Pavur Sundaresan

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).

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 μg/L, respectively, and AUC was 66.78 and 67.09 μg•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 μg/L, respectively, and AUC was 51.97 and 59.12 μg•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.

Pharmacokinetics, Safety, and Tolerability of BAY 12–9566 and Nonsteroidal Anti‐inflammatory Agents (Naproxen, Ibuprofen) during Coadministration in Patients with Osteoarthritis

The pharmacokinetic interactions between BAY 12–9566 and two nonsteroidal anti‐inflammatory drugs (NSAIDs), naproxen and ibuprofen, were investigated in osteoarthritis (OA) patients. The study comprised six groups: two NSAID groups with three levels of treatment (BAY 12–9566 400 mg, BAY 12–9566 100 mg, and placebo). Plasma pharmacokinetic parameters (AUCτ’ Cmax’, and tmax) were determined for each treatment group following 5 days of NSAID administration, 14 days of BAY 12–9566 administration, and 14 days of concurrent NSAID and BAY 12–9566 administration. For most conditions, the total plasma drug concentrations of both NSAID and BAY 12–9566 were diminished by coadministration; total plasma BAY 12–9566 was not affected by ibuprofen treatment. Importantly, the free drug concentrations were largely unaffected by coadministration. Most side effects were mild or moderate in intensity, and all events, with the exception of headache, were reported in both NSAID groups and in both placebo and BAY 12–9566 groups.

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 Cmax 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.

Safety and Tolerance of Intravenous Nimodipine

OBJECTIVE: To evaluate the safety and tolerance of intravenous nimodipine administered via a peripheral vein in healthy male volunteers. DESIGN: Double-blind, placebo- and vehicle-controlled trial with three fixed-dose panels. SETTING: Inpatient infusion and observation periods. SUBJECTS: 61 healthy male volunteers, aged 18–40 years. METHODS: Subjects in panel 1 received nimodipine 0.4 mg/h, vehicle 2 mL/h, or placebo 2 mL/h; subjects in panel 2 received nimodipine 1 mg/h, vehicle 5 mL/h, or placebo 5 mL/h; subjects in panel 3 received nimodipine 2 mg/h, vehicle 10 mL/h, or placebo 10 mL/h. All infusions were administered intravenously for 48 hours and volunteers were observed for 48 hours after cessation of the infusion. In addition to standard safety assessments (physical examination, electrocardiogram, laboratory studies, and adverse event reporting), supine and standing blood pressures and pulse rates were measured frequently. Plasma samples were also analyzed for nimodipine and its two demethylated metabolites. RESULTS: Of 61 subjects, 55 completed the 48-hour infusion and 6 discontinued the study because of adverse events. Intravenous nimodipine was well tolerated at 0.4 and 1 mg/h. However, all six subjects who received nimodipine 2 mg/h experienced moderate-to-severe adverse events, and one subject was discontinued because of dizziness, diaphoresis, and postural hypotension. The matched vehicle (10 mL/h) also was not well tolerated, with three subjects who discontinued because of phlebitis. Two subjects who received placebo were also discontinued during the study. Small (2 mm Hg) decreases in mean supine diastolic blood pressure were observed in the 0.4- and 1-mg/h nimodipine groups, but the 2-mg/h group showed a slight (5 mm Hg) increase in blood pressure. These changes were not clinically significant. Clearance and half-life of nimodipine and its metabolites were similar at all three dosages. CONCLUSIONS: Using peripheral vein administration, nimodipine 2 mg/h and matched vehicle at 10 mL/h were not well tolerated in this healthy normal population. The maximum tolerated dose of nimodipine was found to be 1 mg/h.

Effect of age and gender on the safety, tolerability, and pharmacokinetics of BAY 12-9566 in healthy subjects

The impact of age and gender on the single‐dose pharmacokinetics, safety, and tolerability of BAY 12–9566 was evaluated in healthy subjects. Volunteers were grouped according to age and gender (13 young males, 11 elderly males, and 12 elderly females) and then randomized in a 2:1 ratio to receive a single oral 50 mg dose of BAY 12–9566 or placebo. Serial plasma samples were collected up to 336 hours post dose and assayed for BAY 12–9566. Peak plasma concentration, time to reach peak plasma concentration, the area under the concentration‐time curve, oral clearance, volume of distribution, and elimination half‐life were calculated. BAY 12–9566 was well tolerated in all treatment groups, and no serious adverse events occurred during the study. Substantial age‐ or gender‐related differences were not observed for any of the pharmacokinetic parameters tested. Based on these pharmacokinetic and tolerability profiles, age‐ or gender‐related dose adjustments were not required for BAY 12–9566.