Daniel Tatosian

Equivalent Dynamic Human Brain NK1-Receptor Occupancy Following Single-Dose i.v. Fosaprepitant vs. Oral Aprepitant as Assessed by PET Imaging

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single‐dose i.v. infusion of 150‐mg fosaprepitant and single‐dose oral administration of 165‐mg aprepitant, using serial [18F]MK‐0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (Tmax; ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41–75%, respectively. After aprepitant, NK1R occupancy rates at these time points (Tmax ~4 h) were ≥99, ≥99, ≥97, and 37–76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A

A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion‐transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P‐glycoprotein (P‐gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst‐case scenario for P‐gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.

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.

Single and multiple dose pharmacokinetics and pharmacodynamics of omarigliptin, a novel, once‐weekly dipeptidyl peptidase‐4 inhibitor, in healthy Japanese men

Omarigliptin is a novel, potent, long‐acting oral dipeptidyl peptidase‐4 inhibitor being developed as a once‐weekly (q.w.) treatment for type 2 diabetes mellitus patients, with 25 mg and 12.5 mg tablets recently being approved as market formulations in Japan.

Pharmacokinetic and Pharmacodynamic Effects of Multiple-dose Administration of Omarigliptin, a Once-weekly Dipeptidyl Peptidase-4 Inhibitor, in Obese Participants With and Without Type 2 Diabetes Mellitus.

PURPOSE Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM. METHODS This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks. Participants included 24 obese but otherwise healthy subjects (panel A; omarigliptin, n = 18; placebo, n = 6) and 8 obese patients with T2DM (treatment naive, hemoglobin A1c ≥ 6.5% and ≤ 10.0% [panel B]; omarigliptin, n = 6; placebo, n = 2). Participants were 45 to 65 years of age with a body mass index of ≥ 30 and ≤ 40 kg/m(2). Blood sampling occurred at select time points, depending on the study panel, to evaluate the PK properties of omarigliptin, DPP-4 activity, active glucagon-like peptide 1 levels, and plasma glucose concentrations. Body weight was an exploratory end point. Due to sparse sampling in panel A, a thorough PK analysis was performed in obese patients with T2DM (panel B) only. PD analyses were performed in the overall study population (pooled panels A and B). FINDINGS PK profiles in obese participants with and without T2DM were similar to those observed in nonobese reference subjects (historical data). Steady state was achieved after 1 or 2 weekly doses in obese participants with and without T2DM. In obese patients with T2DM, omarigliptin was rapidly absorbed, with a median Tmax of 1 to 2.5 hours (days 1 and 22). Compared with those in reference subjects, the geometric mean ratios (95% CI) (Obese T2DM/reference) for steady-state plasma AUC0-168h, Cmax, and C168h were 0.80 (0.65-0.98), 0.86 (0.53-1.41), and 1.08 (0.88-1.33), respectively. Trough DPP-4 activity was inhibited by ~90%; postprandial (PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2-fold; and PP glucose was significantly reduced with omarigliptin versus placebo in the pooled population. Omarigliptin was generally well-tolerated in the pooled population, and there were no hypoglycemic events. Consistent with other DPP-4 inhibitors, omarigliptin had no effect on body weight in this short-duration study. IMPLICATIONS The administration of omarigliptin was generally well-tolerated in obese participants with and without T2DM, and the favorable PK and PD profiles support once-weekly dosing. Omarigliptin may provide an important once-weekly treatment option for patients with T2DM. ClinicalTrials.gov identifier: NCT01088711.

A Thorough QTc Study Confirms Early Pharmacokinetics/QTc Modeling: A Supratherapeutic Dose of Omarigliptin, a Once‐Weekly DPP‐4 Inhibitor, Does Not Prolong the QTc Interval

Omarigliptin is a dipeptidyl peptidase‐4 inhibitor being developed as a once‐weekly treatment for type 2 diabetes. This double‐blind, double‐dummy, randomized, 3‐period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population‐specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4‐week washout: (1) single‐dose 25 mg omarigliptin (day 1), single‐dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single‐dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least‐squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin‐placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration‐QTc analysis.

A Single‐Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects

Fosaprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Intravenous (IV) fosaprepitant and oral aprepitant are used in combination with other antiemetics to prevent chemotherapy‐induced nausea and vomiting. This randomized, phase 1 study was designed to assess the aprepitant area under the curve (AUC0‐∞) equivalence of a single, oral 165‐mg or 185‐mg dose of aprepitant to a single 150‐mg fosaprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165‐mg and 185‐mg aprepitant doses. Plasma samples were analyzed for aprepitant, and linear mixed‐effects models were applied to natural log‐transformed aprepitant AUC data. A 2 one‐sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0‐∞ of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of aprepitant is equivalent to the AUC0‐∞ of a single IV infusion of fosaprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of aprepitant. Single‐dose administration of oral 165 mg and 185 mg aprepitant and IV 150 mg fosaprepitant was generally well tolerated.

