Raju D. Amin

The Efficacy and Six-Week Tolerability of Simvastatin 80 and 160 mg/Day

The hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin is the most effective of the currently approved hypolipidemic drugs and has been shown to reduce mortality and coronary morbidity in patients with coronary artery disease. For these patients the United States National Cholesterol Education Program advocates reducing low-density lipoprotein (LDL) cholesterol to <100 mg/dl. However, in some patients this cannot be achieved using monotherapy with simvastatin 40 mg/day, the current maximal recommended dose. To evaluate the effectiveness of extending the dosage range, 156 subjects with LDL cholesterol >160 mg/dl and triglycerides (TG) <350 mg/dl were randomized to simvastatin at doses of 40, 80, and 160 mg/day in a 26 week, double-blind, 3-period, complete block crossover study. Each active treatment period was 6 weeks in duration with intervening 2 week washout periods. Median reductions from baseline in LDL cholesterol were 41%, 47%, and 53% in the 40-, 80-, and 160-mg groups, respectively. The corresponding reductions in plasma TG were 21%, 23%, and 33%. High-density lipoprotein (HDL) cholesterol increased by 6% to 8% in each group. One patient (0.7%) taking 160 mg developed myopathy; 1 patient (0.7%) taking 80 mg, and 3 (2.1%) taking 160 mg had transaminase elevations > 3 times the upper limit of normal. No new or unexpected adverse effects were observed. We conclude that simvastatin at doses of 80 and 160 mg/day provides additional efficacy with a low short-term incidence of adverse effects; our results support the continued investigation of simvastatin at these doses.

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.

AbstractPurpose. The safety, tolerability, and pharmacokinetics of intravenous (i.v.) montelukast sodium (Singulair™, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. Methods. This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1–3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. Results. In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng · hr/ml, 385 ng/ml, 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng·hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. Conclusions. The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.

Grapefruit juice has minimal effects on plasma concentrations of lovastatin‐derived 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors

To evaluate the effect of regular‐strength grapefruit juice, a cytochrome P4503A4 (CYP3A4) inhibitor, on the pharmacokinetics of a commonly prescribed regimen of oral lovastatin.

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

A study was conducted to (i) characterize the multiple‐dose pharmacokinetics of oral montelukast sodium (MK‐0476), 10 mg d−1 in healthy young subjects (N =12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N =12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d−1 (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration–time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL−1 on days 3–7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1·14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady‐state volume of distribution (Vss), plasma terminal half‐life (t1/2), and mean residence time in the body (MRTIV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30·8 mL min−1, 9·7 L, 6·7 h, and 5·4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC0→∞, Cmax, tmax, and t1/2, and the mean plasma concentration–time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age.

Interactions between Simvastatin and Troglitazone or Pioglitazone in Healthy Subjects

Two randomized, two‐period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG‐CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once‐daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once‐daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once‐daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration‐time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG‐CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by ∼30% for Cmax and ∼40% for AUC), but time to reach Cmax(tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (∼25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG‐CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug‐metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.

Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin.

The effects of age and of gender on the plasma profiles of HMG-CoA reductase inhibitors following separate once-a-day dosage regimens (17 days) of lovastatin (80 mg/day) and simvastatin (40 mg/day) were studied in hypercholesterolemic patients. In general, plasma concentrations of active and total HMG-CoA reductase inhibitors were higher in elderly individuals (age, 70 to 78 years) and in females for both drugs. However, the Tmax of these inhibitors was not significantly affected by either age or gender. Following the last dose of lovastatin, the mean steady-stage plasma concentrations of total and active HMG-CoA reductase inhibitors were 30-60% higher in the elderly than in young individuals (age, 19 to 30 years). Also, the mean plasma concentrations were 20-50% higher in female than in male patients. Similarly, following the last dose of simvastatin, the mean plasma concentrations of HMG-CoA reductase inhibitors were 40-60% higher in the elderly than in young patients and were 20-50% higher in female than in male patients. These age- and gender-related differences do not appear to be large enough to warrant modification of dosage regimens, because plasma concentrations of these inhibitors are not necessarily indicative of efficacy and the therapeutic windows for lovastatin and simvastatin are broad.

Montelukast dose selection in 6- to 14-year-olds : Comparison of single-dose pharmacokinetics in children and adults

Montelukast, an oral leukotriene‐receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once‐daily 10 mg dose (film‐coated tablet) was selected as the optimal adult dose based on dose‐ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film‐coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose‐ranging studies in children. Therefore, the dose of montelukast for 6‐ to 14‐ year‐old children was selected by identifying the chewable tablet dose of montelukast yielding a single‐dose area under the plasma concentration‐time curve (AUC) comparable to that achieved with the adult 10 mg film‐coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6‐ to 14‐year‐old children with asthma.

Determination of MK-0476 in human plasma by liquid chromatography.

A simple and accurate assay for quantitating MK-0476 [sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-(ethenyl)phenyl)(3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)-methyl)cyclopropane)acetate], which is a potent and selective leukotriene D4-receptor antagonist, in human plasma has been developed. The method involves precipitation of protein and reversed-phase liquid chromatography with fluorescence detection. The assay is linear in the range of 30-3000 ng ml-1 of MK-0476, and the limit of detection is 5 ng ml-1. The interday precision (% relative standard deviation) values of this method at 51 and 2040 ng ml-1 are 10 and 3%, respectively. The interday accuracy values at these concentrations are 94 and 104%, respectively. The absolute recovery of MK-0476 is 99%. The utility of this method to determine plasma concentrations of MK-0476 in humans receiving the drug orally was demonstrated.

Evaluation of Sustained/Controlled-Release Dosage Forms of 3-Hydroxy-3-methylglutaryl–Coenzyme A (HMG-CoA) Reductase Inhibitors in Dogs and Humans

Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.

Grapefruit juice (GFJ) has a small effect on lovastatin plasma HMG‐CoA reductase inhibitor (HMGRI) profiles

Clinical Pharmacology & Therapeutics (1999) 65, 149–149; doi: