The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women.

A stable-label i.v./oral study design was conducted to investigate the pharmacokinetics (PK) of odanacatib. Healthy, postmenopausal women received oral doses of unlabeled odanacatib administered simultaneously with a reference of 1 mg i.v. stable (13)C-labeled odanacatib. The absolute bioavailability of odanacatib was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is consistent with solubility-limited absorption. Odanacatib exposure (area under the curve from zero to infinity) increased by 15% and 63% when 50 mg was administered with low-fat and high-fat meals, respectively. This magnitude of the food effect is unlikely to be clinically important. The volume of distribution was ∼100 liters. The clearance was ∼0.8 l/h (13 ml/min), supporting that odanacatib is a low-extraction ratio drug. Population PK modeling indicated that 88% of individuals had completed absorption of >80% bioavailable drug within 24 hours, with modest additional absorption after 24 hours and periodic fluctuations in plasma concentrations contributing to late values for time to Cmax in some subjects.

Prednisone has no effect on the pharmacokinetics of CYP3A4 metabolized drugs - midazolam and odanacatib.

We evaluated the effect of prednisone on midazolam and odanacatib pharmacokinetics. In this open-label, 2-period crossover study in healthy male subjects, midazolam 2 mg was administered (Day -1) followed by odanacatib 50 mg (Day 1) during Part 1. In Period 2, prednisone 10 mg once daily (qd) was administered on Days 1-28; odanacatib was co-administered on Day 14 and midazolam 2 mg was co-administered on Days 1 and 28. Subjects were administered midazolam 2 mg on Days 42 and 56. Safety and tolerability were assessed throughout the study. A physiologically-based pharmacokinetic (PBPK) model was also built. There were 15 subjects enrolled; mean age was 31 years. The odanacatib AUC(0- ∞) GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC(0-∞) GMR (90%CI) [midazolam + prednisone (Day 28, Period 2)/midazolam alone (Day -1, Period 1] was 1.08 (0.93,1.26). There were no serious AEs or AEs leading to discontinuation. PBPK modeling showed that prednisone does not cause significant effects on the exposure of sensitive CYP3A4 substrates in vivo at therapeutic doses. Co-administration of prednisone 10 mg qd had no effect on pharmacokinetics of either odanacatib 10 mg or midazolam 2 mg.

Absence of clinically relevant drug-drug interaction between odanacatib and digoxin after concomitant administration.

OBJECTIVES: This study was conducted in order to assess the effect of multiple doses of odanacatib, a cathepsin (Cat)-K inhibitor, on the pharmacokinetics of digoxin. MATERIALS: Twelve healthy male and female subjects received 0.5 mg digoxin and 50 mg odanacatib. METHODS: This open label study was conducted to determine the effect of odanacatib on the plasma pharmacokinetics of immunoreactive digoxin. Subjects received a single oral dose of 0.5 mg digoxin followed by a 10-day washout, followed by 3 once-weekly oral doses of 50 mg odanacatib and co-administration with 0.5 mg digoxin with the last odanacatib dose. A linear mixed-effect model was used to analyze AUC0-120h. Safety and tolerability were assessed. RESULTS: The estimated geometric-mean-ratio (90% confidence interval) for AUC0-120h was 0.95 (0.89, 1.01), which was within (0.80, 1.25) determined to demonstrate a lack of interaction. There were no serious AEs, discontinuations due to AEs, or clinically significant abnormalities in ECG or vital sign measurements. CONCLUSIONS: This study demonstrated that 50 mg odanacatib did not lead to clinically important effects on the pharmacokinetics of 0.5 mg digoxin.

Pharmacokinetics and tolerability of rizatriptan in pediatric migraineurs in a randomized study.

OBJECTIVE: To evaluate the pharmacokinetic profile and tolerability of single doses of rizatriptan oral disintegrating tablets (ODTs) in pediatric migraineurs. BACKGROUND: Acute migraine treatment options for children are limited despite a rising migraine prevalence. No triptans are approved in those under 12, and only sumatriptan nasal spray (European Union) and almotriptan tablets (USA) are approved for those aged 12-17. Appropriate dose selection based on body weight may be a factor in establishing treatment efficacy in this population. METHODS: Randomized, double-blind, placebo-controlled, parallel group, single-dose study in 6- to 17-year-old migraineurs. The study was performed between acute migraine attacks. Subjects were allocated to 1 of 2 groups based on body weight: (1) those weighing <40kg received rizatriptan ODT 5mg or placebo; (2) those weighing ≥40kg received rizatriptan 10mg ODT or placebo. Pharmacokinetic data were compared with historical data on rizatriptan ODT 10mg in healthy adults. RESULTS: The geometric mean area under the plasma concentration-time curve from time 0 to infinity (AUC((0-∞)) ) (hours·ng/mL) and maximum peak plasma concentration (C(max) ) (ng/mL) were 56.68 (95% confidence interval [CI]: 48.60, 66.09) and 22.39 (95% CI: 17.90, 28.02), respectively, for the <40kg group and 78.49 (95% CI: 68.93, 89.38) and 22.27 (95% CI: 18.43, 26.92), respectively, for the ≥40kg group. For the comparison of children vs adults, the geometric mean ratios for rizatriptan AUC((0-∞)) and C(max) were 0.85 (90% CI: 0.73, 0.98) and 1.07 (90% CI: 0.86, 1.34), respectively, for the <40kg group vs historical adult data and 1.17 (90% CI: 1.02, 1.34) and 1.06 (90% CI: 0.87, 1.30), respectively, for the ≥40kg group vs historical adult data. There were no serious adverse events, and rizatriptan was generally well tolerated. CONCLUSIONS: In pediatric migraineurs, a weight-based dosing scheme generated plasma rizatriptan AUC((0-∞)) and C(max) values that were generally similar to those historically observed in adults administered a 10-mg dose of rizatriptan ODT (a proven effective dose). The data support further evaluation of the safety, tolerability, and efficacy of this rizatriptan dosing scheme in larger scale clinical trials in the pediatric migraineur population.

