Predictive Potential of Acido-Basic Properties, Solubility and Food on Bioequivalence Study Outcome: Analysis of 128 Studies.

BACKGROUND AND OBJECTIVES: Risk assessment related to bioequivalence study outcome is critical for effective planning from the early stage of drug product development. The objective of this research was to evaluate the associations between solubility and acido-basic parameters of an active pharmaceutical ingredient (API), study conditions and bioequivalence outcome. METHODS: We retrospectively analyzed 128 bioequivalence studies of immediate-release products with 26 different APIs. Bioequivalence study conditions and acido-basic/solubility characteristics of APIs were collected and their predictive potential on the study outcome was assessed using a set of univariate statistical analyses. RESULTS: There was no difference in bioequivalence rate between fasting and fed conditions. The highest proportion of non-bioequivalent studies was for weak acids (10/19 cases, 53%) and neutral APIs (23/95 cases, 24%). Lower non-bioequivalence occurrence was observed for weak bases (1/15 cases, 7%) and amphoteric APIs (0/16 cases, 0%). The median dose numbers at pH 1.2 and pH 3 were higher and the most basic acid dissociation constant (pKa) was lower in the non-bioequivalent group of studies. Additionally, APIs with low calculated effective permeability (cPeff) or low calculated lipophilicity (clogP) had lower non-bioequivalence occurrence. Results of the subgroup analysis of studies under fasting conditions were similar as for the whole dataset. CONCLUSION: Our results indicate that acido-basic properties of API should be considered in bioequivalence risk assessment and reveal which physico-chemical parameters are most relevant for the development of bioequivalence risk assessment tools for immediate-release products.

Predictive Potential of BCS and Pharmacokinetic Parameters on Study Outcome: Analysis of 198 In Vivo Bioequivalence Studies.

BACKGROUND AND OBJECTIVES: Understanding predictive potential of parameters to perform early bioequivalence (BE) risk assessment is crucial for good planning and risk mitigation during product development. The objective of the present study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE study. METHODS: Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia) sponsored BE studies [52 active pharmaceutical ingredients (API)] where characteristics of BE study and APIs were collected for immediate-release products and their predictive potential on the study outcome was assessed using univariate statistical analysis. RESULTS: Biopharmaceutics Classification System (BCS) was confirmed to be highly predictive of BE success. BE studies with poorly soluble APIs were riskier (23% non-BE) than with highly soluble APIs (0.1% non-BE). APIs with either lower bioavailability (BA), presence of first-pass metabolism, and/or being substrate for P-glycoprotein substrate (P-gP) were associated with higher non-BE occurrence. In silico permeability and time at peak plasma concentrations (Tmax) were shown as potentially relevant features for predicting BE outcome. In addition, our analysis showed significantly higher occurrence of non-BE results for poorly soluble APIs with disposition described by multicompartment model. The conclusions for poorly soluble APIs were the same on a subset of fasting BE studies; for a subset of fed studies there were no significant differences between factors in BE and non-BE groups. CONCLUSION: Understanding the association of parameters and BE outcome is important for further development of early BE risk assessment tools where focus should be first in finding additional parameters to differentiate BE risk within a group of poorly soluble APIs.

Evaluating the Impact of Physiological Properties of the Gastrointestinal Tract On Drug In Vivo Performance Using Physiologically Based Biopharmaceutics Modeling and Virtual Clinical Trials.

The physiological properties of the gastrointestinal tract, such as pH, fluid volume, bile salt concentration, and gastrointestinal transit time, are highly variable in vivo. These properties can affect the dissolution and absorption of a drug, depending on its properties and formulation. The effect of gastrointestinal physiology on the bioperformance of a drug was studied in silico for a delayed-release pantoprazole tablet and an immediate-release dolutegravir tablet. Physiologically based absorption models were developed and virtual clinical trials were performed. Reasons for the variability in drug bioperformance between subjects were investigated, taking into account differences in gastrointestinal tract characteristics, pharmacokinetic parameters, and additional parameters (e.g., permeability). Default software parameters describing gastrointestinal physiology in the fasted and fed states, and variation in these parameters, were altered to match variability in these parameters reported in vivo. The altered model physiologies better described the variability of gastrointestinal conditions, and therefore the results of virtual trials using these physiologies are likely to be more relevant in vivo. With such altered gastrointestinal physiologies used to develop models, it is possible to obtain additional knowledge and improve the understanding of subject-formulation interactions.

The biorelevant simulation of gastric emptying and its impact on model drug dissolution and absorption kinetics.

