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Given that appropriate long-term iron chelation is essential in the treatment of transfusion-dependent anaemias,14,15 deferiprone b.i.d. has the potential to improve treatment adherence and health outcomes in patients with transfusional iron overload. Twenty-seven patients had a primary diagnosis of thalassaemia major, one patient had -thalassaemia/haemoglobin H disease and one patient had sickle -thalassaemia. Fourteen patients reported mild AEs, 13 patients reported moderate AEs and one patient reported a severe AE. Lifelong iron chelation therapy is critical for patients with transfusion-dependent anaemias, and full adherence to therapy is essential to optimise long-term patient outcomes.1,2 Deferiprone is an oral iron chelator with high efficiency in binding and removing excess intracellular and extracellular iron.3,4 Owing to its elimination half-life of approximately 2 h, deferiprone is administered three times daily (t.i.d.) to promote longer extent of exposure and better control of labile iron.5-7 Clinical trial data show adherence rates with deferiprone t.i.d. from 79% to 98%8,9; however, real-world adherence is generally lower than in clinical trials, as the t.i.d. regimen may be inconvenient and the midday dose may often be missed.10-12 The United States Food and Drug Administration recently approved a twice-a-day modified-release formulation of deferiprone (Ferriprox TAD 1000 mg tablet; manufactured by Apotex Inc., Toronto, Ontario, Canada) for the treatment of patients with transfusional iron overload due to thalassaemia syndromes, sickle cell disease or other anaemias.13 In single-dose and multiple-dose pharmacokinetic studies of deferiprone in healthy volunteers (Tables S1 and S2), we found that the twice-daily (b.i.d.) formulation had equivalent 24-h drug exposure to the original immediate-release tablet administered t.i.d. (Figure S1), and exposure was not affected by administration with food (Table S3). [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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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 (C max ) 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 C max 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., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To show the clinical development of Ornibel ® (ExeltisHealthcare, Spain) a contraceptive vaginal ring manufactured with a new polymer composition and containing etonogestrel/ethinylestradiol, compared to Nuvaring ® (MSD, Spain)., Subjects and Methods: Randomised, single dose, 2-period, 2-sequence, 2-stage crossover, comparative bioavailability study conducted in 40 healthy female subjects. All subjects received both treatments for 28 days in each of two periods, separated by a 28 days washout. Ornibel ® contains etonogestrel/ethinylestradiol 11.00/3.47 mg and Nuvaring ® contains etonogestrel/ethinylestradiol 11.7/2.7 mg, both rings delivering 120/15 µg/day. For the calculation of pharmacokinetic parameters, 37 blood samples were collected up to 840 h after each ring insertion to quantify plasma concentrations of etonogestrel and ethinylestradiol using a validated MS/MS-HPLC. Safety was assessed by adverse events recording, clinical laboratory and vital signs and tolerability by vaginal examination. Acceptability was investigated by a 5-point scale questionnaire., Results: Bioequivalence was demonstrated in the first stage as the 94.12% Confidence Intervals of the primary parameters laid within the 80-125% acceptance range for both etonogestrel (C max : 96.81-112.20%; AUC 0-504h : 98.71-108.61%; AUC 0-t : 100.14-109.10%) and ethinylestradiol. (C max : 105.91-120.62%; AUC 0-504h : 105.47-114.59%; AUC 0-t : 108.31-117.61%). During the first day of use a burst effect was observed with Nuvaring ® , with significantly higher level of ethinylestradiol (C max0-24h ratio: 78.34%, 94.12CI: 73.55-83.45%). Both products were well tolerated and accepted, without significant differences between them., Conclusion: Ornibel ® is bioequivalent to Nuvaring ® in terms of efficacy, safety, tolerability and acceptability. The new polymer composition provides Ornibel ® with more stability and gradual hormonal release during the first day of use, particularly for ethinylestradiol.

Objective: Combination therapy is frequently required in the management of epilepsy. The primary objective of this study was to investigate the pharmacokinetic interaction between eslicarbazepine acetate (ESL) 1200 mg once daily and topiramate (TPM) 200 mg once daily in healthy subjects., Methods: Multiple-dose, open-label, one-sequence study in two parallel groups of 16 healthy male volunteers. After an 8-day treatment with ESL (Group A) or TPM (Group B), ESL and TPM were co-administered for 19 days. A bioequivalence approach based on a within-subject comparison was used to investigate a potential drug-drug interaction. End/start of treatment geometric mean ratios (GMR, %) and 90% confidence intervals (90% CI) were calculated for maximum plasma concentration (C(max)) and area under the plasma concentration-time curve over the dosing interval at steady-state (AUC(ss)) of eslicarbazepine (ESL major active metabolite), R-licarbazepine (ESL minor active metabolite) and TPM at Day 8 and Day 27., Results: In Group A, eslicarbazepine GMR (90% CI) was 86.79% (81.06%; 92.94%) for C(max) and 92.70% (89.21%; 96.32%) for AUC(ss). In Group B, TPM GMR (90% CI) was 81.50% (77.48%; 85.89%) for C(max) and 81.81% (79.69%; 84.00%) for AUC(ss). The 90% CI of eslicarbazepine C(max) and AUC(ss) fell within the pre-specified bioequivalence range (80.00%; 125.00%), allowing it to be concluded that the extent of systemic exposure to eslicarbazepine was unaffected by the concomitant administration of TPM. The 90% CI for topiramate AUC(ss) was borderline in relation to the pre-specified bioequivalence range and topiramate C(max) fell outside the pre-specified bioequivalence range. Therefore, the extent of systemic exposure to TPM following co-administration with ESL was not formally bioequivalent to the extent of systemic exposure to TPM when TPM was administered alone. However, there was no difference between TPM elimination half-life following TPM co-administered with ESL and TPM administered alone (24.0 and 24.3 h, respectively). The bioavailability of R-licarbazepine was essentially bioequivalent. Two subjects discontinued due to adverse events. No clinical interaction appeared to be present in terms of adverse events when both drugs were given concomitantly., Conclusion: Concomitant administration of eslicarbazepine acetate 1200 mg once daily and topiramate 200 mg once daily showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required.