Arthur Mazzu

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).

Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin

3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug‐drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug‐drug interactions.

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.

Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mg dose of cerivastatin in patients with primary hypercholesterolemia

Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28% to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodynamics, and pharmacokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial conducted at 2 study centers, 41 patients (63% women) with primary hypercholesterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events were mild and transient. One cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8x the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol compared with placebo (-44.0 +/- 2.0% vs 2.2 +/- 2.8%, p <0.0001); total cholesterol (-30.8 +/- 1.4% vs 2.6 +/- 2.1%, p <0.0001), triglycerides (-11.2 +/- 5.9% vs 15.9 +/- 8.6%, p <0.02), but did not significantly alter high-density lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs -1.2 +/- 3.1%, p = NS). The pharmacokinetics of the 0.8-mg dose revealed dose proportional elevations in the 24-hour area under the curve and maximum plasma concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum concentration or the elimination half-life in plasma. The increased efficacy and lack of clinically significant laboratory abnormalities or adverse events demonstrates a need for a large long-term study to confirm the safety and efficacy of this dose of cerivastatin.

Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults.

AbstractObjective: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this non-randomized, non-blinded, 7-day, multiple-dose study. Methods: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CLCR >90 ml/min/1.73 m2, n=9), or patients with either mild (CLCR 61 ml/min/1.73 m2 to ≤90 ml/min/1.73 m2, n=9), moderate (CLCR 30 ml/min/1.73 m2 to ≤60 ml/min/1.73 m2, n=8), or severe (CLCR <30 ml/min/1.73 m2, but not on dialysis, n=9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration–time curve (AUC)0–24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. Results: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 μg/h/l vs 19.2 μg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40–60% higher (30.8 μg/h/l and 29.0 μg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 μg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. Conclusion: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.

Lack of mutual pharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin in healthy normocholesterolemic volunteers

The potential mutual interaction between cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, and digoxin was assessed in this nonmasked, nonrandomized, multiple-dose study. The effect of cerivastatin 0.2 mg on mean plasma digoxin levels and the effect of digoxin on the single-dose pharmacokinetics of cerivastatin were assessed in 20 healthy normocholesterolemic men between 18 and 45 years of age weighing 140 to 200 lbs (63.3 to 90.0 kg). Subjects were given a single dose of cerivastatin 0.2 mg. After a 2-day washout period, subjects were given a loading dose of digoxin 0.5 mg for 3 days followed by 0.25 mg daily for 5 additional days (period 1-digoxin alone). Concurrent dosing with cerivastatin 0.2 mg continued for 14 days (period 2-digoxin and cerivastatin), followed by an 8-day course of digoxin-only administration and an optional 6-day extension of digoxin-only treatment for a total of 14 days (period 3). Safety was assessed through physical examination, electrocardiography, laboratory tests, and ophthalmologic examination. Ratio analyses of mean digoxin plasma trough levels, 24-hour urinary digoxin levels, and digoxin clearance with and without concurrent cerivastatin dosing also were carried out. In addition, single-dose pharmacokinetic variables for cerivastatin, including area under the curve (AUC(0-24)), peak concentration (C(max)), time to peak concentration (T(max)), and elimination half-life (t1/2), were examined with and without concurrent digoxin dosing. Eleven of the 20 subjects completed the entire study. Seven subjects discontinued the study because of treatment-emergent adverse events or laboratory abnormalities that were mostly unrelated to cerivastatin, and 2 subjects were discontinued because of protocol violations. Treatment-emergent adverse events developed in 12 subjects receiving cerivastatin; 11 of these subjects were receiving digoxin concurrently. Six adverse events that led to discontinuation of treatment were unrelated to cerivastatin but were related to digoxin or to a preexisting condition. The most commonly reported event was headache, which occurred with equal frequency compared with placebo groups in large cerivastatin clinical trials. Other events were mild or moderate and resolved without intervention. Mild and transient elevations in hepatic transaminase and creatine kinase values (all <2 times the upper limit of normal) were observed in 7 subjects. After 14 days of concurrent dosing of cerivastatin and digoxin, steady-state digoxin plasma levels, urinary digoxin levels, and urinary digoxin clearance were unchanged compared with steady-state digoxin levels when digoxin was given alone. Compared with dosing with digoxin alone, the AUC(0-24), Cmax, and t1/2 for cerivastatin increased 3%, 20%, and 7%, respectively, while the T(max) was reduced by 18% during concurrent treatment with digoxin. These changes are minimal and would not be expected to be clinically relevant. These results demonstrate that when cerivastatin is administered concurrently with digoxin, neither digoxin nor cerivastatin plasma levels are altered. The combination therapy was generally well tolerated.

Influence of Age on the Safety, Tolerability, and Pharmacokinetics of the Novel HMG‐CoA Reductase Inhibitor Cerivastatin in Healthy Male Volunteers

The safety, tolerability, and pharmacokinetics of cerivastatin, a novel, synthetic, potent, and highly selective HMG‐CoA reductase inhibitor, were studied in 48 young and elderly male volunteers in a randomized, double‐blind, placebo‐controlled study. Eight men ranging from 18 to 38 years of age (young) and 15 men ranging from 65 to 78 years of age (elderly) received 0.1‐mg cerivastatin tablets daily for 7 days. The remaining subjects (8 young and 17 elderly) received matching placebo tablets. Cerivastatin was well tolerated in elderly and young subjects. Adverse events were mild and occurred less frequently in the participants receiving cerivastatin than in those receiving placebo. In those participants given cerivastatin, the incidence of adverse events was similar for both age groups (4 of 8 young subjects and 8 of 15 elderly subjects). Transient and mild elevations in creatine kinase and transaminase levels were evenly distributed across the cerivastatin and placebo groups. Pharmacokinetic parameters, including area under the concentration curve (AUC), peak plasma concentration (Cmax), time to Cmax (tmax), and elimination half‐life (t1/2), were similar between the two age groups. The mean elimination t1/2 for both groups was approximately 4 hours. These results indicate that cerivastatin is well tolerated in elderly male volunteers at a dosage of 0.1 mg/day. Further, the pharmacokinetics of cerivastatin are not altered as a consequence of age. Dose adjustment is therefore not required in elderly men.