Characteristics of contents in the upper gastrointestinal lumen after a standard high-calorie high-fat meal and implications for the in vitro drug product performance testing conditions.

OBJECTIVES: To measure the pH, buffer capacity, lipid content, bile acid content, and viscosity in the upper gastrointestinal (GI) lumen after a standard high-calorie, high-fat meal as well as the osmolality, lipid content and bile acid content in the aqueous phase of the gastric contents and the micellar phase of contents of the upper small intestine. To evaluate the implications of these findings for the composition of biorelevant media employed in vitro oral drug product performance testing representing the upper GI conditions after ingestion of the standard meal. METHODS: Eight healthy male adult volunteers participated in a two-phase, crossover study in which a homogenized standard meal was administered to the antrum via the gastric port of a naso-gastro-intestinal tube. A glass of tap water and single paracetamol and danazol doses were administered to the antrum of the stomach 30 min after the initiation of meal administration (Pentafragka et al., 2020). Samples were aspirated from the antrum and the upper small intestine over the next four hours. The pH and the buffer capacity of the samples were measured immediately upon aspiration, while viscosity, osmolality, and presence of solubilizing agents were measured after storage at -70 °C. RESULTS: The composition of gastric contents over time fluctuated less after the homogenized standard meal than after liquid meals with similar composition. Intra-subject variability of pH and buffer capacity in the stomach and in the upper small intestine was low. Mean viscosity values in the stomach at 100 s-1 were 80-800 times higher than in the fasted state for more than 3 h after the standard meal. In the upper small intestine, mean viscosity values at 100 s-1 were at least 100 times higher than in the fasted state for 4 h after the standard meal. CONCLUSIONS: Based on data collected in this study, Level I and Level II biorelevant media simulating the intragastric conditions after ingestion of a standard meal could be simplified whereas FeSSIF-V2 composition was confirmed to be representative of the composition of contents in the upper small intestine. Representative values of viscosity in the stomach and the upper small intestine and Level II composition of the aqueous phase of gastric contents, after the standard meal, are proposed for first time.

Disposition of two highly permeable drugs in the upper gastrointestinal lumen of healthy adults after a standard high-calorie, high-fat meal.

OBJECTIVES: To quantify the presence of two model highly permeable drugs, paracetamol and danazol, in the upper gastrointestinal lumen under conditions simulating the situation after disintegration of immediate release dosage forms administered in bioavailability/bioequivalence studies in the fed state. To understand the drug transfer process from the antral contents through the upper small intestine based on luminal drug data. METHODS: 8 healthy male adult volunteers participated in a randomized, single dose, two-phase, crossover study. After evaluating the impact of homogenization on meal's viscosity and particle size, the meal, containing phenol red as non-absorbable marker, was administered to the antrum via the gastric lumen of a naso-gastro-intestinal tube. The drugs were administered in solution form (Phase I) and in suspension form (Phase II) with a glass of tap water to the antrum of the stomach, 30 min after the initiation of meal administration. Samples were aspirated from the antrum and the upper small intestine up to 4 hours post drug administration. RESULTS: Apparent concentrations in the aqueous contents of the antrum were higher than apparent concentrations in the micellar contents of the upper small intestine for paracetamol; the opposite was observed for danazol. Based on total drug amount per volume data in contents of the upper gastrointestinal lumen, the transfer of paracetamol (aqueous solution or suspension) and danazol (aqueous suspension) through the upper small intestine could be described as an apparent first-order process. Transfer of a long-chain triglyceride solution of danazol was highly variable. CONCLUSIONS: Concentrations in the aqueous/micellar phase of luminal contents and values of parameters controlling the transfer from bulk gastric contents through the upper small intestine after a high-calorie, high-fat meal, were reported for the first time for highly permeable drugs. Data are expected to enhance the development of biorelevant in vitro and physiologically based biopharmaceutics modelling methodologies.

On the Design of Food Effect Studies in Adults for Extrapolating Oral Drug Absorption Data to Infants: an Exploratory Study Highlighting the Importance of Infant Food.

