M. Gail Murphy

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone

Aprepitant is a neurokinin1 receptor antagonist that, in combination with a corticosteroid and a 5‐hydroxytryptamine3 receptor antagonist, has been shown to be very effective in the prevention of chemotherapy‐induced nausea and vomiting. At doses used for the management of chemotherapy‐induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated.

Tolerability of Fosaprepitant and Bioequivalency to Aprepitant in Healthy Subjects

Fosaprepitant is an intravenous formulation of aprepitant, an oral NK1 antagonist used to prevent chemotherapy‐induced nausea and vomiting. This randomized study was designed to evaluate fosaprepitant in polysorbate 80 vehicle for tolerability and bioequivalency to aprepitant. Tolerability was assessed by physical and laboratory examinations and adverse events. Plasma collected for 72 hours was assayed for aprepitant and fosaprepitant. Analysis of variance models were applied to natural log‐transformed aprepitant area under the curve (AUC) data. Fosaprepitant up to 150 mg (1 mg/mL) was generally well tolerated. Fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg; the 90% confidence interval for the geometric mean ratio of aprepitant AUC for fosaprepitant 115 mg/aprepitant 125 mg fell within prespecified equivalence bounds of 0.80 to 1.25.

Effects of aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects

BACKGROUND The neurokinin-1-receptor antagonist aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT(3))-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV). OBJECTIVE Two studies were conducted to determine whether concomitant administration of aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT(3)-receptor antagonists commonly used as antiemetic therapy for CINV. METHODS The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years. Study 1 involved the following 2 treatment regimens: aprepitant 375 mg PO, dexamethasone 20 mg PO, and ondansetron 32 mg IV on day 1, followed by aprepitant 250 mg PO and dexamethasone 8 mg PO on days 2 through 5; and dexamethasone 20 mg PO and ondansetron 32 mg IV on day 1, followed by dexamethasone 8 mg PO on days 2 through 5. Study 2 involved the following 2 treatment regimens: aprepitant 125 mg PO with granisetron 2 mg PO on day 1, followed by aprepitant 80 mg PO on days 2 and 3; and granisetron 2 mg PO on day 1 only. Individual plasma samples were used to estimate area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )), peak plasma concentration, and apparent terminal elimination half-life (t(12)) of both ondansetron and granisetron. RESULTS Study 1 included 19 subjects (10 women, 9 men), and study 2 included 18 subjects (11 men, 7 women). Coadministration of aprepitant 375 mg produced a small but statistically significant increase in the AUC(0- infinity ) for intravenous ondansetron (from 1268.3 to 1456.5 ng.h/mL; P = 0.019), with no significant effect on peak concentration at the end of the infusion (360.8 ng/mL with aprepitant vs 408.4 ng/mL without) or t(12) (5.0 vs 4.5 hours, respectively). Coadministration of aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC(0- infinity ), 101.4 ng.h/mL with aprepitant vs 92.2 ng.h/mL without; maximum plasma concentration, 9.0 ng/mL with and without aprepitant; time to maximum plasma concentration, both 3.0 hours; t(12), 6.5 vs 6.9 hours, respectively). CONCLUSION Concomitant administration of aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects.

