Open forum conference on the ICH M13A bioequivalence guideline.

The Network on Bioavailability and Biopharmaceutics of EUFEPS (European Federation for Pharmaceutical Sciences) had organised an Open Discussion Forum on the ICH M13A draft "Guideline on bioequivalence for immediate-release solid oral dosage forms". This conference was cosponsored by the Arbeitsgemeinschaft Pharmazeutische Verfahrenstechnik (APV) and the Frankfurt Foundation Quality of Medicines. Scientists from academia and industry attended this workshop on May 15, 2023, in Frankfurt/Germany, to discuss the suggested regulations with the European members of the ICH drafting group. The aim of this report is to summarise and highlight the main discussion points such as choice of study population (females and/or males), request for fasted and/or fed studies, consequences of differences in drug product content, handling of aberrant plasma profiles and additional requirements in case of pH-dependant solubility. During the discussion important arguments were presented for a revision of certain requirements suggested in the draft guideline.

Medicinal products with pH-dependent solubility-A problem for BA/BE assessment?

The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification. Main problem in this context is that compounds with very low solubility and slow intrinsic dissolution in the intestinal environment will cause significant bioavailability problems if their solid oral dosage forms are emptied from the stomach undisintegrated. Also, very low plasma profiles may result under these circumstances. Such cases can occur accidentally and are not resultant of non-compliance. Thus, limitation for one case per study only as suggested in the guideline is not justified.

Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin.

OBJECTIVES: To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. MATERIALS AND METHODS: 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. RESULTS: Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. CONCLUSION: To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

The global bioequivalence harmonisation initiative: Report of EUFEPS/AAPS third conference.

The European Federation of Pharmaceutical Sciences (EUFEPS) and American Association of Pharmaceutical Scientists (AAPS) have collaborated since 2015 to organize international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. This collaboration has resulted in three Global Bioequivalence Harmonization Initiative (GBHI) workshops which provided a unique opportunity for scientists from academia, industry, and regulatory agencies to discuss current, complex BE issues. The 3rd GBHI workshop was held in April 2018 in Amsterdam/The Netherlands and covered the following topics: (a) the necessity of multiple-dose studies in BE testing; (b) BE of transdermal delivery systems, and (c) liposomal parenteral preparations. This report summarizes the extensive discussions that led to better understanding of the similarities and differences across the major regulatory agencies on these topics and paved the way for future international harmonization.

Summary report of second EUFEPS/AAPS conference on global harmonization in bioequivalence.

The Global Bioequivalence Harmonization Initiative (GBHI) was launched by the Network on Bioavailability and Biopharmaceutics (BABP) under the auspices of European Federation for Pharmaceutical Sciences (EUFEPS) several years ago. Since 2015, EUFEPS in collaboration with the American Association of Pharmaceutical Scientists (AAPS) has organized three international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. These conferences provided an open forum for pharmaceutical scientists from academia, industry and regulatory agencies to discuss various BE topics at issue. The current report summarizes the discussion of BE issues at the 2nd GBHI conference held in 2016, Rockville, USA. Three important BE topics were discussed at the meeting: (a) prodrugs and compounds with pre-systemic extraction, (b) scaling procedures and two-stage designs, and (c) exclusion of pharmacokinetic data in BE assessment. The presentations and discussions of these issues have enhanced the mutual understanding of scientific background for BE evaluation and further facilitated harmonization of regulatory approaches for establishing BE of multisource drug products.

Past, Present, and Future of Bioequivalence: Improving Assessment and Extrapolation of Therapeutic Equivalence for Oral Drug Products.

The growth in the utilization of systems thinking principles has created a paradigm shift in the regulatory sciences and drug product development. Instead of relying extensively on end product testing and one-size-fits-all regulatory criteria, this new paradigm has focused on building quality into the product by design and fostering the development of product-specific, clinically relevant specifications. In this context, this commentary describes the evolution of bioequivalence regulations up to the current day and discusses the potential of applying a Bayesian-like approach, considering all relevant prior knowledge, to guide regulatory bioequivalence decisions in a patient-centric environment.

The Global Bioequivalence Harmonization Initiative: Summary report for EUFEPS international conference.

Bioequivalence (BE) is considered one of the key questions in new and generic drug product development and registration worldwide. However, the regulations and jurisdiction vary from country to country and continent to continent. Harmonization of regulatory requirements and criteria for BE determination may avoid unnecessary repetition of BE studies and minimize drug exposure to humans. Harmonization around the globe may be achieved by a better understanding of scientific principles and expectations from different regulatory authorities. To facilitate global harmonization, the Network on Bioavailability and Biopharmaceutics (BABP) under the European Federation for Pharmaceutical Sciences (EUFEPS) launched a Global Bioequivalence Harmonization Initiative (GBHI) several years ago. This international conference was the first in a series of workshops organized by EUFEPS/BABP under GBHI. The workshop provided a forum for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on selected BE issues in the hope of identifying common ground and arriving at a harmonized view on these topics.