In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. Also, for ibuprofen, Cmax values under infant fed conditions were significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants.

The impact of food intake on the luminal environment and performance of oral drug products with a view to in vitro and in silico simulations: a PEARRL review.

OBJECTIVES: Using the type of meal and dosing conditions suggested by regulatory agencies as a basis, this review has two specific objectives: first, to summarize our understanding on the impact of food intake on luminal environment and drug product performance and second, to summarize the usefulness and limitations of available in vitro and in silico methodologies for the evaluation of drug product performance after food intake. KEY FINDINGS: Characterization of the luminal environment and studies evaluating product performance in the lumen, under conditions suggested by regulatory agencies for simulating the fed state, are limited. Various in vitro methodologies have been proposed for evaluating drug product performance in the fed state, but systematic validation is lacking. Physiologically based pharmacokinetic (PBPK) modelling approaches require the use of in vitro biorelevant data and, to date, have been used primarily for investigating the mechanisms via which an already observed food effect is mediated. SUMMARY: Better understanding of the impact of changes induced by the meal administration conditions suggested by regulatory agencies on the luminal fate of the drug product is needed. Relevant information will be useful for optimizing the in vitro test methods and increasing the usefulness of PBPK modelling methodologies.

The BioGIT System: a Valuable In Vitro Tool to Assess the Impact of Dose and Formulation on Early Exposure to Low Solubility Drugs After Oral Administration.

The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC0-0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC0-0.75h values were evaluated versus differences in AUC0-1h and in AUC0-2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC0-0.75h, mean AUC0-1h, and mean AUC0-2h values were estimated using the lowest dose or the formulation with the lower AUC0-0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC0-0.75h ratios correlated significantly with log-transformed mean plasma AUC0-1h ratios. Based on this correlation, BioGIT AUC0-0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC0-1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs.

In vitro evaluation of the impact of gastrointestinal transfer on luminal performance of commercially available products of posaconazole and itraconazole using BioGIT.

Biorelevant Gastrointestinal Transfer system (BioGIT) has been shown to be useful in reproducing concentrations of drugs in the fasted upper small intestine after their administration in the stomach. In the present investigation, we evaluated the impact of gastrointestinal transfer on luminal performance of commercially available products of two highly lipophilic weak bases, posaconazole (Noxafil® suspension) and itraconazole (Sporanox® hard gelatin capsules and Sporanox® oral solution) by comparing % solid fraction, concentrations and supersaturation in the duodenal compartment of BioGIT with recently reported data in the upper small intestine of healthy adults. BioGIT was useful for estimating the % solid fraction in the upper small intestine, in cases where dissolution during gastric residence was incomplete, i.e. after administration of Noxafil® and Sporanox® capsules, and the precipitated fraction of itraconazole in the upper small intestine after administration of Sporanox® solution; median values in vitro were similar to the luminal values. Based on the values for the area under the concentration vs. time data estimated up to 45min post initiation of the experiment, concentrations in the duodenal compartment of BioGIT were similar to previously measured concentrations in the upper small intestine of healthy adults or they overestimated them by up to 2.5 times. In most cases, supersaturation of contents in the upper small intestine was overestimated, partly due to underestimation of luminal solubility.

Evaluation of the Impact of Excipients and an Albendazole Salt on Albendazole Concentrations in Upper Small Intestine Using an In Vitro Biorelevant Gastrointestinal Transfer (BioGIT) System.