In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist

3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d][1,2,4]triazine (MRK-016) is a pyrazolotriazine with an affinity of between 0.8 and 1.5 nM for the benzodiazepine binding site of native rat brain and recombinant human α1-, α2-, α3-, and α5-containing GABAA receptors. It has inverse agonist efficacy selective for the α5 subtype, and this α5 inverse agonism is greater than that of the prototypic α5-selective compound 3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-hdyl)methyloxy]-1,2,4-triazolo[3,4-a]phthalazine (α5IA). Consistent with its greater α5 inverse agonism, MRK-016 increased long-term potentiation in mouse hippocampal slices to a greater extent than α5IA. MRK-016 gave good receptor occupancy after oral dosing in rats, with the dose required to produce 50% occupancy being 0.39 mg/kg and a corresponding rat plasma EC50 value of 15 ng/ml that was similar to the rhesus monkey plasma EC50 value of 21 ng/ml obtained using [11C]flumazenil positron emission tomography. In normal rats, MRK-016 enhanced cognitive performance in the delayed matching-to-position version of the Morris water maze but was not anxiogenic, and in mice it was not proconvulsant and did not produce kindling. MRK-016 had a short half-life in rat, dog, and rhesus monkey (0.3–0.5 h) but had a much lower rate of turnover in human compared with rat, dog, or rhesus monkey hepatocytes. Accordingly, in human, MRK-016 had a longer half-life than in preclinical species (∼3.5 h). Although it was well tolerated in young males, with a maximal tolerated single dose of 5 mg corresponding to an estimated occupancy in the region of 75%, MRK-016 was poorly tolerated in elderly subjects, even at a dose of 0.5 mg, which, along with its variable human pharmacokinetics, precluded its further development.

Single- and Multiple-Dose Pharmacokinetics and Tolerability of Telcagepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, in Adults

Telcagepant is a novel, orally active, and selective calcitonin gene‐related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half‐life was approximately 6 hours. A greater than dose‐proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice‐daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Lack of Effect of Aprepitant on Digoxin Pharmacokinetics in Healthy Subjects

Aprepitant is a highly selective neurokinin‐1 receptor antagonist that, in combination with a corticosteroid and a 5‐hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy‐induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P‐glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P‐glycoprotein substrate, was examined in a double‐blind, placebo‐controlled, randomized, two‐period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0–24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24‐hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5‐day regimen, did not interact with a known substrate of the P‐glycoprotein transporter.

The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men

AIMS To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG). METHODS Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI). RESULTS The aortic AIx following NTG decreased by -18.50 (-21.02, -15.98) % after telcagepant vs. -17.28 (-19.80, -14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated. CONCLUSIONS Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.

Tolerability, pharmacokinetics and night-time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Body sway increases in older adults and may lead to an increase in the risk of falling. The problem of impaired stability in the elderly may be compounded by the use of hypnotics, which have been associated with an increased risk of next-day falls as well as drowsiness. The potential adverse effects of hypnotic drugs on steadiness may be exacerbated during the night, in the event that an individual needs to get out of bed. WHAT THIS STUDY ADDS This study examines the effects of gaboxadol (an investigational treatment for insomnia), zolpidem (a current hypnotic included as an active control) and placebo on body sway and attention/information processing ability following bedtime dosing in elderly subjects who were woken during the night for assessments. Zolpidem and gaboxadol increased body sway at various time points during the night relative to placebo; at 1.5 h post dose, the time of peak concentrations of both drugs, gaboxadol produced less impairment than zolpidem. Compared with placebo, neither gaboxadol nor zolpidem impaired attention/information-processing ability as assessed by critical flicker fusion. AIMS To evaluate tolerability, pharmacokinetics and night-time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects. METHODS Subjects (17 women, seven men) aged 65-75 years received gaboxadol 10 mg, zolpidem 5 mg (active control) or placebo at 22.00 h in a three-period, randomized, double-blind crossover study. They were awakened during the night for evaluation of body sway and CFF. Pharmacokinetics of gaboxadol were assessed during a fourth single-blind treatment period. Adverse events were recorded throughout the study. RESULTS The number of subjects with adverse events was 14 for gaboxadol 10 mg, seven for zolpidem and nine for placebo; most were mild or moderate in intensity. Two women discontinued the study following gaboxadol; one vomited and one experienced a severe vasovagal syncope after venepuncture. Mean gaboxadol t(max) was 2 h, t((1/2)) was 1.7 h, AUC(0-infinity) was 430 ng.h ml(-1) and C(max) was 139 ng ml(-1). At 1.5 h and 4 h post dose, zolpidem increased body sway relative to placebo (P < 0.01). Gaboxadol increased body sway at 4 h (P < 0.001) and 8 h (P < 0.05) relative to placebo. At 1.5 h, the time point closest to peak drug concentrations, zolpidem increased body sway compared with gaboxadol (P < 0.01). Gaboxadol and zolpidem had no effects on CFF vs. placebo. CONCLUSIONS A bedtime dose of gaboxadol 10 mg was generally well tolerated. Changes in body sway at 1.5 h after bedtime dosing were smaller with gaboxadol 10 mg than with zolpidem 5 mg, whereas changes were similar at 4 h for both treatments and returned to near baseline at 8 h.

