Commercially Available Cell-Free Permeability Tests for Industrial Drug Development: Increased Sustainability through Reduction of In Vivo Studies

Abstract

Replacing in vivo with in vitro studies can increase sustainability in the development of medicines. This principle has already been applied in the biowaiver approach based on the biopharmaceutical classification system, BCS. A biowaiver is a regulatory process in which a drug is approved based on evidence of in vitro equivalence, i.e., a dissolution test, rather than on in vivo bioequivalence. Currently biowaivers can only be granted for highly water-soluble drugs, i.e., BCS class I/III drugs. When evaluating poorly soluble drugs, i.e., BCS class II/IV drugs, in vitro dissolution testing has proved to be inadequate for predicting in vivo drug performance due to the lack of permeability interpretation. The aim of this review was to provide solid proofs that at least two commercially available cell-free in vitro assays, namely, the parallel artificial membrane permeability assay, PAMPA, and the PermeaPad® assay, PermeaPad, in different formats and set-ups, have the potential to reduce and replace in vivo testing to some extent, thus increasing sustainability in drug development. Based on the literature review presented here, we suggest that these assays should be implemented as alternatives to (1) more energy-intense in vitro methods, e.g., refining/replacing cell-based permeability assays, and (2) in vivo studies, e.g., reducing the number of pharmacokinetic studies conducted on animals and humans. For this to happen, a new and modern legislative framework for drug approval is required.

Heterogeneity Governs 3D‐Cultures of Clinically Relevant Microbial Communities

“…CF-Mu 3 Gel was coupled with either Transwell supports or PAMPA (parallel artificial membrane permeability assays) membranes, widely used during permeability assessment [46] to evaluate the role of CF-Mu 3 Gel on antimicrobial retention and consequent antimicrobial susceptibility. CF-Mu 3 Gel strongly hindered the passage of the three antimicrobial agents (Figure 3), independently of the supporting system.…”

Evaluation of the Ability of PAMPA Membranes to Emulate Biological Processes through the Abraham Solvation Parameter Model

“…Since the first system developed by Kansy et al [ 1 ], many PAMPA-based systems have emerged with the aim of emulating the permeation of compounds via passive diffusion through biological membranes. Initially, most of the membranes were developed to simulate the intestinal absorption (IA) of compounds [ 2 , 3 , 4 ]. Different lipidic mixtures have been used for this purpose.…”

“…Some of these consist of simple systems like a phospholipid dissolved in a non-polar solvent, such as n-dodecane [ 5 ], whereas other systems use more complex mixtures [ 6 , 7 ]. In fact, the composition of the lipidic mixture in the PAMPA membrane has a direct impact of the obtained permeability values and this has been a key factor for the targeted development of systems that emulate specific biological membranes [ 3 , 8 ]. This is the case, for example, of systems developed to mimic brain [ 9 , 10 , 11 ] or skin permeation [ 12 , 13 ].…”

Decreased Penetration Mechanism of Ranitidine Due to Application of Sodium Sulfobutyl Ether-β-Cyclodextrin

“…According to the International Coordination Committee for the Registration of Pharmaceutical Products for Human Use (ICH) guidelines and the M9 Bioequivalence Exemptions Based on the Biopharmaceutical Classification System [1][2][3][4] permeability is closely related to the rate and extent of drug absorption in the body and is one of the key factors in the transport of drugs in the body through expanded membranes and is relevant to drug development. Pharmaceutical excipients are non-physiologically active substances in pharmaceuticals that affect their absorption and bioavailability in the body [5][6][7].…”