A comprehensively validated IVRT method reliably discriminates sameness and differences between several topical clotrimazole creams.

In vitro release testing (IVRT) has gained increasing acceptance for use as a biowaiver for topical products intended for local action. Whereas the United States Food and Drug Administration (US FDA) has issued product specific guidances (PSGs) recommending IVRT for several products, the PSG for clotrimazole cream does not include an IVRT option. However, an important requirement to include supplemental selectivity in the validation process as described in the recent FDA draft guidance on IVRT studies for topical drug products has generally been conspicuously absent in the published literature describing the application of IVRT as a biowaiver. Supplemental selectivity involves the comparison of a reference product and altered formulations containing the same strength of the active pharmaceutical ingredient (API). In order to demonstrate supplemental selectivity, cream formulation containing the same API (clotrimazole), at the same strength (1 %) and in the same dosage form (cream) but manufactured using different excipients were used. This will help assess the impact that excipients may have on the release rate of clotrimazole and whether the method is capable of identifying differences in the microstructure and arrangement of matter (Q3) as an important performance parameter. In addition, products containing <30 % or >40 % clotrimazole to serve as negative controls were also included for the discriminatory power assessment. Hence, the primary objective was to develop and validate a simple, reliable, reproducible, and cost-effective in vitro technique in accordance with the recent draft FDA guidance to assess the "sameness" of topical creams containing 1 % clotrimazole. An in vitro release testing (IVRT) system was used and an IVRT method was developed and accordingly validated. The validated IVRT method showed the potential to accurately measure the release from 1 % clotrimazole creams and demonstrated supplemental selectivity and appropriate discriminatory power to identify "sameness" and/ or differences.

In Vitro-In Vivo Correlations (IVIVC) for Predicting the Clinical Performance of Metronidazole Topical Creams Intended for Local Action.

The safety and efficacy of a generic medicine can be confirmed by demonstrating bioequivalence (BE) between the generic product and its reference listed drug (RLD) by measuring drug concentrations in the blood following administration. However, for topical dermatological products that are not absorbed into the systemic circulation, clinical trials in patients are required. The objective of this investigation was to use an in vitro method to predict in vivo performance by correlating in vitro release testing (IVRT) data with tape stripping (TS) data following the application of metronidazole (MTZ) creams to the skin of healthy human participants. Whereas IVRT is generally used to characterize the release of a drug from topical products across a synthetic membrane into a suitable receptor medium, TS involves the sequential removal of layers of stratum corneum (SC) with an adhesive tape to determine the amount of the drug in the skin. The resulting IVRT and TS data were correlated using the IVRT parameter of the apparent release constant (ARC), which is the slope obtained from the release rate profile, with the TS parameter of the area under the curve (AUC) obtained from a plot of the amount of drug per tape strip vs. the relative SC depth. A rank order relationship for these parameters was established for the reference and test products. A graph of AUC vs. ARC was plotted to establish a Level C in vitro-in vivo correlation (IVIVC). Although the ARC for T1 was slightly lower than that for the reference, the rank order was essentially consistent. A linear relationship was observed between the AUCs and ARCs. The equation derived was used to predict the AUCs for all the tested products based on their respective ARCs. The predicted AUC values based on the observed ARCs were similar to the observed AUCs. The lower and upper limits for the in vitro and in vivo parameters for BE were computed based on regulatory acceptance criteria. In order to predict BE from the IVRT studies, the values of the ARC should be between 30.50 and 47.67 when comparing test and reference cream products containing MTZ.

Correction: Zvidzayi et al. A Novel Approach to Assess the Potency of Topical Corticosteroids. Pharmaceutics 2021, 13, 1456.

In the original publication [...].

A network pharmacology-based approach to explore the therapeutic potential of Sceletium tortuosum in the treatment of neurodegenerative disorders.

