Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index.

Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Isavuconazonium Sulfate.

A Biopharmaceutics Classification System (BCS)-based biowaiver monograph is presented for isavuconazonium sulfate. A BCS-based biowaiver is a regulatory option to substitute appropriate in vitro data for in vivo bioequivalence studies. Isavuconazonium sulfate is the prodrug of isavuconazole, a broad-spectrum azole antifungal indicated for invasive fungal infections. While the prodrug can be classified as a BCS Class III drug with high solubility but low permeability, the parent drug can be classified as a BCS Class II drug with low solubility but high permeability. Interestingly, the in vivo behavior of both is additive and leads isavuconazonium sulfate to act like a BCS class I drug substance after oral administration. In this work, experimental solubility and dissolution data were evaluated and compared with available literature data to investigate whether it is feasible to approve immediate release solid oral dosage forms containing isavuconazonium sulfate according to official guidance from the FDA, EMA and/or ICH. The risks associated with waiving a prodrug according to the BCS-based biowaiver guidelines are reviewed and discussed, noting that current regulations are quite restrictive on this point. Further, results show high solubility but instability of isavuconazonium sulfate in aqueous media. Although experiments on the dissolution of the capsule contents confirmed 'very rapid' dissolution of the active pharmaceutical ingredient (API) isavuconazonium sulfate, its release from the commercial marketed capsule formulation Cresemba is limited by the choice of capsule shell material, providing an additional impediment to approval of generic versions via the BCS-Biowaiver approach.

Self-micellizing solid dispersion of tacrolimus: Physicochemical and pharmacokinetic characterization.

The present study was undertaken to develop a self-micellizing solid dispersion (SMSD) of tacrolimus (TAC) to improve the biopharmaceutical properties of TAC. An SMSD formulation of TAC (SMSD/TAC) and amorphous solid dispersion formulation of TAC (ASD/TAC) were prepared with Soluplus® , an amphiphilic copolymer, and hydroxypropyl cellulose, respectively. Physicochemical properties were characterized in terms of morphology, crystallinity, storage stability, interaction of TAC with Soluplus® , and micelle-forming potency; pharmacokinetic behavior was also evaluated in rats. Tacrolimus in both formulations was in an amorphous state. After storage at 40°C/75% relativity humidity for 4 weeks, there were no significant changes in the crystallinity of TAC between nonaged and aged SMSD/TAC, whereas slight recrystallization was observed in aged ASD/TAC. The results of circular dichroism (CD) and infrared spectroscopic analyses were indicative of the potent drug-polymer interaction in SMSD/TAC, possibly leading to the prevention of recrystallization. Compared with other TAC samples, SMSD/TAC exhibited significant improvement in the dissolution behavior of TAC through the immediate formation of fine micelles. After the oral administration of TAC samples (10 mg TAC/kg) to rats, there was marked enhancement in systemic exposure to TAC with both formulations; in particular, SMSD/TAC achieved an increase in bioavailability ca. 20-fold higher than crystalline TAC. The SMSD approach might provide an effective dosage form for TAC with enhanced physicochemical stability and oral absorption.

In Silico Modeling Approaches Coupled with In Vitro Characterization in Predicting In Vivo Performance of Drug Delivery System Formulations.

Optimization of the in vivo performance of dosage forms in humans is essential in developing not only conventional formulations but also drug delivery system (DDS) formulations. Although animal experiments are still useful for these formulations, in silico approaches have become increasingly important for DDS formulations with regard to species-specific differences in physiology that can affect the in vivo performance of dosage forms between animals and humans. Furthermore, it is also important to couple in vitro characterizations with in silico models to predict in vivo performance in humans precisely. In this review article, I summarized in vitro-in silico approaches to predicting the in vivo performance of oral DDS formulations (amorphous solid dispersions, lipid-based formulations, nanosized formulations, cyclodextrins-based formulations, sustained release products, enteric coat products, and orally disintegrating tablets) and parenteral DDS formulations (cyclodextrins-based formulations, liposomes, and inhaled formulations).

[Control and Prediction of Drug Absorption at Mucosal Tissues].