The Two Main Goals of Bioequivalence Studies.

The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits. Both points of view are valid since they represent two aspects of product performance. It has been argued that both should be equally sustained and applied. In practice, however, they collide when regulatory conditions and statements are developed. For instance, some regulators prefer to conduct BE studies following single drug administrations since these conditions are considered to provide the highest sensitivity of discrimination between pharmacokinetic profiles and thus, a product's in-vivo performance. Others suggest that, at least for modified-release products, BE investigations should be performed in the steady state since it represents clinical conditions. Preference for one point of view or the other pervades other regulatory statements including suggestions for subjects to be selected in studies and pharmacokinetic measures to be evaluated. An overview is provided on the disturbing inconsistency of statements within and between regulations. It is argued that harmonization would be highly desirable, and relevant recommendations are offered.

Relative bioavailability of a newly developed 5-mg levomethadone hydrochloride IR tablet (L-Polamidon® 5 mg tablets) in comparison with the 5-mg levomethadone hydrochloride oral solution (L-Polamidon® solution for substitution) as reference product.

OBJECTIVES: To establish the relative bioavailability (rBA) between two p.o. 5-mg levomethadone hydrochloride formulations, i.e., L-Polamidon® 5 mg tablets (test) vs. L-Polamidon® solution for substitution (reference). To assess the safety and tolerability of both formulations. SUBJECT AND METHODS: A total of 33 healthy male subjects, aged 29 ± 6 years (BMI: 23.9 ± 2.5 kg/m2) completed this single center, open-label, randomized, 2-period cross-over study with single dose administrations under fasting conditions and coadministration with naltrexone for safety reasons. Administrations of both investigational products were separated by a washout period of at least 2 weeks, i.e., 13 treatmentfree days. The total dose for each subject was 2 x 5 mg resulting in 10 mg levomethadone hydrochloride. For pharmacokinetic evaluation, blood samples were withdrawn until 72 hours postdose. A validated non-stereoselective liquid chromatography-tandem mass spectroscopy method (LC-MS/MS) was applied for the determination of levomethadone in plasma. The lower limit of quantitation was 0.100 ng/mL. Adverse events were descriptively analyzed in the study population. RESULTS: The geometric means of the parameters related with the extent of total exposure of levomethadone, i.e., AUC(0-tlast) and AUC(0-∞), were 244.422 ng x h/mL and 332.999 ng x h/mL for test and 246.837 ng x h/mL and 329.467 ng×h/mL for reference, respectively. The geometric means of the peak exposure for levomethadone, i.e., Cmax, were 8.923 ng/mL for test and 8.635 ng/mL for reference. The point estimates (PEs) of the Test/Reference (T/R) adjusted geometric mean ratios of AUC(0-last), AUC(0-∞), and C(max) were 99.20%, 101.42%, and 104.11%, respectively, and all of them showed 90%-confidence intervals (CIs) within the range of 80.00 - 125.00% as suggested by regulatory requirements for bioequivalence assessment In total, 21 subjects experienced 55 AEs during the study, the most frequently reported AE, i.e., headache, accounted for 13 out of the total 55 AEs (23.6%) and no AEs of severe intensity were reported. CONCLUSIONS: Bioequivalence could be demonstrated in terms of rate and extent of absorption after administration of test and reference products under naltrexone protection. Concerning the safety evaluation, no negative implications on the possible use of the test formulation could be determined.

The influence of hydroxypropyl methylcellulose (HPMC) molecular weight, concentration and effect of food on in vivo erosion behavior of HPMC matrix tablets.

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion-time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.

Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update.

Proton pump inhibitors (PPIs) are used extensively for the treatment of gastric acid-related disorders, often over the long term, which raises the potential for clinically significant drug interactions in patients receiving concomitant medications. These drug-drug interactions have been previously reviewed. However, the current knowledge is likely to have advanced, so a thorough review of the literature published since 2006 was conducted. This identified new studies of drug interactions that are modulated by gastric pH. These studies showed the effect of a PPI-induced increase in intragastric pH on mycophenolate mofetil pharmacokinetics, which were characterised by a decrease in the maximum exposure and availability of mycophenolic acid, at least at early time points. Post-2006 data were also available outlining the altered pharmacokinetics of protease inhibitors with concomitant PPI exposure. New data for the more recently marketed dexlansoprazole suggest it has no impact on the pharmacokinetics of diazepam, phenytoin, theophylline and warfarin. The CYP2C19-mediated interaction that seems to exist between clopidogrel and omeprazole or esomeprazole has been shown to be clinically important in research published since the 2006 review; this effect is not seen as a class effect of PPIs. Finally, data suggest that coadministration of PPIs with methotrexate may affect methotrexate pharmacokinetics, although the mechanism of interaction is not well understood. As was shown in the previous review, individual PPIs differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole sodium (pantoprazole-Na) have been studied most extensively. Several studies have shown that omeprazole carries a considerable potential for drug interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4. In contrast, pantoprazole-Na appears to have lower potential for interactions with other medications. Lansoprazole and rabeprazole also seem to have a weaker potential for interactions than omeprazole, although their interaction profiles, along with those of esomeprazole and dexlansoprazole, have been less extensively investigated. Only a few drug interactions involving PPIs are of clinical significance. Nonetheless, the potential for drug interactions should be considered when choosing a PPI to manage gastric acid-related disorders. This is particularly relevant for elderly patients taking multiple medications, or for those receiving a concomitant medication with a narrow therapeutic index.

