Assessment of the effects of renal impairment on the pharmacokinetics of the soluble guanylate cyclase activator cinaciguat after a single intravenous dose.

This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (<1%) in all groups. Pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment. Adverse events were mostly mild, and their incidence was similar in all groups. In conclusion, cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function.

A phase I open-label study evaluating the cardiovascular safety of sorafenib in patients with advanced cancer.

PURPOSE: To characterize the cardiovascular profile of sorafenib, a multitargeted kinase inhibitor, in patients with advanced cancer. METHODS: Fifty-three patients with advanced cancer received oral sorafenib 400 mg bid in continuous 28-day cycles in this open-label study. Left ventricular ejection fraction (LVEF) was evaluated using multigated acquisition scanning at baseline and after 2 and 4 cycles of sorafenib. QT/QTc interval on the electrocardiograph (ECG) was measured in triplicate with a Holter 12-lead ECG at baseline and after 1 cycle of sorafenib. Heart rate (HR) and blood pressure (BP) were obtained in duplicate at baseline and after 1 and 4 cycles of sorafenib. Plasma pharmacokinetic data were obtained for sorafenib and its 3 main metabolites after 1 and 4 cycles of sorafenib. RESULTS: LVEF (SD) mean change from baseline was -0.8 (±8.6) LVEF(%) after 2 cycles (n = 31) and -1.2 (±7.8) LVEF(%) after 4 cycles of sorafenib (n = 24). The QT/QTc mean changes from baseline observed at maximum sorafenib concentrations (t(max)) after 1 cycle (n = 31) were small (QTcB: 4.2 ms; QTcF: 9.0 ms). Mean changes observed after 1 cycle in BP (n = 31) and HR (n = 30) at maximum sorafenib concentrations (t(max)) were moderate (up to 11.7 mm Hg and -6.6 bpm, respectively). No correlation was found between the AUC and C(max) of sorafenib and its main metabolites and any cardiovascular parameters. CONCLUSIONS: The effects of sorafenib on changes in QT/QTc interval on the ECG, LVEF, BP, and HR were modest and unlikely to be of clinical significance in the setting of advanced cancer treatment.

Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics.

Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects. A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily (period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4). No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite, sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A.

Effect of gender and age on the pharmacokinetics of repinotan.

OBJECTIVE: Repinotan hydrochloride (repinotan) is a selective, high-affinity, full serotonin receptor agonist at the 5-HT(1A) subtype that is undergoing clinical development in acute stroke. To investigate whether gender is an important covariable for repinotan pharmacokinetics, two studies were performed in subjects of different age and gender who had been phenotyped as extensive metabolisers for cytochrome P450 (CYP)2D6 using dextromethorphan as model substrate. SUBJECTS AND METHODS: Both studies were placebo-controlled, double-blind, randomised, parallel-group studies. Study I was conducted in six healthy young males, five healthy elderly males, and four healthy elderly females receiving a continuous intravenous (IV) infusion of repinotan 0.45 microg/kg/h or placebo for a duration of 12 hours. Study II was performed in healthy elderly male and female volunteers aged >/=65 years with 67 subjects receiving repinotan and 34 receiving placebo. Subjects received a 12-hour infusion of repinotan at doses of 0.1, 0.3, 0.5, 1.0, 2.0 or 3.0 microg/kg/h. RESULTS: Following IV infusion, the steady-state plasma concentration (C(ss)) for repinotan was reached after 4-6 hours consistent with its half-life of 0.8-1.8 hours. In both male and female subjects, the volume of distribution at steady-state and plasma clearance (CL) were independent of dose, indicating linear pharmacokinetics and dose-proportionality for area under the concentration-time curve (AUC) and peak plasma concentration (C(max)) over the dose range of 0.1-3.0 microg/kg/h. Compared with elderly subjects, repinotan CL was unchanged in a subgroup of young subjects. The pooled evaluation of elderly subjects (n = 67) showed that gender had no influence on the pharmacokinetics of repinotan. The ratios male : female and their 90% CIs were: 0.91 (0.789, 1.052) for dose/bodyweight-normalised C(max) (C(max,norm)), 0.95 (0.808, 1.110) for half-life, 0.97 (0.900, 1.044) for V(ss,) and 1.11 (0.923, 1.336) for CL. CONCLUSION: These results indicate that gender does not affect the pharmacokinetics of repinotan in healthy subjects whose age (>/=65 years) was representative of the target patient population for repinotan in acute stroke.

Simultaneous administration of vardenafil and tamsulosin does not induce clinically significant hypotension in patients with benign prostatic hyperplasia.