The mucosal drug delivery system (mDDS) is one of the promising approaches to control the pharmacokinetic behavior of drugs. In this approach, surface properties of drug nanoparticles are key determinants to provide particles with mucoadhesive and mucopenetrating properties for prolonged retention at mucosal tissue and rapid mucosal absorption, respectively. In this paper, we would like to discuss the preparation of mDDS formulations by flash nanoprecipitation using a four-inlet multi-inlet vortex mixer, in vitro and ex vivo evaluation of mucopenetrating and mucoadhesive properties of polymeric nanoparticles as well as the application of mDDS to the pharmacokinetic control of cyclosporine A after oral administration to rats. We also share our current research on in silico modeling and prediction of the pharmacokinetic behavior of drugs after intratracheal administration to rats.

Food effects on gastrointestinal physiology and drug absorption.

Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in the stomach and small intestine, GI transit of water and dosage forms, and microbiota. Additionally, case examples of food effects on GI physiology and subsequent changes in oral drug absorption are provided. Furthermore, the effects of food, especially fruit juices (e.g., grapefruit, orange, apple) and green tea, on transporter-mediated permeation and enzyme-catalyzed metabolism of drugs in intestinal epithelial cells are also summarized comprehensively.

Biowaiver Monograph for Immediate-Release Dosage Forms: Levamisole Hydrochloride.

This work describes the potential applicability of the BCS-based Biowaiver to oral solid dosage forms containing Levamisole hydrochloride, an anthelmintic drug on the WHO List of Essential Medicines. Solubility and permeability data of levamisole hydrochloride were searched in the literature and/or measured experimentally. Levamisole hydrochloride is a highly soluble drug, but there is no clear evidence of high permeability in humans, indicating that it should provisionally be assigned to BCS class III. The biowaiver procedure would thus be applicable for solid oral dosage forms containing levamisole hydrochloride as the only active ingredient. Due to the lack of data in the literature regarding excipient effects on the bioequivalence of products containing levamisole, it is currently recommended that the products comply with the ICH and WHO guidelines: the test formulation should have the same qualitative composition as the comparator, contain very similar quantities of those excipients, and be very rapidly dissolving at pH 1.2, 4.5, and 6.8. However, for certain well-studied excipients, there appears to be opportunity for additional regulatory relief in future versions of the ICH BCS Guidance M9, such as not requiring that the quantities of these common excipients in the test and comparator be the same.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Levocetirizine Dihydrochloride.

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product).

Dynamic Changes in Gastrointestinal Fluid Characteristics after Food Ingestion Are Important for Quantitatively Predicting the In Vivo Performance of Oral Solid Dosage Forms in Humans in the Fed State.

The aim of this study was to develop a simulation model to predict the in vivo performance of solid oral dosage forms in humans in the fed state. We focused on investigating the effect of dynamic changes in gastrointestinal (GI) fluid characteristics in the fed state on the in vivo performance of solid dosage forms. We used six solid dosage forms containing weak base drugs as model formulations, two with positive food effects in humans, two with negative food effects, and two which are not affected by food ingestion. These model drug formulations were used to perform biorelevant dissolution tests in the stomach and small intestine under both prandial states. The in vitro properties of the drug products obtained from these tests were then coupled with in silico models (fasted or fed) to predict food effects in humans. We successfully incorporated the dynamic changes in GI fluid characteristics and their effects on the in vivo dissolution of drugs into the prediction model for the fed state. This newly designed physiologically based biopharmaceutics modeling approach provided the precise and quantitative prediction of food effects (i.e., changes in Cmax and AUC after food ingestion) in humans while considering the dynamic changes in fluid characteristics in the fed state.

Quantitative assessment of disintegration rate is important for predicting the oral absorption of solid dosage forms containing poorly soluble weak base drugs.

This study aimed to develop a novel in silico modeling and simulation that considers the disintegration rate in the stomach to predict the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs. Oxatomide and manidipine hydrochloride were used as model drugs. First, the in vitro disintegration rate and dissolution rate were determined in biorelevant media that simulate the gastrointestinal fluids in fasted humans using a USP apparatus II paddle dissolution tester. Next, the oral absorption of the dosage forms was predicted using the novel simulation model coupled with not only the dissolution rate but also the estimated disintegration rate. As the in vitro disintegration time was 45 min or longer for both drugs in Fasted State Simulated Gastric Fluid, the disintegration rate of these dosage forms was considered slow as immediate release (IR) tablets. While the predicted and observed pharmacokinetic profiles of both drugs were comparable using the new model, the conventional model, which did not consider the disintegration step, underestimated the oral absorption of both drugs. Thus, our novel simulation model coupled with the disintegration rate estimated from in vitro tests is promising for predicting the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs.

