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ACT-280778 is a novel nondihydropyridine dual L/T- type calcium channel blocker. Two clinical studies (AC-067-101 and AC-067-102) were conducted to characterize its safety, tolerability, and pharmacokinetics in healthy male subjects after oral adminis- tration of single and multiple doses. Both trials were single-center, randomized, double-blind, placebo-controlled, adaptive design, ascending-dose studies, in which ACT-280778 was administrated as single doses of 2, 5, 15, or 40 mg, or as once-daily doses of 5 or 15 mg for 7 days. Single and multiple doses up to and including 15 mg were well tolerated, and no serious or severe adverse event was reported in either study. A single dose of 40 mg was associated with abnormal electrocardiogram findings resulting in the discontinuation of further treatment at this dose or higher doses. ACT-280778 was rapidly absorbed, and larger than dose-proportional increases of the maximum plasma concentration and area under the plasma concentration-time curve were observed. Food intake delayed the time to maximum plasma concentration and doubled exposure. Urinary excretion of unchanged ACT-280778 was negligible, and accumulation at steady state was modest. Overall, pharmacokinetic and tolerability profiles of ACT-280778 observed in these 2 studies warranted further evalu- ation of ACT-280778 in a proof-of-concept study in patients with hypertension.

Background Epoprostenol sodium for injection is approved for the treatment of severe cases of primary pulmonary arterial hypertension. Currently, there are 3 approved formulations of this drug containing the same active ingredient (epoprostenol sodium) but differing with regard to excipients. When compared with epoprostenol sodium formulated with glycine-mannitol (epoprostenol GM), 2 new formulations of epoprostenol sodium, one formulated with arginine-mannitol (epoprostenol AM) and one formulated with arginine-sucrose (epoprostenol AS), have improved stability after reconstitution and dilution. The biocomparability of epoprostenol AM and epoprostenol GM, with regard to pharmacokinetic (PK), pharmacodynamic (PD), safety, and tolerability profiles, has been shown previously. Objective This study compared PK, PD, safety, and tolerability profiles of the 3 different formulations of epoprostenol sodium for injection. Methods This was a prospective, single-center, open-label, 2-period, 2-treatment, randomized, crossover, ascending dose study in 2 parts. Twenty healthy men in part 1 and 20 different individuals in part 2 received epoprostenol AM and epoprostenol AS and epoprostenol GM and epoprostenol AS, respectively, in a crossover fashion, as sequential IV infusions of 2, 4, 6, and 8 ng/kg/min for 2 hours each. In each part, the PK profile of epoprostenol was characterized via analysis of the concentration-time profiles of its 2 primary metabolites: 6-keto-prostacyclin F1α and 6,15-diketo-13,14-dihydro-prostacyclin F1α. The effect of the formulations was assessed using the 90% CI of the geometric mean ratio calculated for the exposure PK parameters. The PD variables cardiac output, cardiac index, and heart rate were assessed using echocardiography. Adverse events were recorded through the study. Results The plasma concentration versus time curves of epoprostenol AM and epoprostenol AS in part 1 and epoprostenol GM and epoprostenol AS in part 2 were similar in shape and almost superimposable. For each study part, the 90% CIs of ratios of geometric means for AUC 0−∞ of the assessed epoprostenol formulations were within the range for bioequivalence (0.8−1.25). The increases in cardiac output, cardiac index, and heart rate resulting from infusion with epoprostenol sodium were comparable between all formulations, with maximum values attained after 8 hours. Almost all study participants reported at least one treatment-emergent adverse event, the most common being headache, which was reported in 80% to 85% of study participants. Conclusions Overall, the PK, PD, safety, and tolerability profiles of the 3 formulations of epoprostenol sodium for injection are comparable and meet the criteria of bioequivalence. Australian New Zealand Clinical Trials Registry identifier: ACTRN12612001086853.