A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects.

A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.

Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson's disease.

The glutamatergic system is thought to contribute to the motor disturbances observed in Parkinson's disease. Blockade of glutamatergic activity by a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is associated with improvement in motor symptoms in a preclinical model of Parkinson's disease. A randomized, double-blind, double-dummy, placebo-controlled, 3-period crossover study was conducted in patients with moderate Parkinson's disease to evaluate the pharmacologic activity of MK-0657, an NR2B-selective NMDA receptor antagonist. Patients (n=16) received single oral doses of MK-0657 7 mg, carbidopa/levodopa 25/250 mg (LD) as a positive control, and placebo, after which motor function was serially evaluated by means of the Unified Parkinson's Disease Rating Scale-Motor Examination (UPDRS-ME). LD administration resulted in significant improvement in the UPDRS-ME relative to placebo (P=.025), confirming the sensitivity of the test paradigm; however, the UPDRS-ME change following MK-0657 administration showed no improvement compared with placebo (P=.110) despite exceeding the target MK-0657 plasma concentration of 400 nM. Although the administration of MK-0657 was generally well tolerated, it was associated with increases in systolic and diastolic blood pressure relative to placebo. The results of this study do not support ongoing clinical development of MK-0657 as a novel monotherapy for Parkinson's disease.

Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects.

AIMS: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics. METHODS: In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22-44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. x 6 days) in the other period. RESULTS: The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC(0-infinity) and C(max) were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively. CONCLUSION: Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.

Effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs on urinary sodium excretion, blood pressure, and other renal function indicators in elderly subjects consuming a controlled sodium diet.

This multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessed renal function during dosing with etoricoxib 90 mg daily, celecoxib 200 mg twice daily, and naproxen 500 mg twice daily. Male and female subjects 60 to 81 years old (n = 85), in sodium balance on a controlled, normal sodium diet, were treated for 15 days. There were no clinically meaningful between-treatment differences in urinary sodium excretion, creatinine clearance, body weight, or serum electrolytes during the 2 weeks of treatment. Etoricoxib and celecoxib had no effect on the urinary thromboxane metabolite, 11-dehydrothromboxane B(2), while significantly decreasing the urinary prostacyclin metabolite, 2,3-dinor-6-keto PGF(1alpha). Decreases were greater for both metabolites following naproxen. Ambulatory systolic blood pressures were significantly higher than placebo for all treatments, with moderately greater increases for etoricoxib relative to other active treatments on day 14. Ambulatory diastolic blood pressures were significantly higher than placebo for etoricoxib and naproxen but not for celecoxib.

Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme.

Raltegravir is a potent human immunodeficiency virus 1 (HIV-1) integrase strand transfer inhibitor that is being developed as a novel anti-AIDS drug. The absorption, metabolism, and excretion of raltegravir were studied in healthy volunteers after a single oral dose of 200 mg (200 microCi) of [(14)C]raltegravir. Plasma, urine, and fecal samples were collected at specified intervals up to 240 h postdose, and the samples were analyzed for total radioactivity, parent compound, and metabolites. Radioactivity was eliminated in substantial amounts in both urine (32%) and feces (51%). The elimination of radioactivity was rapid, since the majority of the recovered dose was attributable to samples collected through 24 h. In extracts of urine, two components were detected and were identified as raltegravir and the glucuronide of raltegravir (M2), and each accounted for 9% and 23% of the dose recovered in urine, respectively. Only a single radioactive peak, which was identified as raltegravir, was detected in fecal extracts; raltegravir in feces is believed to be derived, at least in part, from the hydrolysis of M2 secreted in bile, as demonstrated in rats. The major entity in plasma was raltegravir, which represented 70% of the total radioactivity, with the remaining radioactivity accounted for by M2. Studies using cDNA-expressed UDP-glucuronosyltransferases (UGTs), form-selective chemical inhibitors, and correlation analysis indicated that UGT1A1 was the main UGT isoform responsible for the formation of M2. Collectively, the data indicate that the major mechanism of clearance of raltegravir in humans is UGT1A1-mediated glucuronidation.