Sceletium tortuosum (SCT) has been utilized medicinally by indigenous Koi-San people purportedly for mood elevation. SCT extracts are reported to be neuroprotective and have efficacy in improving cognition. However, it is still unclear which of the pharmacological mechanisms of SCT contribute to the therapeutic potential for neurodegenerative disorders. Hence, this study investigated two aspects-firstly, the abilities of neuroprotective sub-fractions from SCT on scavenging radicals, inhibiting some usual targets relevant to Alzheimer's disease (AD) or Parkinson's disease (PD), and secondly utilizing the network pharmacology related methods to search probable mechanisms using Surflex-Dock program to show the key targets and corresponding SCT constituents. The results indicated sub-fractions from SCT could scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, inhibit acetylcholinesterase (AChE), monoamine oxidase type B (MAO-B) and N-methyl-D-aspartic acid receptor (NMDAR). Furthermore, the results of gene ontology and docking analyses indicated the key targets involved in the probable treatment of AD or PD might be AChE, MAO-B, NMDAR subunit2B (GluN2B-NMDAR), adenosine A2A receptor and cannabinoid receptor 2, and the corresponding constituents in Sceletium tortuosum might be N-trans-feruloyl-3-methyldopamine, dihydrojoubertiamine and other mesembrine type alkaloids. In summary, this study has provided new evidence for the therapeutic potential of SCT in the treatment of AD or PD, as well as the key targets and notable constituents in SCT. Therefore, we propose SCT could be a natural chemical resource for lead compounds in the treatment of neurodegenerative disorders.

Fitting Pharmacodynamic Data to the Emax Model to Assess the Inherent Potency of Topical Corticosteroids.

The widespread use of topical corticosteroids (TCs) in dermatotherapy requires a consideration of their potency and benefit/risk ratios. Although there are a variety of topical corticosteroid products (TCPs) available on the market and their potencies are ranked using different classification systems, to our knowledge, no classification system to rank the inherent potencies of TC active pharmaceutical ingredients (APIs) currently exists. Most of the published classification systems for TCPs are based on randomized clinical comparative studies and/or vasoconstrictor assay (VCA) data. The objective was to apply the US FDA's VCA to classify the inherent potencies of several TCs using standardized doses to make appropriate comparisons of the relevant APIs in solutions of the same molar concentrations. Six TC APIs were assessed for their relative potencies using healthy human participants. The Emax model was used to fit skin blanching data following application of the respective TCs, and the parameters, Emax and ED50, were derived. Emax values were used as the metric to assess potency. Statistical analyses of the data revealed that the inherent potencies of fluticasone propionate, mometasone furoate, and hydrocortisone butyrate were similar. However, there was no significant difference between hydrocortisone butyrate and clobetasol propionate, while there was a significant difference between clobetasol propionate, fluticasone propionate, and mometasone furoate. Hence, the potency of hydrocortisone butyrate appears to overlap two potency classes. Furthermore, the potencies of betamethasone valerate and methylprednisolone aceponate were similar but lower than those of all of the other APIs. The application of the VCA to classify inherent potency provides a reliable method to establish a classification system for TCs. Inherent potency assessment of TCs provides information that will be useful when choosing an appropriate TC for the development of a TCP for a specific clinical indication.

Application of Emax model to assess the potency of topical corticosteroid products.

The objective of this study was to compare the potencies of two topical corticosteroid products (TCPs) using the Emax model to fit the skin blanching responses obtained from the US FDA's vasoconstrictor assay (VCA) and to illustrate the influence of formulation on potency. The potencies of two marketed TCPs, Dermovate® cream containing clobetasol propionate (CP) and Elocon® cream containing mometasone furoate (MF), were assessed using healthy human subjects. In order to investigate the influence of formulation and associated vehicle properties, the creams were compared with their respective topical corticosteroids (TCs) from a previously published study wherein the inherent potencies of those TCs were assessed using a validated VCA method. Whereas the inherent potency of MF (Emax = -94.45 ± 0.21) was found to be greater than CP (Emax = -58.80 ± 15.65), when formulated as creams, the TCP containing CP had a higher potency (Emax = -86.15 ± 0.17) than that containing MF (Emax = -42.61 ± 26.04). This reversal of potency may be attributed to the effect of formulation factors. The comparison of the potencies of TCPs with inherent potencies of their corresponding TCs confirmed the influence of formulation parameters on the potency of those products.

Comparative in vitro release testing (IVRT) of acyclovir products.

The aim was to evaluate whether an in vitro release test (IVRT) could differentiate the release rates from five pharmaceutically equivalent acyclovir cream products and one ointment compared to that from a reference product, Zovirax cream (USA), to identify a test product with an inequivalent drug release rate that could serve as negative control for bioequivalence (BE) in a separate in vivo study. The reference product showed equivalent drug release rates compared to itself. The six test products failed to show equivalent drug release rates compared to the reference product. Aciclovir 1A pharma cream was selected to serve as a negative control for subsequent BE studies, since it exhibited the greatest difference in release rate among all creams, compared to the reference product. The results of this study indicate that IVRT results can be highly sensitive and may discriminate clinically relevant differences between products. Results from an appropriately validated IVRT method can support a demonstration of BE by showing that the drug release rates from test and reference products are statistically equivalent, mitigating the risk that differences may exist between the products which may influence in vivo performance of the drug product.