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

WHAT IS ALREADY KNOWN • Continuous infusion with synthetic prostacyclin (epoprostenol) is generally regarded as the most effective treatment against severe cases of primary pulmonary arterial hypertension, associated with decreased pulmonary vascular resistance, increased cardiac index (CIn), and survival benefits. To date, the pharmacokinetics (PK) of epoprostenol have not been fully characterized due in part to the instability of epoprostenol. WHAT THIS STUDY ADDS • The present study provides the first characterization of the PK of epoprostenol in man via assessment of 6-keto-prostacyclin F1α and another primary metabolite, 6,15-diketo-13,14-dihydro-prostacyclin F1α. Overall, PK/pharmacodynamic (PD) modelling showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto-prostacyclin F1α suggesting that this major metabolite represents a suitable surrogate marker of plasma concentrations of epoprostenol. AIM The aim of the study was to report the first thorough characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of epoprostenol in an integrated manner. METHOD Twenty healthy male subjects received two formulations of i.v. epoprostenol, in a crossover design, in sequential infusions of 2, 4, 6 and 8 ng kg−1 min−1 for 2 h each. A sensitive assay was developed which allowed accurate PK characterization of epoprostenol via analysis of the concentration–time profiles of its two primary metabolites, 6-keto-prostacyclin F1α and 6,15-diketo-13,14-dihydro-prostacyclin F1α. PD parameters included cardiac output (CO), cardiac index (CIn) and heart rate (HR). RESULTS The pharmacokinetics of epoprostenol deviated slightly from dose-proportionality, probably due to a food effect. After infusion of the two formulations of epoprostenol, the t1/2 values expressed as geometric mean (95% confidence interval) were 0.25 h (0.14, 0.46) and 0.22 h (0.13, 0.38) for 6-keto-prostacyclin F1α, and 0.32 h (0.22, 0.45) and 0.34 h (0.26, 0.46) for 6,15-diketo-13,14-dihydro-prostacyclin F1α. A single compartment infusion model with first order elimination adequately described the PK of 6-keto-prostacyclin F1α. This model also characterized the food effect. Stepwise infusions with epoprostenol resulted in a progressive increase in CO, CIn and HR. CONCLUSION Of the two metabolites analyzed, the appearance of 6-keto-prostacyclin F1α in plasma was more closely associated with the haemodynamic effects of i.v. epoprostenol. PK and PD profiles showed that CIn relates proportionally and linearly to the plasma concentrations of 6-keto-prostacyclin F1α. These results suggest that 6-keto-prostacyclin F1α is a suitable surrogate marker of plasma concentrations of epoprostenol.

Study Objective. To determine whether the pharmacokinetics of the antidepressant citalopram are affected by ketoconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4. Design. Single-center, double-blind, randomized, three-way crossover trial. Setting. Research facility. Participants. Eighteen healthy male and female volunteers. Intervention. Subjects received three treatments with a 14-day washout period: single dose of ketoconazole 200 mg plus placebo, single dose of citalopram 40 mg plus placebo, and single dose of ketoconazole 200 mg plus single dose of citalopram 40 mg. Measurements and Main Results. Pharmacokinetic parameters were determined after each treatment. The pharmacokinetic profile of citalopram administered alone was essentially identical to that when administered with ketoconazole. Similarly, the pharmacokinetics of the metabolite desmethylcitalopram were unaltered by ketoconazole. Conclusion. No changes in pharmacokinetics of citalopram were observed after coadministration of ketoconazole, suggesting that ketoconazole and other CYP3A4 inhibitors may be administered safely with citalopram. Furthermore, no adjustment of citalopram dosage should be necessary in most patients who receive the drug in combination with a CYP3A4 inhibitor.

Current treatment options for Clostridium difficile-associated diarrhoea (CDAD) leave a high unmet medical need for new therapies. Cadazolid is a new antibiotic in development for the treatment of CDAD. The objectives of this study were to evaluate its tolerability and pharmacokinetics following single ascending doses (AC-061-101) and multiple ascending doses (AC-061-102).Single and multiple (twice daily for 10 days) oral doses of cadazolid between 30 mg and 3000 mg, or placebo, were tested in a total of 64 healthy male subjects. Safety assessments were conducted at regular intervals. Blood, urine and faeces were sampled, and cadazolid concentrations were measured.Cadazolid was well tolerated up to 3000 mg given twice daily for 10 days. The most common adverse event was headache, with no observed relationship between dose or treatment duration and adverse events. Plasma concentrations of cadazolid were low. No plasma concentrations3.3 ng/mL were observed after single doses or6.9 ng/mL after 10 days of multiple doses. Food increased the mean C(max) from 0.73 to 1.87 ng/mL and mean AUC(0-t) from 3.13 to 15.69 ng ·h/mL after a single 300 mg dose. The increase in systemic exposure to cadazolid across doses was less than dose-proportional. The mean cumulative faecal recovery was 81.0%-93.5%. Urinary recovery of unchanged compound was0.015%.Cadazolid was well tolerated and its systemic exposure was low. The majority of compound was recovered unchanged in the faeces, thus resulting in high concentrations at the site of action (colon).