Predicting the oral pharmacokinetic profiles of multiple-unit (pellet) dosage forms using a modeling and simulation approach coupled with biorelevant dissolution testing: case example diclofenac sodium.

The objective of this research was to characterize the dissolution profile of a poorly soluble drug, diclofenac, from a commercially available multiple-unit enteric coated dosage form, Diclo-Puren® capsules, and to develop a predictive model for its oral pharmacokinetic profile. The paddle method was used to obtain the dissolution profiles of this dosage form in biorelevant media, with the exposure to simulated gastric conditions being varied in order to simulate the gastric emptying behavior of pellets. A modified Noyes-Whitney theory was subsequently fitted to the dissolution data. A physiologically-based pharmacokinetic (PBPK) model for multiple-unit dosage forms was designed using STELLA® software and coupled with the biorelevant dissolution profiles in order to simulate the plasma concentration profiles of diclofenac from Diclo-Puren® capsule in both the fasted and fed state in humans. Gastric emptying kinetics relevant to multiple-units pellets were incorporated into the PBPK model by setting up a virtual patient population to account for physiological variations in emptying kinetics. Using in vitro biorelevant dissolution coupled with in silico PBPK modeling and simulation it was possible to predict the plasma profile of this multiple-unit formulation of diclofenac after oral administration in both the fasted and fed state. This approach might be useful to predict variability in the plasma profiles for other drugs housed in multiple-unit dosage forms.

Understanding the in vivo performance of enteric coated tablets using an in vitro-in silico-in vivo approach: case example diclofenac.

Individual pharmacokinetics after administration of enteric coated tablets are often highly variable and this has been ascribed to the interaction of the dosage form with the physiology of the gastrointestinal tract. This research aimed to explore the influence of interactions between enteric coated tablets and physiological factors such as gastric and intestinal pH as well as gastric emptying on the release of drug from the dosage form and the subsequent plasma profile, using diclofenac as a case example. A physiologically based pharmacokinetic (PBPK) model for monolithic enteric coated dosage forms was designed and coupled with biorelevant dissolution results to predict PK profiles of diclofenac from Voltaren® tablets in both fasted and fed humans. The paddle method was used to obtain the dissolution profiles of diclofenac in biorelevant media. The Noyes-Whitney model was employed to describe the dissolution kinetics. The PBPK model was set up using STELLA® software. A single unit enteric coated tablet was assumed to be emptied from stomach only with the house-keeping wave. Timing of the emptying was simulated using a random number generator to statistically estimate gastric emptying times after ingestion. The lag times and the dissolution rate used as input parameters in the STELLA® model were adjusted according to the pre-exposure period. The oral PK profiles were predicted for each virtual subject individually, and then the mean profiles and standard deviations were calculated. The dissolution profiles were highly affected by the period of pre-exposure in FaSSGF. A long period of pre-exposure of the tablet prolonged the lag time and decreased the dissolution rate. The results of the pharmacokinetic simulations showed that not only the mean profiles in the fasted state but also the variability could be predicted successfully using data generated for the individual virtual subjects. The results emphasize the importance of accounting for the range of pH profiles and gastrointestinal transit in the target population when predicting plasma profiles of enteric coated dosage forms and point to problems in demonstrating bioequivalence for dosage forms of this type.

Bioavailability and pharmacodynamics of two 10-mg estradiol valerate depot formulations following IM single dose administration in healthy postmenopausal volunteers.