An in vitro biorelevant gastrointestinal transfer (BioGIT) system was assessed for its ability to mimic recently reported albendazole concentrations in human upper small intestine after administration of free base suspensions to fasted adults in absence and in presence of supersaturation promoting excipients (hydroxypropylmethylcellulose and lipid self-emulsifying vehicles). The in vitro method was also used to evaluate the likely impact of using the sulfate salt on albendazole concentrations in upper small intestine. In addition, BioGIT data were compared with equilibrium solubility data of the salt and the free base in human aspirates and biorelevant media. The BioGIT system adequately simulated the average albendazole gastrointestinal transfer process and concentrations in upper small intestine after administration of the free base suspensions to fasted adults. However, the degree of supersaturation observed in the duodenal compartment was greater than in vivo. Albendazole sulfate resulted in minimal increase of albendazole concentrations in the duodenal compartment of the BioGIT, despite improved equilibrium solubility observed in human aspirates and biorelevant media, indicating that the use of a salt is unlikely to lead to any significant oral absorption advantage for albendazole.

Effectiveness of supersaturation promoting excipients on albendazole concentrations in upper gastrointestinal lumen of fasted healthy adults.

PURPOSE: To evaluate the impact of dosage form relevant levels of a polymeric precipitation inhibitor and of lipid excipients on supersaturation of upper gastrointestinal contents with albendazole, a lipophilic weak base. MATERIALS AND METHODS: Albendazole concentrations in stomach and in duodenum were evaluated after administration of 1) a suspension in water (Susp-Control), 2) a suspension in water in which hydroxyprolylmethylcellulose E5 (HPMC E5) had been pre-dissolved (Susp-HPMC), and 3) and 4) two contrasting designs of lipid based suspensions dispersed in water (Susp-IIIA and Susp-IV), on a cross-over basis to fasted healthy adults. RESULTS: Limited, but statistically significant supersaturation of duodenal contents was observed after Susp-HPMC, Susp-IIIA, and Susp-IV; supersaturation was more consistent after Susp-HPMC administration. Based on total albendazole amount per volume, gastric secretions did not significantly alter volumes of bulk gastric contents during the first 40min post administration of a glass of non-caloric water-based fluid. Αlbendazole gastric concentrations were higher than in the administered suspensions, but similar for all four formulations. Gastric emptying of albendazole after administration of Susp-Control or Susp-HPMC was slower than after administration of Susp-IIIA or Susp-IV. CONCLUSIONS: Small amounts of HPMC E5 were as effective as lipid excipients in achieving supersaturation of duodenal contents with albendazole, a fast precipitating weak base, in fasted adults. However, compared with the effect of HPMC E5 the effect of lipid excipients was delayed and variable.

In-vitro evaluation of performance of solid immediate release dosage forms of weak bases in upper gastrointestinal lumen: experience with miconazole and clopidogrel salts.

OBJECTIVES: Evaluate the impact of salt and counterion identity on performance of solid immediate release dosage forms of miconazole and clopidogrel, respectively, in fasted upper gastrointestinal lumen using in-vitro methodologies. METHODS: Two miconazole chemical forms (free base and nitrate salt) and three clopidogrel chemical forms (bisulfate, besylate and hydrochloride salts) were studied. Solubilities of miconazole forms were measured in simulated gastric fluids. Gastrointestinal transfer of the five chemical forms was evaluated by using a flow-through, three-compartmental set-up. Precipitation in duodenal compartment was evaluated by using solutions in gastric compartment. KEY FINDINGS: Solubilities in simulated gastric fluids, concentrations in duodenal compartment and solubilities in duodenal compartment indicated poorer performance of miconazole nitrate vs. miconazole free base in upper gastrointestinal lumen. In line with the low crystallization tendency of free base, duodenal precipitation of miconazole from a free base solution was limited. Concentrations in duodenal compartment indicated that counterion identity does not affect the performance of clopidogrel; precipitation in duodenal compartment was extensive in all cases. CONCLUSIONS: Miconazole data indicate that salts may adversely affect performance of immediate release dosage forms of weak bases. In line with existing in-vivo data, clopidogrel data indicate that counterion identity is unimportant for the performance of clopidogrel salts in upper intestinal lumen.

An in vitro biorelevant gastrointestinal transfer (BioGIT) system for forecasting concentrations in the fasted upper small intestine: Design, implementation, and evaluation.

