using a nonlinear mixed effects approach (NONMEM® 7.3.0). RESULTS: The pharmacokinetics of Avastin® and MYL-1402O were adequately described with a two-compartment linear model. Fourteen covariates were found to be statistically significant predictors of bevacizumab pharmacokinectics. The impact of each covariate on area under the concentration-time curve, half-life, and maximum plasma concentration was modest, and ranges were similar between the treatment groups, MYL-1402O and EU-Avastin®, in patients with nsNSCLC. The pharmacokinectics of bevacizumab appeared to be linear. CONCLUSIONS: PopPK analysis revealed no significant differences between pharmacokinetics of MYL-1402O and Avastin® in patients with nsNSCLC. The developed PopPK model was considered robust, as it adequately described bevacizumab pharmacokinetics in healthy participants and nsNSCLC patients.