Development of immediate-release formulation with reliable absorption of rivaroxaban in various meal regimes.

The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.

Crushing tablets or sprinkling capsules: Implications for clinical strategy and study performance based on BE studies of rivaroxaban and deferasirox.

Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two-way crossover design and were conducted after a single-dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36-110.37% and 97.98-108.45% for rivaroxaban, respectively, and 96.69-107.29% and 94.19-109.45% for deferasirox, respectively. Thus, the BE criteria (80.00-125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic.

Dasatinib anhydrate containing oral formulation improves variability and bioavailability in humans.

Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.

The bioequivalence of fixed-dose combination tablets of bisoprolol and ramipril and its drug-drug interaction potential.

Chronic antihypertensive treatment often includes combination of two or more therapies with complementary mechanism of action targeting different blood pressure (BP) control system. If available, these components are recommended to be administered as a fixed-dose combination (FDC) to reduce tablet burden, improve adherence and thus BP control. A combination of ramipril (RAMI) and bisoprolol (BISO) is one of the options used in clinical practice and is supported by therapeutic guidelines. The clinical program for a novel BISO/RAMI FDC consisted of two randomized, open-label, bioequivalence (BE) studies and one drug-drug interaction (DDI) study. The BE was examined between two FDC strengths of BISO/RAMI (10/10 and 10/5 mg) and the individual reference products administered concomitantly at respective doses after a single oral dose under fasting conditions. In both BE studies, 64 healthy subjects were randomized according to a two-way crossover design. The DDI study evaluated a potential pharmacokinetic (PK) interaction between BISO 10 mg and RAMI 10 mg following their single or concomitant administrations in 30 healthy subjects under fasting condition. BE for BISO/RAMI 10/5 mg and absence of a clinically relevant PK DDI between BISO and RAMI was demonstrated as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) for area under the concentration time curve (AUC) and maximum concentration (Cmax ) remained within the acceptance range of 80.00 to 125.00%. However, BE for BISO/RAMI 10/10 mg was not demonstrated, as the lower bound of the 90% CI of Cmax for RAMI was outside the acceptance range of BE. Both drugs administered alone or combined were well-tolerated. No PK interaction was observed between BISO and RAMI/ramiprilat, since the co-administration of BISO and RAMI 10 mg single doses resulted in comparable rate and extent of absorption for BISO and RAMI when compared to their individual products.

Single-dose, 2-way crossover, bioequivalence study of two rosuvastatin formulations in normal healthy subjects under fasting conditions.

BACKGROUND: Rosuvastatin, a synthetic lipid-lowering agent acts selectively by competitive inhibition of 3-hydroxy- 3-methylglutaryl-coenzyme A. It is indicated as an adjunct to diet in patients with hypercholesterolemia and mixed dyslipidemia. OBJECTIVE: The purpose of this study was to demonstrate bioequivalence between a generic rosuvastatin 40 mg tablet (Zentiva, Prague, Czech Republic) and a reference product (Crestor, AstraZeneca, Luton, UK), under fasting conditions as required by the European Medicinal Agency. METHODS: A single-oral 40 mg-dose, randomized, open-label, 2-way crossover design study was conducted in 42 healthy volunteers under fasting conditions. Rosuvastatin was administered following an overnight-fast in two occasions with a 14-day washout period in-between. Blood samples were collected in EDTA-K2 tubes prior to dosing and over a 96-hour period. Rosuvastatin was measured in plasma using an automated LC-MS/MS assay (range 81.02 - 40,512.00 pg/ml). Pharmacokinetics were performed using non-compartmental analyses approach to evaluate AUC(last), AUC∞ and C(max). ANOVA was performed on the ln-transformed data and the 90% Confidence Interval (CI) was determined. Bioequivalence will be concluded if the 90% CI falls within 80.00 - 125.00% for AUC(last) and C(max). Safety and tolerability were also evaluated. RESULTS: 39 volunteers completed the study and were considered for the pharmacokinetic and statistical analyses. Descriptive safety data analyses were performed on all subjects. All pharmacokinetic parameters met the acceptance criteria as the 90% CI were within 80.00 - 125.00%. Both formulations were well tolerated and no serious adverse events were reported. CONCLUSION: This study showed that the test and reference products met the regulatory criteria for bioequivalence following a 40 mg oral dose under fasting conditions.