PURPOSE: Design an in vitro methodology for studying gastrointestinal transfer in the fasted state and implement the methodology in vitro by using a biorelevant gastrointestinal transfer system(BioGIT); evaluate the usefulness of BioGIT in predicting luminal concentrations of lipophilic weak bases in the fasted upper small intestine. METHODS: The methodology was designed after modeling existing luminal data. Its implementation in vitro was based on a three compartment setup. Reproducibility of the transfer process was evaluated under conditions where solutions and/or suspensions were present in gastric and/or duodenal compartment and by using ranitidine, dipyridamole, ketoconazole, and posaconazole as model drugs. The transfer process as well as concentrations of dipyridamole, ketoconazole and posaconazole measured in the duodenal compartment were compared with data previously collected in the upper small intestine, after administration of identical preparations/dosage forms to fasted adults. RESULTS: Using BioGIT, the transfer process was performed reproducibly in all cases (RSD b 12.9%); data with dipyridamole and ketoconazole were in line with luminal data in humans. Dipyridamole, ketoconazole and posaconazole concentrations in duodenal compartment were also in line with previously measured concentrations in the fasted upper small intestine of healthy adults. CONCLUSIONS: BioGIT system could be useful for the evaluation of the impact of gastrointestinal transfer on concentrations in the upper intestinal lumen during the first hour, after oral administration of dispersing/solution dosage forms of lipophilic weak bases.

Two-Stage Single-Compartment Models to Evaluate Dissolution in the Lower Intestine.

The purpose was to propose two-stage single-compartment models for evaluating dissolution characteristics in distal ileum and ascending colon, under conditions simulating the bioavailability and bioequivalence studies in fasted and fed state by using the mini-paddle and the compendial flow-through apparatus (closed-loop mode). Immediate release products of two highly dosed active pharmaceutical ingredients (APIs), sulfasalazine and L-870,810, and one mesalamine colon targeting product were used for evaluating their usefulness. Change of medium composition simulating the conditions in distal ileum (SIFileum ) to a medium simulating the conditions in ascending colon in fasted state and in fed state was achieved by adding an appropriate solution in SIFileum . Data with immediate release products suggest that dissolution in lower intestine is substantially different than in upper intestine and is affected by regional pH differences > type/intensity of fluid convection > differences in concentration of other luminal components. Asacol® (400 mg/tab) was more sensitive to type/intensity of fluid convection. In all the cases, data were in line with available human data. Two-stage single-compartment models may be useful for the evaluation of dissolution in lower intestine. The impact of type/intensity of fluid convection and viscosity of media on luminal performance of other APIs and drug products requires further exploration.

Gastrointestinal transfer: in vivo evaluation and implementation in in vitro and in silico predictive tools.

INTRODUCTION: The purpose of this study was to explore the transfer of drug solutions from stomach to small intestine and its impact on intraluminal drug concentrations in humans. The collected intraluminal data were used as reference to evaluate simulations of gastrointestinal transfer currently implemented in different in vitro and in silico absorption models. METHODS: Gastric and duodenal concentrations of the highly soluble and non-absorbable compound paromomycin were determined following oral administration to 5 healthy volunteers under the following conditions: fasted state, fed state and fed state in the presence of a transit-stimulating (domperidone) or transit-inhibiting (loperamide) agent. Based on the obtained intraluminal concentration-time profiles, gastrointestinal transfer (expressed as the half-life of gastric emptying) was analyzed using physiologically-based parameter estimation in Simcyp®. Subsequently, the observed transfer profiles were used to judge the implementation of gastrointestinal transfer in 2 in vitro simulation tools (the TNO Intestinal Model TIM-1 and a three-compartmental in vitro model) and the Simcyp® population-based PBPK modeling platform. RESULTS: The observed duodenal concentration-time profile of paromomycin under fasting conditions, with a high average Cmax obtained after 15 min, clearly indicated a fast transfer of drug solutions from stomach to duodenum (estimated gastric half-life between 4 and 13 min). The three-compartmental in vitro model adequately reflected the in vivo fasted state gastrointestinal transfer of paromomycin. For both TIM-1 and Simcyp®, modifications in gastric emptying and dilutions were required to improve the simulation of the transfer of drug solutions. As expected, transfer from stomach to duodenum was delayed in the fed state, resulting in lower duodenal paromomycin concentrations and an estimated gastric half-life between 21 and 40 min. Administration of domperidone or loperamide as transit-stimulating and transit-inhibiting agent, respectively, did not affect the fed state gastric half-life of emptying. CONCLUSION: For the first time, the impact of gastrointestinal transfer of solutions on intraluminal drug concentrations was directly assessed in humans. In vitro and in silico simulation tools have been validated and optimized using the in vivo data as reference.