Effects of Age, Sex, and Obesity on the Single‐Dose Pharmacokinetics of Omarigliptin in Healthy Subjects

Omarigliptin is being developed as a potent, once‐weekly, oral dipeptidyl peptidase‐4 inhibitor for the treatment of type 2 diabetes. This double‐blind, randomized, placebo‐controlled study evaluated the effects of age, sex, and obesity on the pharmacokinetics of omarigliptin in healthy subjects. A single oral dose of omarigliptin 10 mg (n = 6/panel) or placebo (n = 2/panel) was administered in the fasted state to elderly nonobese men and women, young obese (30 ≤ body mass index [BMI] ≤ 35 kg/m2) men and women, and young nonobese women of nonchildbearing potential. Plasma was collected at selected postdose times for evaluation of omarigliptin concentrations. Pharmacokinetic parameters were compared with historical data from a previously‐conducted single‐dose study in young, healthy, nonobese men. There were no clinically significant differences in omarigliptin AUC0–∞, the primary pharmacokinetic parameter for assessing efficacy and safety, based on age, sex, or BMI (pooled nonobese elderly versus pooled nonobese young, young nonobese female versus young nonobese male, and pooled young obese versus pooled young nonobese). There were no serious adverse events or hypoglycemic events attributable to omarigliptin administration. Demographic factors and BMI had no meaningful effect on omarigliptin pharmacokinetics, suggesting that dose adjustment based on age, sex, or obesity is not required.

Use of Minipig Skin Biopsy Model as an Innovative Tool to Design Topical Formulation to Achieve Desired Pharmacokinetics in Humans

In vitro cadaver skin permeation studies are often conducted to characterize the permeation profile of compounds for dermal delivery. However, its utility could be limited in the case of topical products because of lack of reliable prediction of in vivo skin kinetics. In this paper, the use of in vivo skin biopsy data to guide topical formulation development is described. A formulation was developed by compounding MK-0873, a phosphodiesterase 4 (PDE4) inhibitor, into a commercially available cream base. The cream was characterized by skin pharmacokinetic studies in minipigs, which demonstrated that MK-0873 concentrations in the epidermis and dermis were substantially higher than the IC80 for human whole blood PDE4 inhibition of ∼200 nM, suggesting that cream should provide sufficient skin exposure to assess clinical efficacy. In toxicological studies, after 1 month repeat application in minipigs minor dermal irritation and minimal systemic exposure were observed. Based on these preclinical data, the cream formulation was chosen for single rising dose clinical studies, where plasma levels of MK-0873 were mostly below the LOQ, whereas skin biopsy concentrations ranged from 6.5 to 25.1 μM. These data suggested that minipig skin biopsy model can be a valuable tool to assess performance of topical formulations and guide formulation development.

Placebo- and Amitriptyline-Controlled Evaluation of Central Nervous System Effects of the NK1 Receptor Antagonist Aprepitant and Intravenous Alcohol Infusion at Pseudo-Steady State

Recent interest in NK1 receptor antagonists has focused on a potential role in the treatment of drug addiction and substance abuse. In the present study, the potential for interactions between the NK1 receptor antagonist aprepitant and alcohol, given as an infusion at a target level of 0.65 g/L, was evaluated. Amitriptyline was included as positive control to provide an impression of the profile of central nervous system (CNS) effects. In a double‐blind, randomized, placebo‐ and amitriptyline‐controlled study, the pharmacokinetics and CNS effects of aprepitant and alcohol were investigated in 16 healthy volunteers. Cognitive and psychomotor function tests included the visual verbal learning test (VVLT), Bond and Lader visual analogue scales (VAS), digit symbol substitution test (DSST), visual pattern recognition, binary choice reaction time, critical flicker fusion (CFF), body sway, finger tapping, and adaptive tracking. Alcohol impaired finger tapping and body sway. Amitriptyline impaired DSST performance, VAS alertness, CFF, body sway, finger tapping, and adaptive tracking. No impairments were found after administration of aprepitant. Co‐administration of aprepitant with alcohol was generally well tolerated and did not cause significant additive CNS effects, compared with alcohol alone. Therefore, our study found no indications for clinically relevant interactions between aprepitant and alcohol.