OBJECTIVE: To establish the bioequivalence (BE) between two i.m. estradiol valerate (E2V) depot formulations, i.e., Estradiol-Depot 10 mg® (test) and Progynon Depot-10® (reference). To compare the effect of both treatments on the vaginal maturation index and on the increase of the endometrial thickness after administration of both formulations. METHODS: A total of 24 postmenopausal females aged 54.7 ± 5.35 year (BMI 25.84 ± 1.98 kg/m2) completed this BE assessment. The investigation was planned and designed as a single center, openlabel, single dose, cross-over study including 2 periods with 2 treatments and 2 sequences. Baseline levels were obtained for all subjects. Single doses of 10-mg E2V of each product were administered and pharmacokinetics and pharmacodynamics were assessed over 2 weeks with a washout period of 4 weeks. A gas chromatographic-mass spectrometric method with negative chemical ionization and selected ion monitoring was applied, after validation, for the determination of estradiol (E2), estrone (E1) and internal standard estradiol-D4 derivatives. The cytology of the vaginal smear (parabasal, intermediate and superficial cells from lateral wall opposite tip of cervix) was assessed by investigation of ~ 200 cells. The vaginal maturation index (VMI) was calculated by the equation: VMI (%) = (superficial cells × 1) (%) + (intermediate cells × 0.5) (%). Endometrial thickness was measured by transvaginal ultrasonic scans and recorded in mm. RESULTS: The geometric means (Gmeans) of the measured values of Cmax and AUC0-t for E2 were 543.5 pg/ ml and 84,734 pg × h/ml for test and 505.7 pg/ml and 82,660 pg × h/ml for reference, whereas those for E1 were 219.0 pg/ml and 38,950 pg × h/ml for test and 204.9 pg/ml and 37,159 pg × h/ml for reference, respectively. The point estimates (PEs) of the Test/ Reference (T/R) mean ratios of the variables Cmax and AUC0-t for E2 (measured values) were 107.3% and 102.5%, respectively. The PEs of the T/R mean ratios of the variables Cmax and AUC0-t for E1 (measured values) were 106.9% and 105.0%, respectively. Median endometrial thickness increased in Period I from baseline levels of ~ 3 mm (Day -2) to ~ 7 mm (Day 21) after administration of both products without returning completely to baseline prior to the next administration. In Period II, median values of 7 mm were also reached (Day 21) after administration of both products. Median vaginal maturation indices increased in Period I from baseline levels of ranging from 45 - 60% (Day -2) to 86 - 94.5% (Day 21). In Period II maturation indices of ≥ 90% were calculated as baselines (Day -2) and these levels remained constant until the end of the assessment (Day 21) independently from the products. After 21 days of treatment, test and reference presented practically no differences in terms of their effects on endometrial thickness and vaginal maturation index. CONCLUSIONS: The 95% CIs for the T/R mean ratios of AUC0-t and Cmax for E2 and E1 fell within the acceptance limits of 80 - 125% and therefore bioequivalence could be demonstrated for both formulations. The changes in endometrial thickness and the vaginal maturation index indicated that the pharmacodynamic effect is pronounced already after the first administration and that the effect continued notably for longer time compared to the presence of E2 and E1 in plasma. A 4-week washout phase was insufficient to avoid residual pharmacological effects after the administration of both preparations.

Improved therapeutic entities derived from known generics as an unexplored source of innovative drug products.

With a New Drug Application (NDA) innovative drug therapies are reaching the market in a specific dosage form for one or more clinically proven indications of which after expiration of the patent or the data exclusivity copies are launched using Abbreviated New Drug Applications (ANDA). Advanced therapies that emerged from launched molecules during their product life-cycle have gained considerable attention as clinical practice provides evidence for additional therapeutic values, patient centric delivery systems show improved therapeutic outcomes or emerging technologies offer efficiency gains in manufacturing or access to emerging markets. The USA and European regulatory framework has set reasonable regulations in place for these "Supergenerics" or "hybrid" applications. While these regulations are relatively recent the pharmaceutical industry is just starting to use this route for their product development and life-cycle management. From a clinical perspective the potential for advanced product development have been demonstrated. Yet, there is still a lag of common understanding between the different stakeholders regarding the development, application process and commercial incentive in developing enhanced therapeutic entities based on existing drug products for the market.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Harmonization of regulatory approaches for evaluating therapeutic equivalence and interchangeability of multisource drug products: workshop summary report.

Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

Workshop/conference report on EMA draft guideline on validation of bioanalytical methods.

This is a summary report of the workshop on the EMA Draft Guideline on Validation of Bioanalytical Methods held April 15-16th 2010 in Brussels (Belgium) and jointly organised by the European Bioanalysis Forum (EBF) and the European Federation for Pharmaceutical Sciences (EUFEPS). Aim of the workshop was to discuss the current scientific knowledge in the area of bioanalysis, the regulatory requirements with special focus on the new Draft Guideline and their subsequent implementation to the work in bioanalytical laboratories. Comments on the Draft Guideline were presented and discussed with representatives from regulatory authorities in Europe. The workshop started with discussions on the scope of the Guideline and the need for implementation of GLP. A special focus was set on method validation of chromatographic procedures and subsequent study sample analysis. In addition, requirements for ligand-binding assays were briefly addressed. Intention of this Conference Report is to summarise important aspects of the discussions in order to draw certain conclusions, and to identify points which remain open and may require clarification at a later stage.