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.
- MeSH
- Administration, Oral MeSH
- Biological Availability * MeSH
- Adult MeSH
- Factor Xa Inhibitors pharmacokinetics administration & dosage MeSH
- Food-Drug Interactions * MeSH
- Meals MeSH
- Cross-Over Studies * MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Fasting * MeSH
- Drug Compounding methods MeSH
- Rivaroxaban * pharmacokinetics administration & dosage MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
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.
- MeSH
- Administration, Oral MeSH
- Deferasirox MeSH
- Drugs, Generic * MeSH
- Humans MeSH
- Rivaroxaban * MeSH
- Tablets MeSH
- Therapeutic Equivalency MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
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.
- MeSH
- Administration, Oral MeSH
- Biological Availability MeSH
- Dasatinib MeSH
- Cross-Over Studies MeSH
- Humans MeSH
- Omeprazole * pharmacokinetics MeSH
- Area Under Curve MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
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.
- MeSH
- Antihypertensive Agents administration & dosage MeSH
- Bisoprolol administration & dosage MeSH
- Adult MeSH
- Drug Therapy, Combination * MeSH
- Drug Interactions * MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Ramipril administration & dosage MeSH
- Therapeutic Equivalency * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
Losartan je nejdéle používaným blokátorem receptorů pro angiotenzin II v klinické praxi [1]. V léčbě hypertenzní choroby patří mezi léky první linie a v současné době je dostatek dat o jeho použití v léčbě hypertenzní choroby včetně některých specifických situací (hypertrofie levé komory, prevence mozkových příhod) anebo v případech, kdy je hypertenzní choroba spojena s dalším onemocněním (diabetická nefropatie) [2]. Primárním cílem neintervenčního, multicentrického, prospektivního, observačního, otevřeného klinického hodnocení NCT-CZ 14/04/LOZ bylo ověřit na rozsáhlém souboru pacientů bezpečnost Lozapu® a Lozapu H® v běžné klinické praxi. Materiál a metodika: Do půlročního klinického sledování byli zařazeni pacienti s nově zjištěnou hypertenzí anebo s nedostatečně kontrolovanou hypertenzí [krevní tlak . 140/90 mm Hg: 4 432 pacientů (96 %); krevní tlak . 139/89 mm Hg: 84 pacientů (2 %); hodnota nezadána: 83 pacientů (2 %)]. Pro získání dat byl použit standardní formulář. Celkem bylo hodnoceno 4 599 pacientů (2 386 žen; 51,9 %), průměrného věku 61 +/- 12 let (18-95 let; medián 60 let) s dalšími rizikovými faktory (kardiovaskulární onemocnění v 48%, diabetes mellitus v 33 %, porucha lipidového metabolizmu v 42 %, obezita v 45 %, kuřáctví v 26 %). Dříve zjištěnou hypertenzi mělo 2 631 (57 %) pacientů. Průměrná hodnota krevního tlaku (TK) při vstupu do sledování byla 159/95 mm Hg (medián 160/95 mm Hg) a průměrná tepová frekvence byla 76 tepů/min (medián 76). Výsledky: Nejčastěji použitou dávkou bylo 50 mg losartanu (Lozap® nebo Lozap H®) - u 4 006 (87 %) pacientů při vstupu do studie a u 3 982 (87 %) pacientů na konci studie. Nežádoucí účinky v souvislosti s léčbou se během sledování vyskytly u celkem 9 pacientů (0,2 %). Terapie byla hodnocena jako dobře snášená 96 % pacientů (4 409), jako přijatelně snášená 3 % pacientů (131) a jako špatně snášená 0,1 % pacientů (4). Krevní tlak se snížil o 23 mm Hg v systole a o 14 mm Hg v diastole na průměrnou hodnotu 136/81 mm Hg (medián 135/80 mm Hg) (P < 0,001 pro systolický i diastolický TK). Lékaři hodnotili stav pacienta jako zlepšený v 93 % případů (4 254 pacientů) a jako nezměněný v 6 % případů (294 pacientů). Závěr: Losartan ve formě přípravku Lozap?, resp. Lo-zap H® představuje bezpečnou a účinnou léčbu pacientů s hypertenzní chorobou. Je účinný a bezpečný již v dávce 50 mg a jeho kombinace s diuretikem představuje vhodnou a bezpečnou léčbu u pacientů, kteří nejeví dostatečnou tlakovou odpověď na 50 mg losartanu. V případě nedostatečné tlakové odpovědi je nutné titrovat dávku na 100 mg.
Losartan is the longest used angiotensin II receptor blocker in clinical practice. It is one of the first-line drugs for the treatment of hypertensive disease and there is enough data available today about its use in the treatment of the disease, including some specific situations (left ventricular hypertrophy, cerebrovascular accidents) and cases when the hypertension disease combines with another disease (e.g. diabetic nephropathy). The primary objective of the non-intervention multicentre prospective observational open clinical assessment NCT-CZ 14/04/LOZ was to verify on a large sample of patients the safety of Lozap and Lozap H in current clinical practice. MATERIAL AND METHOD: The six-month clinical study enrolled patients with recently diagnosed hypertension and/or poorly controlled hypertension [blood pressure > or = 140/90 mm Hg: 4432 patients (96%); blood pressure: < or = 139/89 mm Hg 84 patients (2%); value unspecified: 83 patients (2%)]. A standard form was used for data acquisition. A total of 4,599 patients was enrolled (of which 2,386 women, i.e. 51.9%) with mean age 61 +/- 12 years (18-95 years; median 60 years) with additional risk factors (cardiovascular diseases in 48%, diabetes mellitus in 33%, lipid metabolism disorder in 42%, obesity in 45% and smoking in 26% of cases, respectively). 2,631 patients (57%) had previously diagnosed hypertension. The average blood pressure (BP) at enrolment in the study was 159/95mm Hg (median 160/95 mm Hg), and the average heart rate was 76 strokes/min (median 76). RESULTS: The most frequently used dose was 50 mg of losartan (Lozap or Lozap H)--in 4,006 patients (87%) at enrolment in the study and in 3,982 patients (87%) at the end of the study. Adverse effects related to the treatment during the study were reported in a total of 9 patients (0.2%). The therapy was assessed as well tolerated in 96% of patients (4,409), as fairly tolerated in 3% of patients (131) and as poorly tolerated in 0.1% of patients (4). Systolic and diastolic blood pressure decreased by 23mm Hg and 14mm Hg respectively to a mean value of 136/81 mm Hg (median 135/80mm Hg) (P < 0.001 for both systolic and diastolic BP). Improvement in patient status was recorded in 93% of cases (4,254 patients) and no change was recorded in 6% of cases (294 patients). CONCLUSION: Losartan in the form of Lozap or Lozap is a safe and effective treatment of patients with hypertensive disease. It is effective and safe beginning with the dose of 50 mg and its combination with a diuretic represents a good and safe therapy in patients with insufficient BP response to a 50 mg dose of losartan alone. In case of poor blood pressure response the dose has to be titrated to 100 mg.
- MeSH
- Antihypertensive Agents adverse effects therapeutic use MeSH
- Angiotensin II Type 1 Receptor Blockers adverse effects therapeutic use MeSH
- Adult MeSH
- Hypertension drug therapy physiopathology MeSH
- Blood Pressure radiation effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Losartan adverse effects therapeutic use MeSH
- Adolescent MeSH
- Young Adult MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