A Novel Approach to Assess the Potency of Topical Corticosteroids.

The potencies of topical corticosteroid products have mainly been classified using clinical data but in some instances, the US Food and Drug Administration's (FDA's) vasoconstrictor assay (VCA) to assess the skin blanching response has also been used. However, the reported skin blanching response data were often based on a single visual reading and lack information on the dose (amount/quantity) or dose duration. Although several lists classifying potencies of various topical corticosteroid products have been published, the inherent potencies of topical corticosteroid raw materials used as active pharmaceutical ingredients (APIs) have not been investigated. The objective was to rank the inherent potencies of topical corticosteroid APIs and to standardize dosing such that the relevant compounds could be compared on a normalized molar basis. The potencies of clobetasol propionate, halcinonide, mometasone furoate, and fluocinolone acetonide were compared using the resulting Emax data following the fitting of the relevant response data to the Emax model where mometasone furoate > fluocinolone acetonide = clobetasol propionate > halcinonide. This ranking lists the respective inherent potencies of the APIs, which will facilitate the choice of a suitable candidate for incorporation into an appropriate topical corticosteroid product for a specific clinical indication.

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

PURPOSE: The main aim of the current research was to develop and apply a dermatopharmacokinetic (DPK) approach for the bioequivalence assessment of metronidazole (MTZ) topical cream products, indicated in the treatment of rosacea. METHODS: A DPK methodology using tape stripping (TS) technique was developed by investigating the factors that may influence the TS results viz. tapes, dose durations, number of tapes to be used, pressure application, dose applied and gravimetric analysis of the tapes. An initial dose duration study was performed on 6 healthy participants to determine an appropriate application time duration using the Emax model. The SC thickness was normalised between participants using TEWL measurements. A pivotal study was conducted using both the arms of 10 healthy human participants to demonstrate the ability of the TS method for bioequivalence assessment by comparing the reference product to itself as a positive control and including products with higher and lower strengths of MTZ to serve as negative controls in order to confirm bioinequivalence. RESULTS: Whereas the reference was found to be bioequivalent when compared to itself, the creams containing 0.56% and 0.95% MTZ (negative controls) were not bioequivalent (bioinequivalent). Furthermore, another product containing 0.75% MTZ was also assessed and was found to be bioequivalent to the reference product. In addition, the use of both forearms of each participant offered an important advantage of significantly reducing the number of human subjects required to demonstrate BE with a high statistical power of > 80%. CONCLUSION: The data obtained provides compelling evidence that the developed TS method has the potential to be a cost-effective surrogate alternative for lengthy and expensive clinical trials. Consequently, its application can facilitate faster development of generic products which would, in turn, lower the economic burden of healthcare.

A Validated IVRT Method to Assess Topical Creams Containing Metronidazole Using a Novel Approach.

An IVRT method was developed and validated to confirm its reproducibility, precision, sensitivity, selectivity, accuracy, robustness, and reliability. A novel approach was used to demonstrate the appropriateness of the IVRT method to accurately assess "sameness" between topical products and to confirm that the methodology applied also possesses the requisite discriminatory power to detect differences should such differences exist between products. In the first instance, the reference product (Metrocreme®) containing 0.75% metronidazole (MTZ) was tested against itself as a positive control, to accurately demonstrate "sameness", where the results met the relevant acceptance criteria falling within the limits of 75-133.33% in accordance with the FDA's SUPAC-SS guidance. In addition, two specially prepared creams containing 25% less and 26% more MTZ, i.e., 0.563% and 0.945%, served as negative controls and were compared against the reference product. Neither of these creams fell within the "sameness" acceptance criteria, thereby confirming the discriminatory ability of the IVRT method to detect differences between MTZ products. Furthermore, another cream containing 0.75% MTZ tested against the reference product was shown to be pharmaceutically equivalent to the reference product. These results confirm the appropriateness of the IVRT method as a valuable tool for use in the development of topical MTZ products intended for local action and indicate the potential for general use with other topical products.

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

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.

Revisiting FDA's 1995 Guidance on Bioequivalence Establishment of Topical Dermatologic Corticosteroids: New Research Based Recommendations.

PURPOSE: As per the US FDA guidance issued on June 2, 1995, the establishment of bioequivalence for topical dermatologic corticosteroids is based on comparing the pharmacodynamic (PD) effects of Test and Reference products at the dose duration corresponding to the population ED50, determined either by naïve pooled data or nonlinear mixed effect modeling (NLME). The guidance was introduced using a study case example where the expectation maximization (EM) NLME algorithm, as implemented in P-PHARM®, was used. Although EM methods are relatively common, other methods such as the First-Order Conditional Estimation (FOCE) as implemented in the NONMEM® software are even more common. The objective of this study was to investigate the impact of using different parametric population modeling/analysis methods and distribution assumptions on population analysis results. METHODS: The dose duration-response data from 11 distinct skin blanching blinded pilot studies were fitted using FOCE (NONMEM®) and an EM algorithm (ADAPT5® (MLEM)). Three different Emax models were tested for each method. Population PD estimates and associated CV%, and the agreement between model predicted values and observed data were compared between the two methods. The impact of assuming different distributions of PD parameters was also investigated. RESULTS: The simple Emax model, as proposed in the FDA guidance, appeared to best characterize the data compared to more complex alternatives. The MLEM method in general appeared to provide better results than FOCE; lower population PD estimates with less inter-individual variability, and no variance shrinkage issues. The results also favored ln-normal versus normal distribution assumptions. CONCLUSIONS: The population ED50 estimates were influenced by both the type of population modeling methods and the distribution assumptions. We recommend updating the FDA guidance with more specific instructions related to the population approach to be used (EM-like versus FOCE-like methods) and to the normality assumptions that need to be set (ln-normal versus normal distribution).

Identification of Mechanism and Pathway of the Interaction between the African Traditional Medicine, Sutherlandia Frutescens, and the Antiretroviral Protease Inhibitor, Atazanavir, in Human Subjects Using Population Pharmacokinetic (PK) Analysis.

Although the use of the indigenous Southern African plant, Sutherlandia frutescens (SF) for the treatment of HIV/AIDS has previously been described, the risk which it may pose to the safety and efficacy of ARVs and the potential mechanisms which underlie such effects may have clinical significance and relevance. The protease inhibitor (PI), atazanavir (ATV) is a substrate of the efflux transporter, P-gp which modulates absorption in the small intestine, as well as CYP3A4 and CYP3A5enzymes which facilitate metabolism in the small intestine and liver. The objective of this study was to investigate the effect of SF on the pharmacokinetics (PK) of atazanavir (ATV) and to use a population PK analysis to fit and explain plasma concentration vs. time profiles of ATV generated in a previously conducted study in healthy male subjects in order to understand and postulate on the potential mechanism(s) of the drug-drug interaction. The population PK Compartmental Analysis of ATV before and after a two-week regimen of Phyto Nova Sutherlandia SU1 tablets which contain SF plant material indicated that a two compartment model with a dual absorption mechanism best explained the data. The dual absorption mechanism is hypothesized to reflect "passive" (first-order, Ka parameter) and "active" (zero-order, K0 parameter) absorption processes. The model suggested that the mechanism by which SF reduced the overall bioavailability of ATV may be modulated via the inhibition of the "active" absorption process. This study has highlighted the utility of population PK analyses in postulating probable mechanism(s) whereby an ATM or a herbal medicine interacts with an allopathic drug.

Application of an Optimized Tape Stripping Method for the Bioequivalence Assessment of Topical Acyclovir Creams.

This study indicates the application of tape stripping (TS) for bioequivalence (BE) assessment of a topical cream product containing 5% acyclovir. A TS method, previously used successfully to assess BE of topical clobetasol propionate and clotrimazole formulations, was used to assess BE of an acyclovir cream (5%) formulation as well as a diluted acyclovir formulation (1.5%) applied to the skin of healthy humans. An appropriate application time was established by conducting a dose duration study using the innovator product, Zovirax® cream. Transepidermal water loss was measured and used to normalize thicknesses between subjects. The area under the curve (AUC) from a plot of amount of acyclovir/strip vs cumulative fraction of stratum corneum (SC) removed was calculated for each application site. BE was assessed using Fieller's theorem in accordance with FDA's guidance for assessment of BE of topical corticosteroids. Adco-acyclovir cream (5%) was found to be BE to Zovirax® cream, where the mean test/reference (T/R) ratio of the AUC's was 0.96 and the bioequivalence interval using a 90% confidence interval was 0.91-1.01 with a statistical power > 95%, whereas the diluted test product fell outside the BE acceptance criteria with T/R ratio of AUC of 0.23 and a 90% CI of 0.20-0.26. This study indicates that the data resulting from the application of this TS procedure has reinforced the potential for its use to assess BE of topical drug products intended for local action, thereby obviating the necessity to undertake clinical trials in patients.

A comprehensive approach to qualify and validate the essential parameters of an in vitro release test (IVRT) method for acyclovir cream, 5.

The rate of release of an active pharmaceutical ingredient (API) from a topical semisolid dosage form can be influenced by its physical and structural properties. An In Vitro Release Test (IVRT) is an established method to characterize this rate of API release and compare the underlying sameness in product quality characteristics. The purpose of this work was to validate an IVRT method to compare acyclovir cream, 5% products. However, despite widespread use of the IVRT since 1997, there has been no established approach to validate an IVRT method. Our approach included: 1) qualification of the diffusion cell apparatus, 2) qualification of the laboratory, 3) validation of the HPLC analytical method, and 4) validation of numerous critical parameters of the IVRT method, itself, and resulted in a comprehensive and successful IVRT method validation. Subsequent to the IVRT validation work described here, the U.S. Food and Drug Administration (FDA) drafted a guidance on the development and validation of an IVRT method for acyclovir cream, 5%. Although there are notable differences between our approach and the approach in that guidance, this report illustrates how many of the same essential qualification parameters and validation concepts were considered and systematically addressed in our approach to IVRT validation.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient.

Investigation of Biowaivers for Immediate Release Formulations Containing BCS III Drugs, Acyclovir, Atenolol, and Ciprofloxacin Hydrochloride, Using Dissolution Testing.

The dissolution of several products containing Biopharmaceutical Classification System (BCS) class III drugs, acyclovir, atenolol, and ciprofloxacin hydrochloride, listed in the WHO essential drug list (EDL), was tested and compared with their respective comparator pharmaceutical products (CPPs) marketed in South Africa and India. US Pharmacopeia (USP) buffers of pH 1.2, 4.5, and 6.8 were used as dissolution media and tested using USP apparatus 2 at 75 rpm and 900 ml. Nine acyclovir products were tested, and only three dissolved very rapidly in all media; i.e., they showed a release of >85% in 15 min. Eight atenolol products tested were all very rapidly dissolving in all three pH media. Ten ciprofloxacin hydrochloride products were tested, and the results showed that only five products met the WHO biowaiver criteria. This study indicates that not all marketed products containing the same BCS III active pharmaceutical ingredient (API) in similar strength and dosage form are necessarily in vitro equivalent as per the WHO biowaiver criteria. Furthermore, selection and availability of an innovator product as CPP are important considerations that can affect the outcomes of such studies.

Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence.

BACKGROUND: The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products. OBJECTIVE: To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product. METHODS: In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum dermal concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25. RESULTS: The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent. CONCLUSIONS: dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study).

BCS Biowaivers: Similarities and Differences Among EMA, FDA, and WHO Requirements.

The Biopharmaceutics Classification System (BCS), based on aqueous solubility and intestinal permeability, has enjoyed wide use since 1995 as a mechanism for waiving in vivo bioavailability and bioequivalence studies. In 2000, the US-FDA was the first regulatory agency to publish guidance for industry describing how to meet criteria for requesting a waiver of in vivo bioavailability and bioequivalence studies for highly soluble, highly permeable (BCS Class I) drugs. Subsequently, the World Health Organization (WHO) and European Medicines Agency (EMA) published guidelines recommending how to obtain BCS biowaivers for BCS Class III drugs (high solubility, low permeability), in addition to Class I drugs. In 2015, the US-FDA became better harmonized with the EMA and WHO following publication of two guidances for industry outlining criteria for obtaining BCS biowaivers for both Class I and Class III drugs. A detailed review and comparison of the BCS Class I and Class III criteria currently recommended by the US-FDA, EMA, and WHO revealed good convergence of the three agencies with respect to BCS biowaiver criteria. The comparison also suggested that, by applying the most conservative of the three jurisdictional approaches, it should be possible for a sponsor to design the same set of BCS biowaiver studies in preparing a submission for worldwide filing to satisfy US, European, and emerging market regulators. It is hoped that the availability of BCS Class I and Class III biowaivers in multiple jurisdictions will encourage more sponsors to request waivers of in vivo bioavailability/bioequivalence testing using the BCS approach.