Predicting the oral absorption of a poorly soluble, poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model.

For predicting food effects and simulating plasma profiles of poorly soluble drugs, physiologically based pharmacokinetic models have become a widely accepted tool in academia and the pharmaceutical industry. Up till now, however, simulations appearing in the open literature have mainly focused on BCS class II compounds, and many of these simulations tend to have more of a "retrospective" than a prognostic, predictive character. In this work, investigations on the absorption of a weakly basic BCS class IV drug, "Compound A", were performed.

Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir.

The aim of this study was to evaluate the utility of biorelevant dissolution tests coupled with in silico simulation technology to forecast in vivo bioperformance of poorly water-soluble bases, using nelfinavir mesylate as a model compound. An in silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (GI) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media.

Biowaiver monographs for immediate release solid oral dosage forms: lamivudine.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing lamivudine as the only active pharmaceutical ingredient were reviewed. The solubility and permeability data of lamivudine as well as its therapeutic index, its pharmacokinetic properties, data indicating excipient interactions, and reported BE/bioavailability (BA) studies were taken into consideration. Lamivudine is highly soluble, but its permeability characteristics are not well-defined.

Biorelevant in vitro dissolution testing of products containing micronized or nanosized fenofibrate with a view to predicting plasma profiles.

The ability of in vitro biorelevant dissolution tests to predict the in vivo performance of nanosized fenofibrate (Lipidil 145 ONE®) and microsized fenofibrate (Lipidil - Ter®) was evaluated in this study. In vitro dissolution was carried out using USP apparatus 2 (paddle method) with updated biorelevant media to simulate the pre- and postprandial states. Membrane filters with different pore sizes were evaluated for their ability to hold back undissolved, nanosized drug particles.

The biowaiver procedure: its application to antituberculosis products in the WHO prequalification programme.

In 2005, the World Health Organization (WHO) proposed that provided an active pharmaceutical ingredient could meet certain criteria, bioequivalence could be evaluated with a set of laboratory tests, obviating the need for expensive and time-consuming pharmacokinetic studies in humans. The aim of this work was to determine whether this so-called "biowaiver" procedure can be applied to antituberculosis products. Antituberculosis products from the WHO Prequalification Programme, including three ethambutol, two isoniazid and one pyrazinamide product, were investigated.

Biowaiver monographs for immediate release solid oral dosage forms: mefloquine hydrochloride.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing mefloquine hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. The solubility and permeability data of mefloquine hydrochloride as well as its therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability studies were taken into consideration. Mefloquine hydrochloride is not a highly soluble API.

Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans.

This study coupled results from biorelevant dissolution tests with in silico simulation technology to forecast in vivo oral absorption of micronized and nanosized aprepitant formulations in the pre- and post-prandial states. In vitro dissolution tests of the nanosized aprepitant formulation and micronized drug were performed in biorelevant and compendial media. An in silico physiologically based pharmacokinetic (PBPK) model was developed based on STELLA software using dissolution kinetics, standard gastrointestinal (GI) parameters and post-absorptive disposition parameters.

Analysis of nifedipine absorption from soft gelatin capsules using PBPK modeling and biorelevant dissolution testing.

Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data.

Biowaiver monographs for immediate release solid oral dosage forms: Doxycycline hyclate.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing doxycycline hyclate are reviewed. According to the Biopharmaceutics Classification System (BCS), doxycycline hyclate can be assigned to BCS Class I. No problems with BE of IR doxycycline formulations containing different excipients and produced by different manufacturing methods have been reported and hence the risk of bioinequivalence caused by these factors appears to be low.

Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption.

Objectives: Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated.

Methods: Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature.

Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form.

In vitro biorelevant dissolution tests enabling the prediction of in vivo performance of an oral modified-release (MR) dosage form were developed in this study. In vitro dissolution of MR diclofenac sodium pellets containing 100mg active ingredient was evaluated under simulated pre- and postprandial conditions using USP Apparatus 3 (reciprocating cylinder, Bio-Dis) and 4 (flow-through cell) and results compared with compendial methods using USP Apparatus 1 (basket) and 2 (paddle). In vivo, the effects of food on the absorption of diclofenac sodium from the pellet dosage form were investigated by administering the product to 16 healthy volunteers pre- and postprandially in a crossover-design study.

Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling.

Since the rate-determining step to the intestinal absorption of poorly soluble drugs is the dissolution in the gastrointestinal (GI) tract, postprandial changes in GI physiology, in addition to any specific interactions between drug and food, are expected to affect the pharmacokinetics and bioavailability of such drugs. In this study, in vitro dissolution testing using biorelevant media coupled with in silico physiologically based pharmacokinetic (PBPK) modeling was applied to the prediction of food effects on the absorption of a poorly soluble drug, celecoxib, from 200mg capsules. A PBPK model was developed based on STELLA software using dissolution kinetics, solubility, standard GI parameters and post-absorptive disposition parameters.

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products.

Objectives: The dissolution characteristics of immediate-release doxycycline hyclate products with certified in-vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver-based approval.

Methods: Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin-ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy-Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.

Towards quantitative prediction of oral drug absorption.

Although several routes of administration can be considered for new drug entities, the oral route remains the most popular. To predict the in vivo performance of a drug after oral administration from in vitro data, it is essential that the factors limiting absorption can be modelled. Factors limiting oral drug absorption are typically slow and/or incomplete dissolution, formation of insoluble complexes and/or decomposition in the gastrointestinal lumen, poor net permeability and first-pass metabolism.

Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update.

Purpose: The aim of this study was to update the compositions of biorelevant media to represent the composition and physical chemical characteristics of the gastrointestinal fluids as closely as possible while providing physical stability during dissolution runs and short-term storage.

Methods: Media were designed to reflect postprandial conditions in the stomach and proximal small intestine in the "early", "middle", and "late" phases of digestion. From these "snapshot" media, general media for simulating postprandial conditions were devised.

Designing biorelevant dissolution tests for lipid formulations: case example--lipid suspension of RZ-50.

Biorelevant dissolution test methods for lipid formulations of RZ-50, an experimental Roche compound, were developed and compared with standard compendial methods in terms of their in vivo predictability. Release of RZ-50, a poorly soluble weakly acidic drug, from lipid suspensions filled in soft gelatin capsules was studied in compendial and biorelevant media using the USP Apparatus 2 (paddle method) and the USP Apparatus 3 (Bio-Dis method). Pharmacokinetic data were obtained in dogs after oral administration of a single 2.

Convenient and rapid determination of cimetidine in human plasma using perchloric acid-mediated plasma protein precipitation and high-performance liquid chromatography.

This study demonstrates the analysis of cimetidine in human plasma with HPLC using a simplified sample preparation by protein precipitation with perchloric acid. Plasma cimetidine concentration was determined by plotting peak height ratio of cimetidine to ranitidine (internal standard, IS) against cimetidine concentrations in plasma. The cimetidine and ranitidine peaks were completely separated and no interference from plasma was observed.

Feasibility of biowaiver extension to biopharmaceutics classification system class III drug products: cimetidine.

Background: The extension of biowaivers (drug product approval without a pharmacokinetic bioequivalence study) to drugs belonging to Class III of the Biopharmaceutics Classification System (BCS) is currently a subject of much discussion.

Objectives: To assess the relationship between in vitro dissolution characteristics and in vivo absorption performance of immediate-release (IR) products containing cimetidine, a BCS Class III compound, in human subjects. To evaluate the feasibility and appropriateness of an extension of the biowaiver concept to BCS Class III compounds.

Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) problems were also taken into consideration.