S. Aubrey Stoch

[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

[18F]MK-9470 is a selective, high-affinity, inverse agonist (human IC50, 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [18F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4–5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of [18F]MK-9470 very similar to that seen in monkeys, with very good test–retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in [18F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [18F]MK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.

Pitavastatin is a more sensitive and selective organic anion‐transporting polypeptide 1B clinical probe than rosuvastatin

AIMS Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion-transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive in vitro assessment of rifampicin inhibitory potential on statin transporters. METHODS The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The in vitro transporter studies were performed using hepatocytes and recombinant expression systems. RESULTS Rifampicin markedly increased exposures of both statins, with greater differential increases after PO vs. IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration-time curve were 5.7- and 7.6-fold for pitavastatin and 4.4- and 3.3-fold for rosuvastatin, after PO and IV rifampicin, respectively. In vitro studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3. CONCLUSIONS The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.

Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics – results from single oral dose studies in healthy volunteers

AIMS To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. METHODS Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). RESULTS Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction. CONCLUSIONS Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

Once-Weekly Oral Alendronate 70 mg in Patients with Glucocorticoid-Induced Bone Loss: A 12-Month Randomized, Placebo-Controlled Clinical Trial

Objective. Glucocorticoid-induced osteoporosis is the most common iatrogenic form of osteoporosis. We evaluated the efficacy and safety of once-weekly bisphosphonate therapy for prevention and treatment of bone loss in patients on glucocorticoid therapy. Methods. We conducted a 12-month, multicenter, randomized, double-blind, placebo-controlled trial with 114 and 59 patients in the treatment and placebo arms, respectively. Participants were stratified according to the duration of prior oral glucocorticoid therapy at randomization. Participants received alendronate 70 mg once weekly (ALN OW) or placebo; all received supplemental daily calcium (1000 mg) and 400 IU vitamin D. Clinical evaluations were performed at baseline, 3, 6, 9, and 12 months. Results. At 12 months, there was a significant mean percentage increase from baseline in the ALN OW group for lumbar spine (2.45%), trochanter (1.27%), total hip (0.75%), and total body (1.70%) bone mineral density (BMD). Comparing ALN OW versus placebo at 12 months, a significant treatment difference for the mean percentage change from baseline was observed for lumbar spine (treatment difference of 2.92%; p ≤ 0.001), trochanter (treatment difference 1.66%; p = 0.007), and total hip (treatment difference 1.19; p = 0.008) BMD. Biochemical markers of bone remodeling also showed significant mean percentage decreases from baseline. Conclusion. Over 12 months ALN OW significantly increased lumbar spine, trochanter, total hip, and total body BMD compared with baseline among patients taking glucocorticoid therapy. A significant treatment difference versus placebo was observed at 12 months for the mean percentage change from baseline for lumbar spine, trochanter, and total hip.

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.

Pharmacokinetics and Pharmacodynamics of MK‐5046, a Bombesin Receptor Subtype‐3 (BRS‐3) Agonist, in Healthy Patients

MK‐5046 is an orally active, potent, selective agonist of the orphan G protein—coupled receptor bombesin receptor subtype‐3 (BRS‐3) that is under evaluation for treatment of obesity. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK‐5046 (10–160 mg) in a double‐blind, randomized, placebo‐controlled study in healthy and obese male volunteers. MK‐5046 exposure increased dose proportionally, and MK‐5046 was eliminated with an apparent terminal half‐life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (Tmax) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections suggest a possible, unanticipated, role for BRS‐3 in reproductive physiology. Oral administration of MK‐5046 achieves plasma concentrations that are projected to activate BRS‐3 and therefore should be suitable for exploring its biological role in humans.

Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable pharmacodynamics and pharmacokinetics in older men and postmenopausal women.

BACKGROUND Odanacatib is a cathepsin K inhibitor in development for the treatment of osteoporosis. Evaluation of therapies to ensure that treatment effects are relevant regardless of sex is clinically important. METHODS In this double-blind, randomized controlled trial, older men (aged 50-75 years) and postmenopausal women (aged 45-75 years) were given odanacatib 50 mg once weekly or placebo for 4 weeks. Pharmacodynamic (PD) evaluation measured weighted average inhibition (WAI) of urine amino-terminal cross-linked telopeptide of type I collagen/creatinine (uNTx/Cr) after odanacatib administration. Pharmacokinetic (PK) parameter data were collected, and an analysis of sex as a factor in the PK/PD relationship was conducted. Adverse events were monitored. The hypotheses were that WAI of uNTx/Cr would be >40% (including >40% for the lower limit of the 90% confidence intervals [CIs]) for older men and postmenopausal women, that there would be no important differences in area under the curve from 0 to 168 hours (AUC0-168 h) between men and women, and that odanacatib would be safe and well tolerated. RESULTS A total of 44 subjects (32 men and 12 women) were randomized. The least squares mean WAI (uNTx/Cr) at week 4 was 42.8% (90% CI, 35.5%-49.3%) for men and 42.7% (90% CI, 30.3%-52.9%) for women; mean values were >40%, but lower bounds were <40% as prespecified in the primary hypothesis. The differences among men and women in PD parameters were not meaningful (0.1; 90% CI, -14.7 to 14.9). PK parameters for both groups were comparable (geometric mean ratio of AUC0-168 h, 0.90; 90% CI, 0.75-1.07). A PK/PD analysis found that the EC50 and maximum fractional inhibition were similar in male and female subjects. There were no notable or serious adverse events in this study. CONCLUSIONS Although the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weekly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.

Best practices for the use of itraconazole as a replacement for ketoconazole in drug–drug interaction studies

Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug–drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Developments Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLGs recommendations are based on careful review of available literature and internal industry experiences.

Effect of Different Durations and Formulations of Diltiazem on the Single‐Dose Pharmacokinetics of Midazolam: How Long Do We Go?

Understanding how inhibition of cytochrome P4503A (CYP3A) affects the metabolism of a new drug is critical in determining if a clinically relevant drug interaction will occur. Diltiazem interaction studies assess a given compounds sensitivity to moderate CYP3A inhibition. The present study compared the effect different durations and formulations of diltiazem (extended release [XR] and conventional release [CR]) had on the single‐dose pharmacokinetics of midazolam. The geometric mean ratio (GMR; midazolam + diltiazemXR × 5 days/midazolam + diltiazemXR × 2 days) for midazolam AUC0‐∞ was 0.98 (90% confidence interval [CI], 0.87, 1.10). The GMR (midazolam + diltiazemXR × 2 days/midazolam + diltiazemCR × 2 days) for midazolam AUC0‐∞ was 0.82 (90% CI, 0.73, 0.92). Simcyp simulations accurately predicted the observed clinical results only when a hepatic CYP3A degradation rate (kdeg) different from that provided by the software was used. The data suggest that dosing diltiazem XR for 2 days predicts the change in midazolam AUC as reliably as 5 days of XR dosing and 2 days of CR dosing. In addition, the authors believe that a hepatic CYP3A kdeg of 0.03 h−1 should be considered for future Simcyp studies.

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, after Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once‐weekly DPP‐4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single‐dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP‐4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once‐weekly doses over the dose range studied. Omarigliptin resulted in ∼2‐fold increases in weighted average postprandial active GLP‐1. Omarigliptin acts by stabilizing active GLP‐1, which is consistent with its mechanism of action as a DPP‐4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once‐weekly dosing. A model‐based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.