Importance of Gastric Secretion and the Rapid Gastric Emptying of Ingested Water along the Lesser Curvature ("Magenstraße") in Predicting the In Vivo Performance of Liquid Oral Dosage Forms in the Fed State Using a Modeling and Simulation.

The objective of the present study was to develop an in silico model of the stomach for predicting oral drug absorption in fed humans. We focused on a model capable of simulating dynamic fluid volume changes and included a simulated Magenstraße "stomach road," a route along the lesser curvature that often carries fluids rapidly to assess the gastric emptying of drugs. Two types of model liquid drug formulations, liquid-filled soft gelatin capsules (enzalutamide, cyclosporine, and nifedipine) and oral solutions (levofloxacin and fenfluramine), were used. An in silico model was assembled, and simulations were performed using Stella Professional software. The secretion rate of the gastric juice induced by food ingestion was assessed along with the gastric emptying of the ingested water via the Magenstraße in the fed state. The model for the fed state successfully described the in vivo performance of the model drug formulations. These results clearly indicate the importance of including gastric secretion and the kinetics of Magenstraße when predicting the in vivo performance of dosage forms using an in silico modeling and simulation of fed humans. This simulation model should be further optimized to allow for the different physiological mechanisms following the ingestion of different types of meals, as well as modifications for interindividual and intraindividual variabilities in gastrointestinal physiology in the fed state in the future.

Towards Virtual Bioequivalence Studies for Oral Dosage Forms Containing Poorly Water-Soluble Drugs: A Physiologically Based Biopharmaceutics Modeling (PBBM) Approach.

The objective of the present study was to develop a physiologically based biopharmaceutics (PBBM) approach to predict the bioequivalence of dosage forms containing poorly soluble drugs. Aripiprazole and enzalutamide were used as model drugs. Variations in the gastrointestinal (GI) physiological parameters of fasted humans were taken into consideration in in vitro biorelevant dissolution testing and in an in silico PBBM simulations. To estimate bioequivalence between dosage forms, the inter-individual variabilities in their performance in virtual human subjects were predicted from the in vitro studies and variability in e.g. gastric emptying and fluid volume in the stomach was also taken into account. Formulations with different in vitro dissolution performance, a solution and a tablet formulation, were used in order to evaluate the accuracy of bioequivalence prediction using the PBBM approach. The bioequivalence parameters, i.e. geometric mean ratio and 90% confidence interval, for both drugs were predicted well in the virtual studies. In order to achieve even more precise predictions, it will be important to continue characterizing GI physiological parameters, along with their variabilities, on both an inter-subject and inter-occasion basis.

Gummi Formulations Comprising Amenamevir Solid Dispersions with Polyvinyl Alcohol.

The aim of the present study was to determine whether solid dispersions (SDs) are applicable to gummi formulations. Amenamevir was selected as a model of a poorly water-soluble drug, and polyvinyl alcohols (PVAs) with various degrees of hydrolysis (PVA 66, PVA 80, PVA 88, and PVA 66/88) were used as SD carriers. Design of experiments (DOE) was used to develop a gummi formulation that was suitable for an amenamevir SD using SD with PVA 66. Dissolution studies and clinical sensory tests on 11 formulations calculated by DOE revealed that a gummi formulation comprising 10.5% gelatin and 22.8% water was suitable for SD of the drug. Gummi formulations comprising amenamevir SDs with various PVAs were prepared using the determined gummi formulation, and their ability to dissolve amenamevir, their stability, and their oral absorption in dogs were evaluated. The results suggested that PVA 66, PVA 66/88, and PVA 80 were appropriate in terms of dissolution, stability, and in vivo absorption, respectively. Considering these results comprehensively, it was concluded that PVA 80, which enabled the highest degree of absorption, was the most suitable SD carrier for gummi formulations. Thus, it was possible to apply a PVA SD of amenamevir to gummi formulations.

Exploring clinically relevant dissolution specifications for oral solid dosage forms of weak acid drugs using an in silico modeling and simulation approach.

The aim of this study was to explore clinically relevant dissolution specifications for weak acid drugs using an in silico drug absorption model. Loxoprofen sodium and ibuprofen were used as model drugs in this study. An in silico drug absorption model was developed using Stella Professional software and the prediction model accurately represented the plasma concentration profiles of the model drugs following oral administration. Theoretical pharmacokinetic profiles and parameters of the model drugs were predicted using various dissolution rate values in gastrointestinal fluid. This in silico modeling and simulation approach suggests that it is possible to estimate the minimum required dissolution rate for bioequivalence, an example of a clinically relevant dissolution specification. Furthermore, an in vitro dissolution test was conducted for selected drug products of each model drug using paddle apparatus and the results were compared with the clinically relevant dissolution specifications predicted using the in silico simulation.