In vitro and ex vivo investigation of the impact of luminal lipid phases on passive permeability of lipophilic small molecules using PAMPA.

PURPOSE: Evaluate the impact of luminal micellar phase on passive permeability of five lipophilic (1.9 ≤ clogP ≤ 9.0) small molecules using biorelevant media and evaluate the impact of luminal coarse lipid particles on danazol permeability after oral administration of a triglyceride solution to fed adults using PAMPA. METHODS: Permeability of carbamazepine, furosemide, danazol, and Compound A was evaluated using Prisma™ HT, FaSSIF-V2, and FeSSIF-V2 in the donor compartment. Compound B could not be tested using Prisma™ HT, due to negligible solubility. Individual intestinal aspirates collected after administration of danazol solution in the olive oil portion of a meal and corresponding micellar phases were subjected to PAMPA. Commercially available Acceptor Sink Buffer was used in all cases. RESULTS: Unlike with furosemide (under constant pH) and Compound B, permeability of carbamazepine, danazol, and Compound A steadily decreased in the presence of increasing micelle concentration of media. Danazol permeability from aspirates was reduced compared to that from micellar phases; fluxes were similar. CONCLUSIONS: Using PAMPA, the impact of luminal micellar phase on passive permeability of lipophilic molecules varies with the molecule. After administration of a triglyceride solution of danazol, high danazol concentrations in coarse lipid particles balance in terms of drug flux the reduced permeability.

Exploring the relationships between scaled bioequivalence limits and within-subject variability.

Assessment of bioequivalence (BE) for highly variable drugs is challenging. As within-subject variability increases, it becomes more difficult to prove BE, unless a large number of subjects is recruited. In order to face this problem, several approaches have been proposed. Among them, scaled BE limits (BEL) have recently attracted special attention because the European Medicines Agency and the US Food and Drug Administration adopted scaled approaches. Scaled BELs expand with variability using specific mathematical functions while include additional regulatory criteria in some cases. The aim of this study is twofold: (1) to provide a deeper insight into the dependence of scaled BELs on variability and (2) to unveil the underlying mathematical relationships. The comparative analysis of these BELs is implemented through algebraic manipulations and graphic illustrations. Special emphasis is placed on the "absolute change" of each BEL and the "relative change," reflecting the portion of the relative to the maximum expansion of a BEL. This analysis reveals the causal differences between the different BELs on the mode of "absolute" and "relative" change. The results derived from this study are in agreement with the observed different performances of the various scaled BE approaches.

Bioequivalence of highly variable drugs: a comparison of the newly proposed regulatory approaches by FDA and EMA.

PURPOSE: To explore the comparative performance of the recently proposed bioequivalence (BE) approaches, FDA(s) and EMA(s), by the FDA working group on highly variable drugs and the EMA, respectively; to compare the impact of the GMR-constraint on the two approaches; and to provide representative plots of % BE acceptance as a function of geometric mean ratio, sample size and variability. METHODS: Simulated BE studies and extreme GMR versus CV plots were used. Three sequence, three period crossover studies with two treatments were simulated using four levels of within-subject variability. RESULTS: The FDA(s) and EMA(s) approaches were identical when variability was <30%. In all other cases, the FDA(s) method was more permissive than EMA(s). The major discrepancy was observed for variability values >50%. The GMR-constraint was necessary for FDA(s), especially for drugs with high variabilities. For EMA(s), the GMR-constraint only became effective when sample size was large and variability was close to 50%. CONCLUSIONS: A significant discrepancy in the performances of FDA(s) and EMA(s) was observed for high variability values. The GMR-constraint was essential for FDA(s), but it was of minor importance in case of the EMA(s).