Lack of Effect of Aprepitant on Hydrodolasetron Pharmacokinetics in CYP2D6 Extensive and Poor Metabolizers

To prevent chemotherapy‐induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5‐hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open‐label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2–3). For hydrodolasetron area under the concentration‐versus‐time curve (AUC0‐∞) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (≤2.0) for clinical significance (AUC0‐∞, 1.09 [90% CI, 1.01–1.18], Cmax, 1.08 [90% CI, 0.94–1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.

Lack of effect of aprepitant or its prodrug fosaprepitant on QTc intervals in healthy subjects.

BACKGROUND: A single 115-mg dose of fosaprepitant, the IV prodrug of the NK1 receptor antagonist aprepitant, is bioequivalent to a 125-mg dose of oral aprepitant. Thus far, fosaprepitant/aprepitant has not shown a meaningful effect on QTc intervals; in this study, we sought to confirm these findings. METHODS: This double-blind, active-controlled, randomized, three-treatment, three-period, crossover study in healthy young subjects evaluated the effect of a 200-mg dose of fosaprepitant on QTc prolongation. In each period, subjects received 400 mg moxifloxacin per os, 200 mg fosaprepitant IV, or placebo in randomized sequence. The effect of fosaprepitant on QTc interval was assessed by 12-lead electrocardiograms (ECGs). The baseline value for QTc interval for each subject during each period was defined as the average of five replicate baseline QTc intervals extracted from predose ECGs. ECGs were performed at predose, 2, 5, 10, 15, 20, 30, 45 min; and 1, 1.5, 2, 3, 4, 6, and 8 h postinfusion. Values for individual QTc change from baseline were evaluated in a repeated-measures mixed model appropriate for a crossover design. A two-sided 90% confidence interval (CI) for the true difference in QTc interval change from baseline at each timepoint was calculated for fosaprepitant versus placebo and for moxifloxacin versus placebo. RESULTS: After fosaprepitant 200-mg administration, the mean (95% CI) QTc interval change from baseline at Tmax was −1.45 (−4.67 to 1.77) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline was −1.37 (−4.78 to 2.05) ms. Neither was statistically significant at &agr; = 0.05. After 400 mg moxifloxacin administration, the mean (95% CI) QTc interval change from baseline at 2 h was 9.71 (6.49–12.93) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline at moxifloxacin Tmax was 10.50 (7.09–13.92) ms. Both were statistically significant at &agr; = 0.05. The maximum aprepitant concentration after fosaprepitant 200 mg administration was 6300 ng/mL (approximately twofold, fourfold, and ninefold higher than that observed historically with fosaprepitant 115 mg [3095 ng/mL], aprepitant 125 mg [1600 ng/mL], and aprepitant 40 mg [675 ng/mL]). CONCLUSIONS: In subjects receiving fosaprepitant 200 mg, no clinically meaningful increases in QTc were seen at any timepoint, whereas after moxifloxacin 400 mg, increases were observed at the approximate Tmax of moxifloxacin and additional timepoints. The lack of QTc increase at this high dose of fosaprepitant and resulting aprepitant plasma exposures support the expectation that clinical doses of fosaprepitant or aprepitant will not be associated with significant QTc prolongation.