Background CRTH2 is a prostaglandin D 2 receptor that plays an important role in allergic inflammation. Setipiprant is a potent CRTH2 antagonist under development for the treatment of allergic diseases. Objective The aim of this study was to evaluate the tolerability and pharmacokinetics of a single oral dose of a setipiprant capsule (reference) and a tablet formulation. Methods This was an open-label, 2-period, 2-way crossover, randomized study in which 20 healthy women and men (1:1 ratio) received either 2 250-mg capsules or a 500-mg tablet of setipiprant. Subjects were between 18 and 45 years old, with a body mass index of 18.0 to 28.0 kg/m 2 . Differences in pharmacokinetics of setipiprant formulations were explored overall and by sex. Results All subjects completed the study. Both formulations were well tolerated, with headache the most frequently reported adverse event (25% of subjects), followed by flatulence (15%) and somnolence and fatigue (10%). The adverse event profile in men and women and between formulations was similar. The ratios of geometric means for C max (0.94; 95% CI, 0.79–1.12) and AUC 0–∞ (1.01; 95% CI, 0.92–1.12) were mostly within the limits of 0.80 to 1.25. When corrected for weight, the differences observed between sexes, within each treatment, for C max (capsules: 1.01; 95% CI, 0.71–1.44; tablet: 0.89; 95% CI, 0.62–1.26) and AUC 0–∞ (capsules: 1.12; 95% CI, 0.86–1.47; tablet: 0.96; 95% CI, 0.73–1.25) were minor. Conclusion Both the setipiprant formulations were well tolerated. Setipiprant pharmacokinetics were similar between formulations, overall, and between sexes. The new tablet formulation may constitute a valid alternative to the capsule formulation for later clinical development phases. ClinicalTrials.gov identifier: NCT01877629.

WHAT IS KNOWN Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH). Since bosentan is frequently used to treat pediatric PAH patients, a pediatric formulation was developed. AIM To evaluate the pharmacokinetic properties of bosentan and its active metabolite, Ro 48-5033, of the quadrisected, dispersible pediatric vs. the adult tablet after single-dose administration to healthy subjects. Secondary objectives of the study were to compare the pharmacokinetics of two inactive metabolites and the safety of both formulations. MATERIALS AND METHODS In this open-label, two-way crossover study, subjects (20 - 43 years) were randomized to receive single oral doses of 62.5 mg of bosentan as 1 adult tablet and 64 mg as 2 pediatric tablets of 32 mg. Blood samples were drawn over a 48-hour period to measure bosentan and its metabolites. RESULTS 16 subjects were enrolled and completed the study. Following treatment with the pediatric formulation, values for Cmax and AUC0-∞ of bosentan were lower than with the adult formulation with geometric mean ratios (90% confidence interval) of 0.82 (0.65, 1.04) and 0.87 (0.78, 0.97), respectively. Similar results were obtained for the primary active metabolite Ro 48-5033. Both treatments were well tolerated. WHAT IS NEW AND CONCLUSION Although the 90% confidence intervals of the geometric mean ratios of Cmax and AUC0-∞ were not entirely within the conventional bioequivalence range (0.80 - 1.25), no clinically relevant effect of formulation on the pharmacokinetics of bosentan and Ro 48-5033 was detected. Both formulations were well tolerated.

To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of escalating single oral doses of ACT-077825, a novel orally active renin inhibitor, in healthy male subjects.In this single-center, double-blind, placebo- and active-controlled (with enalapril) randomized study, 70 subjects received a single dose of ACT-077825 (1-1,000 mg), placebo, or enalapril 20 mg under fasted conditions. The main pharmacokinetic endpoints were area under the plasma ACT-077825 concentration-time curve from time zero to infinity and the terminal half-life (t(1/2)). The pharmacodynamic endpoints included immunoactive active renin (iAR) plasma concentrations and plasma renin activity (PRA). Standard laboratory and safety data were collected.Of the few adverse events reported, diarrhea and headache were the most frequent. The pharmacokinetics of ACT-077825 were dose-proportional in the dose range 100 to 1,000 mg. Terminal t(1/2), best characterized following a dose of 1,000 mg, was 41.6 h and t(max) 4-5 h post-dose. ACT-077825 dose-dependently increased iAR and decreased PRA, effects that were associated with a decrease in blood pressure at 1,000 mg, similar to following treatment with enalapril.The results provide evidence that ACT-077825, with a pharmacokinetic profile consistent with a once-a-day dosing regimen, may represent an effective antihypertensive agent and pave the way toward a multiple-ascending dose study.