On the leveling-off properties of the new bioequivalence limits for highly variable drugs of the EMA guideline.

Recently, the European Medicines Agency (EMA) issued a new guideline on the investigation of bioequivalence (BE). In case of highly variable drugs, this guideline proposes that the acceptance limits for C(max) can gradually be expanded as a function of within-subject variability (CV(wR)). Actually, these BE limits exhibit leveling-off properties since they are not allowed to scale continuously, but only up to CV(wR)=50%. To avoid the risk of accepting two drug products which may differ significantly, this EMA guideline also proposes the use of a secondary constraint criterion on the geometric mean ratio (GMR) of the two products under comparison. Aim of this study was to explore the leveling-off properties of the new EMA limits in comparison to other approaches, as well as to assess the impact of the complementary GMR criterion on the ability to declare bioequivalence. Simulated bioequivalence studies and extreme GMR plots were used to assess the performance of the EMA limits. Three sequence, three period (3×3) crossover studies with two treatments (T and R) were simulated. The R product was considered to be administered twice, while the T only once (i.e., TRR/RTR/RRT). Among others, this study revealed the leveling-off properties of the new EMA limits. It was also shown that the complementary GMR-constraint is only effective when a large sample size is used and at regions of CV(wR) close to 50%. This GMR-criterion begins to be effective at sample sizes around 60 and becomes more prominent as the number of subjects participating in the BE study increases. For CV(wR) values lower than 50%, the GMR-constraint has no role. In case of within-subject variabilities greater than 50%, the impact of the GMR-constraint diminishes due to the leveling-off properties of the EMA limits. Compared to the classic 0.80-1.25 or the extended 0.75-1.33 criteria, the new EMA limits are more liberal at high CV(wR) values and allow greater differences between the two drug products to be declared bioequivalent. Finally, this study showed that the use of an approximate value (0.760) on the scaling factor proposed by EMA, has no impact on the performance of the new BE limits compared to other more accurate approaches.

Novel methods to assess bioequivalence.

IMPORTANCE OF THE FIELD: The ultimate goal of bioequivalence is to assess the expected in vivo equivalence of two drug products of the same active moiety. AREAS COVERED IN THIS REVIEW: In this review, we present the classic approach of bioequivalence assessment, some situations of special importance such as the role of metabolites and highly variable drugs, and the current regulatory state in North America and Europe. Special emphasis is given to the methods proposed for solving the problems caused by high variability such as multiple-dose studies, replicate designs, individual bioequivalence and the widening of bioequivalence limits. Other issues discussed include the concept of biowaivers and the rising field of the equivalence of biologicals (biosimilars). WHAT THE READER WILL GAIN: The reader will gain an understanding of why bioequivalence assessment is necessary, how it is performed and what one should be aware of when planning to conduct a bioequivalence study. TAKE HOME MESSAGE: The aim of bioequivalence studies is to ensure comparable in vivo performance of two drug products. This is accomplished by performing an appropriate clinical study which should be capable of ensuring the drug's safety and efficacy for consumers with less human exposure and costs of producing.

Comparison of the reference scaled bioequivalence semi-replicate method with other approaches: focus on human exposure to drugs.