The Bioequivalence of Two Peficitinib Formulations, and the Effect of Food on the Pharmacokinetics of Peficitinib: Two-Way Crossover Studies of a Single Dose of 150 mg Peficitinib in Healthy Volunteers.

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for Cmax and AUCt of peficitinib were within predefined limits of 0.8 to 1.25). The AUClast and the Cmax of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation.

Scintigraphic evaluation of the in vivo performance of dry-coated delayed-release tablets in humans.

We characterized the gastrointestinal (GI) transit and drug release characteristics of dry-coated delayed-release tablets under both prandial states in humans using a gamma scintigraphy approach. We also estimated the onset time of drug release from the dry-coated tablets after dissolution of the outer layer in a clinical study, and compared findings with those of in vitro release testing. The dry-coated tablets used in this study were composed of a core containing radiolabeled resin (111-Indium) and a gel forming outer layer made of polyethylene oxide and polyethylene glycol. The dry-coated tablets were administered to human subjects in the fasted and fed state (30 min after ingestion of a standard breakfast radiolabeled with 99m-Technetium). Gastric emptying time, small intestinal transit time, and onset of radioactivity release in the GI tract were estimated from scintigraphic imaging. Release characteristics of the radiolabel from the dry-coated tablets were also assessed in in vitro dissolution testing using a USP apparatus 2 (paddle). Ingestion of food affected the gastric emptying time of the dry-coated tablets but not small intestinal transit. Onset timing of the release of radioactivity from the core of two different formulas of dry-coated tablets was characterized. The onset timing of drug release in the fasted subjects was markedly similar to that in the in vitro dissolution testing at a paddle rate of 200 rpm.

A physiologically-based drug absorption modeling for orally disintegrating tablets.

The aim of this research was to simulate oral pharmacokinetic (PK) profiles of atorvastatin from orally disintegrating tablets (ODTs) dosed without water ingestion in fasted humans. The in vitro dissolution profiles of three different formulations of ODTs were evaluated with fasted state biorelevant media using a paddle dissolution apparatus, and the results were coupled with an in silico model to simulate the in vivo oral PK profiles of ODTs following administration to humans. Since the dissolution rates of the ODTs in the intestinal medium (FaSSIF-V2) were highly affected by pre-exposure of the tablets to the stomach medium (FaSSGF), the simulation model took account of the relationship between the gastric emptying time and the dissolution performance of the tablets in the small intestine. The ODTs were formulated with drug-containing pellets. After oral dosing of the ODTs without water ingestion, gastric emptying of the pellets was assumed to follow first order kinetics. Thus, rate constants ranging between 0.69 and 8.3 h-1 were applied in the PK simulations. The simulation model was built using Stella Professional® software. The results of the PK simulations suggest that the plasma concentration profiles of the ODTs can be described using the prediction model, but that different gastric emptying parameters for each ODT formulation are needed in humans.

Characterization of the buccal and gastric transit of orally disintegrating tablets in humans using gamma scintigraphy.

The present study characterized the buccal cavity-emptying and gastric-emptying kinetics of orally disintegrating tablets (ODTs) in fasted humans using gamma scintigraphy. 111Indium-diethylenetriaminepentaacetic acid and technetium-99 m-labeled ion exchange resin were used as a model soluble drug and insoluble pellet-type drug, respectively, and housed in ODTs. These ODTs were then administered to human subjects with or without ingestion of water, after which scintigraphic images were collected in order to characterize the buccal and gastric transit of the radioactivity. The oral disintegration of the ODTs was extremely rapid, with a mean time of ≤1 min. The buccal emptying of the radioactivity was most rapid for the ODT with a water-soluble radiolabel; however, the ODTs with water-insoluble radiolabels showed buccal emptying with median half-times of ≤2.5 min. The ODT with the soluble radiolabel in subjects without water ingestion showed the most rapid gastric emptying compared with the ODTs with the insoluble radiolabels, the gastric-emptying time of which was highly variable. Further, water ingestion did not markedly affect the gastric-emptying time of the tablets with the water-soluble model drug. The observations in the present clinical study will help clarify the in vivo performance of ODTs in humans.