OBJECTIVES: To assess the pharmacodynamic effects of coadministered vardenafil and tamsulosin in patients with benign prostatic hyperplasia (BPH) undergoing stable tamsulosin therapy. METHODS: In this Phase 1, placebo-controlled, two-stage, two-way, crossover study, 22 patients undergoing stable (longer than 4 weeks) tamsulosin therapy for BPH (18 using 0.4 mg and 4 using 0.8 mg tamsulosin daily) received vardenafil 10 mg (or placebo), followed by vardenafil 20 mg (or placebo), simultaneously with tamsulosin. The mean maximal change from baseline with vardenafil use versus placebo was evaluated for supine and standing blood pressure and heart rate for up to 6 hours after dosing. RESULTS: In patients receiving vardenafil 10 mg, the mean maximal change from baseline versus placebo in supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate was -4.5 mm Hg (95% confidence interval [CI] -8.2 to -0.8), -2.3 mm Hg (95% CI -4.9 to 0.4), and 3.7 beats per minute (95% CI 1.1 to 6.3), respectively. In patients receiving vardenafil 20 mg, the mean maximal change from baseline versus placebo in supine SBP, DBP, and heart rate was -4.0 mm Hg (95% CI -6.3 to -1.8), -2.9 mm Hg (95% CI -5.6 to -0.2), and 0.8 beats per minute (95% CI -1.2 to 2.9), respectively. These hemodynamic changes were similar to those obtained in the standing position. Two placebo patients and 1 vardenafil 10-mg patient had a drop of 20 mm Hg or more in standing DBP; 1 vardenafil 10-mg patient had a standing SBP drop of 30 mm Hg or more. No patient exhibited symptomatic hypotension (SBP less than 85 mm Hg with dizziness). Three patients receiving vardenafil 20 mg/tamsulosin 0.4 mg reported dizziness, but never had an SBP of less than 95 mm Hg. No serious adverse events were reported. CONCLUSIONS: In this study, no evidence was found that coadministered vardenafil and tamsulosin induced clinically significant hypotension in patients with BPH.

Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction.

The effects of food on the pharmacokinetics of vardenafil were examined in 25 healthy adult males. Single-dose vardenafil 20 mg was administered in a randomized four-way crossover design after an overnight fast (at 8 a.m.), after consumption of a high-fat breakfast (at 8 a.m.), on an empty stomach (at 6 p.m.), and after a typical moderate-fat evening meal (at 6 p.m.). Serial blood samples were analyzed for vardenafil and metabolite (M1) levels. When administered after an overnight fast and after a high-fat breakfast, vardenafil geometric mean Cmax was 17.14 and 14.0 micrograms/L, respectively, and AUC was 66.78 and 67.09 micrograms./h/L, respectively; the median tmax was 1 hour under fasting conditions and 2 hours with consumption of high-fat breakfast. When administered in the evening on an empty stomach and after a moderate-fat meal, vardenafil geometric mean Cmax was 14.22 and 13.04 micrograms/L, respectively, and AUC was 51.97 and 59.12 micrograms.h/L, respectively. The median tmax was 1 hour after fasting or a moderate-fat meal in the evening. All treatments were well tolerated. Thus, while a high-fat meal may alter Cmax slightly and delay the absorption up to 1 hour, a moderate-fat meal has no clinically relevant effect on vardenafil pharmacokinetics. Dosage changes are not warranted based on the wide therapeutic index and the efficacy observed with vardenafil in Phase III studies that were not restricted with respect to food.

The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease.

OBJECTIVES: The effect of vardenafil, a potent and highly selective phosphodiesterase-5 (PDE5) inhibitor, on symptom-limited exercise time, time to first awareness of angina, and time to ischemic threshold (ST-segment depression > or =1 mm from baseline) during exercise tolerance testing (ETT) was examined in patients with stable coronary artery disease (CAD). BACKGROUND: Erectile dysfunction (ED) is common among men with CAD. PDE5 inhibition is increasingly the preferred treatment option for ED. However, the effect of PDE5 inhibition on exercise-induced ischemia in CAD patients has received limited prospective evaluation. METHODS: In this double-blind, crossover, single-dose multicenter study, 41 men with reproducible stable exertional angina due to ischemic CAD received vardenafil 10 mg or placebo, followed by ETT (5 to 10 metabolic equivalents [METS], Bruce protocol) 1 h postdose. Sublingual nitrate use was prohibited for > or =24 h pre- and postexercise study days. End points included symptom-limited treadmill exercise time, time to first awareness of angina, time to ischemic threshold, and safety. RESULTS: Relative to placebo, vardenafil 10 mg did not alter exercise treadmill time (427 +/- 105 s vs. 433 +/- 109 s, p = 0.39), or time to first awareness of angina (292 +/- 110 s vs. 291 +/- 123 s, p = 0.59), but significantly prolonged time to ischemic threshold (334 +/- 108 s vs. 381 +/- 108, p = 0.0004). At peak exercise, vardenafil 10 mg did not alter blood pressure, heart rate, or rate-pressure product relative to placebo. The most common adverse events (facial flushing and headache) were of mild or moderate intensity, and short-lived. CONCLUSIONS: Vardenafil 10 mg did not impair the ability of patients with stable CAD to exercise at levels equivalent or greater than that attained during sexual intercourse (average of 2.5 to 3.3 METS).

Pharmacokinetics of Nisoldipine Coat--Core Formulation in Subjects with Liver Cirrhosis.

The pharmacokinetics of a controlled-release formulation (coat--core) of the calcium channel blocker nisoldipine was investigated in eight subjects with biopsy-proved liver cirrhosis and eight healthy subjects. In Stage I, subjects received a single 10-mg dose to determine if this dose would be safely tolerated in the subjects with cirrhosis. Because all subjects in both groups tolerated the dose without difficulty, all were continued to Stage II. In Stage II, subjects received a once-daily dose of 10-mg coat-core tablets for 7 days. Serial plasma samples were assayed for nisoldipine in both stages. The C(max) and AUC of nisoldipine were approximately fourfold to fivefold higher (p < 0.01) in subjects with cirrhosis as compared to healthy subjects; however, there was overlap in the range of pharmacokinetic parameters between the two groups. The accumulation factor following multiple dosing was similar in both groups. Results suggest that nisoldipine dose should be optimized by monitoring of a pharmacodynamic end point, such as effect on blood pressure. It is likely that dose requirements for patients with liver disease will be lower.