Pharmacokinetics (PK) and hemodynamics of two formulations of epoprostenol sodium for injection, epoprostenol with expanded stability (EPO-ES, Veletri®) and epoprostenol (EPO, Flolan®), were compared in an open-label, crossover, ascending-dose study in healthy males. Subjects received sequential, 2-hour (h) infusions of EPO-ES or EPO at 2, 4, 6 and 8ng/kg/min. Due to the short half-life (t1/2) of epoprostenol sodium, plasma PK were assessed via the concentration versus time profiles of two primary metabolites, 6-keto-prostacyclin F1α (kPF) and 6,15-diketo-13,14-dihydro-prostacyclin F1α (ddPF). Plasma concentration-versus-time profiles of EPO-ES and EPO with regard to kPF and ddPF were superimposable. Levels of kPF and ddPF 2h after the end of each infusion were comparable. Geometric means of the total area under the curve (AUC 0-∞ ) for kPF, were 2021 and 1972pg·h/mL (90% CI of geometric mean ratio (GMR): 97, 107), and 665 and 654pg.h/mL (90% CI of GMR: 94, 111) for ddPF following administration of EPO-ES and EPO, respectively. Similar changes in hemodynamic variables were observed during EPO-ES and EPO infusion. Average maximum increases from baseline were approximately 30% in both cardiac output and cardiac index with either formulation, and 19% and 27% in heart rate for EPO-ES and EPO, respectively. Both formulations had comparable treatment-emergent adverse event (TEAE) profiles. Headache was the most common TEAE reported. Overall, EPO-ES and EPO have the same PK, hemodynamic, safety, and tolerability profiles.

Background: Depression often coexists with a number of disease states, and patients with a diagnosis of depression often receive multiple medications. Thus, it is desirable to avoid coadministration of agents that have a potential for drug interactions in these patients. Although escitalopram and its metabolites are weak to negligible inhibitors of the cytochrome P450 (CYP) 3A4 isozyme and are therefore unlikely to affect plasma concentrations of ritonavir (a CYP3A4 substrate and prototype CYP3A4 inhibitor), ritonavir may potentially affect plasma concentrations of escitalopram, as CYP3A4 is partially responsible for conversion of escitalopram to its major metabolite, S -demethylcitalopram ( S -DCT). Objectives: The aim of this study was to investigate the potential for pharmacokinetic interaction between escitalopram and ritonavir after concomitant administration of a single dose of each in healthy young subjects. Methods: In this single-center, randomized, open-label, 3-way crossover study, subjects received each of the following: a single dose of escitalopram 20 mg, a single dose of ritonavir 600 mg, and single doses of both escitalopram 20 mg and ritonavir 600 mg. Blood was collected and plasma was analyzed for the pharmacokinetic parameters (maximum plasma concentration [C max ], time to C max [T max ], area under the plasma concentration-time curve, plasma elimination half-life, oral clearance, and apparent volume of distribution) of escitalopram, S -DCT, and ritonavir. Results: Of 21 subjects (11 men, 10 women; mean [SD] age, 28.4 [4.4] years) who were enrolled, 18 completed the study. After concomitant administration of escitalopram and ritonavir, no statistically significant differences were noted in the pharmacokinetics of escitalopram, with the exception of apparent volume of distribution, which was reduced by ∼10% ( P S -DCT were unaffected by coadministration of ritonavir, with the exception of T max , which was increased in the presence of ritonavir. The pharmacokinetic parameters of ritonavir were also unaffected by coadministration of escitalopram. Conclusion: In general, no pharmacokinetic interaction was observed between escitalopram and ritonavir in the present study.

Background: Citalopram tablets fulfill most dosing needs in the treatment of depression, but some patients may have difficulty swallowing tablets and thus may be less likely to comply with their medication regimen. A liquid formulation of citalopram could be beneficial for such patients. Objective: This study was undertaken to compare the pharmacokinetic profiles of oral solution and tablet formulations of citalopram in healthy volunteers. Methods: In this open-label, single-dose, randomized, crossover, bioequivalence study, healthy volunteers alternately received one 60-mg dose of citalopram as an oral solution (10 mg/5 mL) and one 60-mg dose as a tablet. Doses were separated by a 14-day interval. Results: Of 24 subjects enrolled (mean age 27 years), 24 (16 men and 8 women) received the citalopram oral solution and 23 (15 men and 8 women) received the tablet; 1 subject discontinued before receiving the tablet. Citalopram was rapidly absorbed, with peak plasma concentrations occurring at ∼4 hours with both formulations. The rate and extent of absorption were similar between the 2 formulations, and no statistically significant differences were observed in half-life or oral clearance between formulations. Similarly, the pharmacokinetic profile for demethylcitalopram (the major metabolite of citalopram) did not differ between the 2 formulations. Both formulations were well tolerated, with no serious adverse events reported. Conclusion: The oral solution and tablet formulations of citalopram 60 mg were determined to be bioequivalent in this population.