J. Douglas Rogers

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.

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.

Determination of montelukast (MK-0476) and its S-enantiomer in human plasma by stereoselective high-performance liquid chromatography with column-switching

A steoreoselective high-performance liquid chromatographic method was developed for the quantification of montelukast (free acid of Singulair, or MK-0476), a potent and selective leukotriene D4 (cysLT1) receptor antagonist, and it S-enantiomers (L-768,232). The method involves protein precipitation and fluorescence detection. Chromatographic separation of the enantiomers from endogenous components in plasma and chiral resolution of the enantiomers are achieved by using column switching HPLC and an alpha-acid glycoprotein chiral column. The assay is linear in the range of 28.9-386 ng ml-1 of free acids of montelukast and L-768,232. The intraday precision (% relative standard deviation) values of this method were in the range of 2.5-9.1% for montelukast, and 2.4-6.8% for L-768,232, while the intraday accuracy values were in the range of 97-103% for montelukast and 96-104% for L-768,232. The interday precision values of this method at 48.2 and 193 ng ml-1 were 5.3 and 3.6%, respectively, for montelukast, and 4.2 and 3.7%, respectively, for L-768,232, while the interday accuracy values at these concentrations were 97 and 103%, respectively, for montelukast and 99 and 102%, respectively, for L-768,232. The utility of the methodology was demonstrated by analysis of plasma samples from a study in which healthy volunteers received 10 mg per day of montelukast orally for 7 days. Results of this study indicate that there is no apparent bioinversion of montelukast to its S-enantiomer in humans.

Pharmacokinetics and Bioinversion of Ibuprofen Enantiomers in Humans

An open, randomized, six-way crossover study was conducted in 12 healthy males to assess pharmacokinetics and bioinversion of ibuprofen enantiomers. The mean plasma terminal half-life (t1/2) of R(–)ibuprofen was 1.74 hr when intravenously infused as a racemic mixture and was 1.84 hr when intravenously infused alone. The mean t1/2 of S( + )ibuprofen was 1.77 hr when dosed as S( + )ibuprofen. Examination of values of both the absorption and disposition parameters of R(–)ibuprofen revealed that the kinetics of R(–)ibuprofen were not altered by concurrent administration of S( + )ibuprofen. In this study, there was little or no presystemic inversion of R(–)ibuprofen to its S( + )isomer. Also, 69% of the intravenous dose of R(–)ibuprofen was systemically inverted and 57.6% of the oral dose of R(–)ibuprofen lysinate was bioavailable as S ( + )ibuprofen. These results indicate that the bioinversion of R(–)ibuprofen administered orally is mainly systemic. Because bioinversion of R(–)ibuprofen is not complete, S( + )ibuprofen produced higher bioavailability of S( + )ibuprofen (92.0%) than either racemic ibuprofen (70.7%) or R(–)ibuprofen (57.6%). However, bioavailability of R(–)ibuprofen (83.6%) when dosed alone was not significantly different from when dosed as racemic mixture (80.7%).

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.

PHARMACOKINETICS AND FOOD INTERACTION OF MK‐462 IN HEALTHY MALES

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.