Contribution of the Dynamic Intestinal Absorption Model (Diamod) to the Development of a Patient-Centric Drug Formulation.

Compound X is a weak basic drug targeting the early stages of Parkinson's disease, for which a theoretical risk assessment has indicated that elevated gastric pH conditions could potentially result in reduced plasma concentrations. Different in vitro dissolution methodologies varying in level of complexity and a physiologically based pharmacokinetic (PBPK) absorption model demonstrated that the dissolution, solubility, and intestinal absorption of compound X was indeed reduced under elevated gastric pH conditions. These observations were confirmed in a crossover pharmacokinetic study in Beagle dogs. As a result, the development of a formulation resulting in robust performance that is not sensitive to the exposed gastric pH levels is of crucial importance. The dynamic intestinal absorption MODel (Diamod), an advanced in vitro gastrointestinal transfer tool that allows to study the gastrointestinal dissolution and interconnected permeation of drugs, was selected as an in vitro tool for the formulation optimization activities given its promising predictive capacity and its capability to generate insights into the mechanisms driving formulation performance. Different pH-modifiers were screened for their potential to mitigate the pH-effect by decreasing the microenvironmental pH at the dissolution surface. Finally, an optimized formulation containing a clinically relevant dose of the drug and a functional amount of the selected pH-modifier was evaluated for its performance in the Diamod. This monolayer tablet formulation resulted in rapid gastric dissolution and supersaturation, inducing adequate intestinal supersaturation and permeation of compound X, irrespective of the gastric acidity level in the stomach. In conclusion, this study describes the holistic biopharmaceutics approach driving the development of a patient-centric formulation of compound X.

Biorelevant in vitro Tools and in silico Modeling to Assess pH-Dependent Drug-drug Interactions for Salts of Weak Acids: Case Example Potassium Raltegravir.

BACKGROUND: Early assessment of pH-dependent drug-drug-interactions (DDIs) for salts of poorly soluble weakly acidic compounds offers various advantages for patient safety, the pharmaceutical industry, and regulatory bodies. Biorelevant media and tests reflecting physiological changes during acid-reducing agent (ARA) co-administration can be used to explore and predict the extent of the pH effect during therapy with ARAs. METHODS: Solubility, one-stage and two-stage dissolution of tablets containing potassium raltegravir, the marketed salt form of this poorly soluble, weakly acidic drug, was investigated using biorelevant media specially designed to reflect administration without and during ARA co-therapy. The dissolution data were then converted into parameters suitable for input into an in silico model (Simcyp™) and the simulated plasma profiles were compared with available pharmacokinetic (PK) data from the literature. RESULTS: Dissolution of the potassium raltegravir formulation in media reflecting ARA co-administration, and thus elevated gastric pH, was faster and more complete than in experiments reflecting the low gastric pH observed in the absence of ARA co-administration. Simulations using data from dissolution experiments with ARA media appropriately bracketed the in vivo data for ARA co-administration in healthy volunteers. CONCLUSION: Dissolution data from in vitro experiments in biorelevant media reflecting physiological changes due to ARA co-administration provide valuable information about potassium raltegravir's behavior during concomitant ARA therapy. The approach may also be suitable for salts forms of other poorly soluble, weakly acidic drugs.

Evaluating the impact of acid-reducing agents on drug absorption using biorelevant in vitro tools and PBPK modeling - case example dipyridamole.

BACKGROUND: In vitro and in silico methods have become an essential tool in assessing metabolic drug-drug interactions (DDI) and avoiding reduced efficacy and increased side-effects. Another important type of DDI is the impact of acid-reducing agent (ARA) co-therapy on drug pharmacokinetics due to changes in gastric pH, especially for poorly soluble weakly basic drugs. METHODS: One-stage, two-stage and transfer dissolution experiments with dipyridamole tablets using novel biorelevant media representing the ARA effect were conducted and the results were coupled with a PBPK model. Clinical pharmacokinetic data were compared with the simulations from the PBPK model and with output from TIM-1 experiments, an evolved in vitro system which aims to simulate the physiology in the upper GI tract. RESULTS: Two-stage and transfer experiments confirmed that these in vitro set-ups tend to overestimate the extent of dipyridamole precipitation occurring in the intestines in vivo. Consequently, data from one-stage dissolution testing under elevated gastric pH conditions were used as an input for PBPK modeling of the ARA/dipyridamole interaction. Using media representing the ARA effect in conjunction with the PBPK model, the ARA effect observed in vivo was successfully bracketed. As an alternative, the TIM-1 system with gastric pH values adjusted to simulate ARA pre-treatment can be used to forecast the ARA effect on dipyridamole pharmacokinetics. CONCLUSION: Drug-drug interactions of dipyridamole with ARA were simulated well with a combination of dissolution experiments using biorelevant media representing the gastric environment after an ARA treatment together with the PBPK model. Adjustment of the TIM-1 model to reflect ARA-related changes in gastric pH was also successful in forecasting the interaction. Further testing of both approaches for predicting ARA-related DDIs using a wider range of drugs should be conducted to verify their utility for this purpose.

Prediction of plasma profiles of a weakly basic drug after administration of omeprazole using PBPK modeling.

BACKGROUND: Oral medicines must release the drug appropriately in the GI tract in order to assure adequate and reproducible absorption. Disease states and co-administration of drugs may alter GI physiology and therefore the release profile of the drug. Acid-reducing agents (ARAs), especially proton pump inhibitors (PPIs), are frequently co-administered during various therapies. As orally administered drugs are frequently poorly soluble weak bases, PPI co-administration raises the risk of pH-induced drug-drug interactions (DDIs) and the potential for changes in the therapeutic outcome. METHODS: This research compared the dissolution data of a poorly soluble weakly basic drug ("PSWB 001") from capsules in standard fasted state biorelevant media (FaSSGF, FaSSIF V1 and FaSSIF V2), water and recently devised media representing gastric conditions under various levels of PPI co-administration. An in silico simulation model, based on Simcyp software, was developed to compare simulated plasma profiles with clinical data. RESULTS: PSWB 001 capsules showed rapid and complete dissolution in acidic conditions representing gastric fluids, whereas limited dissolution was observed in deionized water, media representing PPI co-administration and in two biorelevant media representing fluids in the upper small intestine. Buffer capacity and the presence of native surfactants were shown to be important factors in the in vitro dissolution of PSWB 001. The data from in vitro experiments were used in conjunction with the in silico simulation model, which correctly predicted the plasma profiles of PSWB 001 when administered without PPIs, as well as bracketing the PPI effect observed in vivo. CONCLUSIONS: Recently developed biorelevant media representing gastric conditions under PPI therapy, combined with PBPK modeling, were able to bracket the observed plasma profiles of PSWB 001. These media may also be useful for predicting PPI effects for other poorly soluble, weakly basic drugs.

Impact of Acid-Reducing Agents on Gastrointestinal Physiology and Design of Biorelevant Dissolution Tests to Reflect These Changes.

BACKGROUND: Of the various drug therapies that influence gastrointestinal (GI) physiology, one of the most important are the acid-reducing agents (ARAs). Because changes in GI physiology often influence the pharmacokinetics of drugs given orally, there is a need to identify in vitro methods with which such effects can be elucidated. OBJECTIVE: Literature concerning the effects of ARAs (antacids, H2-receptor antagonists, and proton pump inhibitors [PPIs]) on GI physiology are reviewed with the aim of identifying conditions under which drugs are released after oral administration in the fasted state. In vitro dissolution tests to mimic the effects in the stomach were designed for H2-receptor antagonists and PPIs. CONCLUSIONS: The impact of ARAs on GI physiology depends on the type, duration, and amount of ARA administered as well as the location in the GI tract, with greatest impact on gastric physiology. While ARAs have a high impact on the gastric fluid pH and composition, changes in volume, viscosity, surface tension, and gastric emptying appear to be less profound. The proposed dissolution tests enable a ready comparison between dosage form performance in healthy adults and those receiving PPIs or H2-receptor antagonists.

Antenatal characteristics of Roma female population in Virovitica-Podravina County, Croatia.

INTRODUCTION: This study reports about antenatal characteristics of Roma minority population. The study was designed to investigate data about health behaviours known to be associated with reproductive outcomes of Roma women that have very good living conditions and relatively high resource availability. METHODS: A retrospective study included 204 Roma and 408 non-Roma hospitalised singleton births that occurred in the Maternity Ward of the General Hospital Virovitica in the period from 1991 to 2010. Data about women's age, marital status, smoking, reproductive health (abortions, delivery), antenatal care, perinatal complications and gestational age were taken from hospital records and analysed. RESULTS: Roma women were averagely more than three years younger than non-Roma women, only 10.8% were married. Smoking was more frequent. The average number of births of Roma and non-Roma women was similar, averagely two children per woman. The rate of induced abortions in the Roma women was higher, while the frequency of spontaneous abortions was equal. Inadequate antenatal care of Roma women was associated with two times higher incidence of perinatal complications. A higher frequency of deliveries at home without professional assistance in Roma pregnancy resulted in lower perinatal outcomes. It was confirmed that Roma mothers give birth earlier (38+6 vs. 39+4 weeks) and have a higher incidence of premature births (9.3% vs. 2.2%). CONCLUSIONS: In the comparison of antenatal parameters between the two researched groups, poorer prenatal outcomes in the Roma population were found, despite full integration and considerable improvement in living standards of this ethnic Roma population.