To compare the performance of the reference scaled average bioequivalence (scABE(R)) method proposed by FDA scientists [Haidar et al., 2008. Pharm. Res. 25, 237-241] with other approaches focusing on the human exposure expressed as the product sample size x periods of drug administration. Simulated bioequivalence studies were generated assuming the partial replicate 3-way crossover design and the classic (2 x 2) crossover design. Intrasubject variability (CV(W)) values ranged from 15% to 60% and sample sizes from 16 to 54. The procedures examined include: the scABE(R) method, the classic 0.80-1.25 approach, a levelling-off scaled BE limit (BELscW), and some other scaled bioequivalence limits. To assess the performance of the aforementioned approaches, the typical as well as novel three-dimensional modified power curves were constructed. A new index, termed %Mean Relative Difference (MRD%), was introduced in order to quantitatively compare the performance of the bioequivalence limits. The recently proposed scABE(R) approach showed the lowest producer risk in particular for highly variable drugs. When exposure was taken into account scABE(R) resulted in a desired behaviour when CV(W) was low. For high CV(W) values the overall performance diminished when geometric mean ratio (GMR) substantially deviated from unity. Application of the MRD% index clearly revealed that the effect of lowering the producer risk at GMR=1 was totally counterbalanced by the rise of consumer risk at high GMR values. The classic 0.80-1.25 limits were favoured at low intrasubject variability and high exposure, whereas the levelling-off limits demonstrated a preferred overall performance when variability was high and exposure was limited.

Novel scaled bioequivalence limits with leveling-off properties.

PURPOSE: (1) To develop novel scaled bioequivalence (BE) limits with levelling-off properties based solely on variability considerations and (2) to evaluate their performance in comparison to the classic unscaled BE limits 0.80-1.25, the expanded BE limits 0.75-1.33 and the recently proposed Geometric Mean Ratio (GMR)-dependent scaled BE limits BELscW (Karalis et al., Eur. J. Pharm. Sci., 26:54-61, 2005). MATERIALS AND METHODS: Two model functions were used to ensure the gradual change of the BE limits from a starting value towards a predefined plateau value. Plots of the new BE limits and extreme GMR values ensuring BE as a function of the coefficient of variation (CV) were constructed. Two-period crossover BE studies with 12, 24, or 36 subjects were simulated assuming CV values from 10 to 60%. Power curves were constructed by recording the percentage of accepted BE studies as the true GMR was raised from 1.00 to 1.50. The percentage of the true GMR within the simulated BE limits vs. true GMR was used to evaluate the estimation accuracy of the scaled methods. RESULTS: Depending on the parameters' values of the model functions, the scaled BE limits exhibit different performance. Four new scaled BE limits, showing favourable performance for the evaluation of average BE are presented. At low variability levels two of the novel BE limits show similar performance to the 0.80-1.25 criterion, while the other two (as expected from their design) appear to be less permissive. At high CV values (30, 40%) all new BE limits exhibit much higher statistical power than the 0.80-1.25 criterion. They show almost identical behavior with the expanded 0.75-1.33 limits and appear to be less permissive than BELscW. Finally, the percentage of the true GMR within the simulated BE limits vs. true GMR shows a sharp decline. Due to the absence of the GMR factor in the model functions a more accurate estimation of the new scaled BE limits, compared to BELscW, is observed. CONCLUSIONS: The new scaled BE limits appear to be highly effective at all levels of variation investigated and present satisfactory estimation accuracy.

Canine versus in vitro data for predicting input profiles of L-sulpiride after oral administration.

The objective of this study was to assess the relative usefulness of canine versus in vitro data sets in the prediction of absorption of L-sulpiride (a low permeability compound) from an immediate and an extended release formulation. To reduce species differences on upper gastrointestinal residence times, human and canine data were collected in the fed state. In vitro permeability data (that were additionally confirmed by rat perfusion data) were obtained from the literature. In vitro release data were obtained in media simulating the gastric composition (without and with simultaneous protein digestion) and intestinal composition in the fed state. The results showed that, regardless of the formulation, canine input profiles were vastly different from human profiles at times longer than 2h after administration and led to 2.7 times higher total amount absorbed in dogs. In contrast, reliable in vitro permeability data in combination with in vitro release data collected in biorelevant media led to successful prediction of the human input profile; regardless of the dosage form, simulated and actual mean input profiles differed by less than 20%.