David Hreniuk

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 μCi) of [14C]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.

The Effect of Moxifloxacin on QTc and Implications for the Design of Thorough QT Studies

A number of issues have remained unanswered in the design of “thorough QT” (TQT) studies. In this randomized, placebo‐controlled, two‐period crossover study in 20 healthy subjects, replicate electrocardiograms (ECGs) were recorded on a digital 12‐lead Holter recorder, extracted in a core ECG laboratory, and interpreted manually by a cardiologist. The observed within‐subject variability was slightly greater when time‐matched baselines were employed than when predose baselines were employed, whereas the magnitude of the increase in QTc was similar for both. Moxifloxacin 400 mg was associated with an observed 7.5–12.5 ms increase in the mean placebo‐ and baseline‐corrected QTc interval. A PK‐QTc model estimated a 3.9 ms increase in the QTc interval for every 1,000 ng/ml increase in moxifloxacin concentration. The QTc increases associated with moxifloxacin support the appropriateness of its use as a positive control in TQT studies. This crossover study failed to justify the use of time‐matched baselines rather than the less resource‐intensive predose definition of baseline.

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.

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 Parkinsons 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 Parkinsons disease. A randomized, double‐blind, double‐dummy, placebo‐controlled, 3‐period crossover study was conducted in patients with moderate Parkinsons disease to evaluate the pharmacologic activity of MK‐0657, an NR2B‐selctive 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 Parkinsons 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 Parkinsons disease.

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.

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 B2, while significantly decreasing the urinary prostacyclin metabolite, 2,3‐dinor‐6‐keto PGF1α. 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.

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.

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 AUC0−∞ GMR (90% CI) [odanacatib + prednisone (Day 14, Period 2)/odanacatib alone (Day 1, Period 1] was 1.06 (0.96, 1.17). AUC0−∞ 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.

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 13C-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.

Effect of rofecoxib, etoricoxib, celecoxib, and naproxen on urinary excretion of prostanoids in elderly volunteers

COX‐2 inhibitors (COX2i) and nonselective NSAIDs affect systemic and renal prostaglandin synthesis and may have differential effects on vasoactive eicosanoids [prostacyclin, PGI2; thromboxane, TxB]. This study evaluated the effects of placebo (P), an NSAID [naproxen (N) 500 mg BID], and 3 COX2i [rofecoxib (R) 25 mg QD, etoricoxib (E) 90 mg QD, and celecoxib (C) 200 mg BID] on urinary prostanoids, 11‐dehydro TxB2 (TxB‐M; systemic TxB production measure), and 2,3 dinor 6‐keto PGF1α, (PGI‐M; systemic PGI2 production measure).