The highly variable physiological conditions within the gastrointestinal tract can cause variable drug release and absorption from the orally administrated dosage forms. The emptying of the gastric content is one of the most critical physiological processes, dictating the amount of the active ingredient available for absorption into the systemic circulation. In this study, we prepared two water gastric emptying regimes on advanced gastric simulator (AGS) with programmable "pyloric" valve. Gastric emptying regimes were designed in such a way to capture the main findings of the MRI (magnetic resonance imaging) in vivo studies, conducted under fasted conditions according to the EMA and FDA guidelines for bioavailability and bioequivalence studies. Four immediate release formulations containing a model drug of BCS class III were tested. Comparative dissolution tests were also performed with the USP2 apparatus. In vitro release profiles were compared to the in vivo data in order to evaluate the importance of gastric emptying for subsequent absorption of the active substance from the tested formulations. Our bio-relevant in vitro dissolution model showed good discriminatory power for all of the tested formulations. Moreover, a better relation to in vivo data was achieved with AGS with respect to the tested conventional dissolution method.

In vitro-In vivo Relationship and Bioequivalence Prediction for Modified-Release Capsules Based on a PBPK Absorption Model.

A physiologically based pharmacokinetic (PBPK) absorption model was developed in GastroPlus™ based on data on intravenous, immediate-release (IR), and modified-release (MR) drug products. The predictability of the model was evaluated by comparing predicted and observed plasma concentration profiles; average prediction errors (PE) were below 10%. IVIVR was developed using mechanistic deconvolution for a MR drug product to evaluate the in vivo effect of a proposed change in dissolution specification. The predictability of the IVIVR was evaluated and PE were below 10%; however, external validation was not possible due to the lack of data. The developed PBPK absorption model and IVIVR were used to predict plasma concentration profiles and pharmacokinetic (PK) parameters for a hypothetical formulation with 0% of drug dissolved in 2 h in in vitro dissolution test. Both methods predicted the insignificant effect of a change in in vitro dissolution profile on in vivo product performance. The bioequivalence of a hypothetical formulation to the test product was evaluated using virtual clinical trial. The performed analysis supported the proposed change in dissolution specification. A validated PBPK absorption model was proposed as an adequate alternative to IVIVC, when IVIVC could not have been developed according to the guidelines.

Neuro-fuzzy models as an IVIVR tool and their applicability in generic drug development.

The usefulness of neuro-fuzzy (NF) models as an alternative in vitro-in vivo relationship (IVIVR) tool and as a support to quality by design (QbD) in generic drug development is presented. For drugs with complicated pharmacokinetics, immediate release drugs or nasal sprays, suggested level A correlations are not capable to satisfactorily describe the IVIVR. NF systems were recognized as a reasonable method in comparison to the published approaches for development of IVIVR. Consequently, NF models were built to predict 144 pharmacokinetic (PK) parameter ratios required for demonstration of bioequivalence (BE) for 88 pivotal BE studies. Input parameters of models included dissolution data and their combinations in different media, presence of food, formulation strength, technology type, particle size, and spray pattern for nasal sprays. Ratios of PK parameters Cmax or AUC were used as output variables. The prediction performance of models resulted in the following values: 79% of models have acceptable external prediction error (PE) below 10%, 13% of models have inconclusive PE between 10 and 20%, and remaining 8% of models show inadequate PE above 20%. Average internal predictability (LE) is 0.3%, and average external predictability of all models results in 7.7%. In average, models have acceptable internal and external predictabilities with PE lower than 10% and are therefore useful for IVIVR needs during formulation development, as a support to QbD and for the prediction of BE study outcome.

A new amoxicillin/clavulanate therapeutic system: preparation, in vitro and pharmacokinetic evaluation.

A new peroral amoxicillin/clavulanate therapeutic system composed of immediate release tablet and controlled release floating capsule was developed and evaluated by in vivo bioavailability study. Pharmacokinetic (PK) parameters for amoxicillin and clavulanic acid of the new therapeutic systems: AUCt, AUCi, (AUCt/AUCi), Cmax, Tmax, kel, T(1/2) and additionally for amoxicillin T(4) and T(2) were calculated from the plasma levels. The study confirmed enhanced pharmacokinetic parameters of a newly developed therapeutic system containing 1500 mg of amoxicillin and 125 mg of clavulanic acid. Prolonged time over MIC of amoxicillin in relation to a regular immediate release amoxicillin/clavulanate formulation was confirmed.