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 NK(1) 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 T(max) 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 alpha = 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 T(max) was 10.50 (7.09-13.92) ms. Both were statistically significant at alpha = 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 T(max) 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.

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.

Effect of aprepitant on the pharmacokinetics of intravenous midazolam.

Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg +/- oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound < or =2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC(0-infinity) 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers.

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.

Effect of impaired renal function and haemodialysis on the pharmacokinetics of aprepitant.

BACKGROUND: The neurokinin NK(1)-receptor antagonist aprepitant has demonstrated efficacy in preventing highly emetogenic chemotherapy-induced nausea and vomiting. OBJECTIVE: The objective of the present study was to investigate the effects of impaired renal function on the pharmacokinetics and safety of aprepitant. SUBJECTS AND METHODS: A total of 32 patients and healthy subjects were evaluated in this open-label, two-part study. Pharmacokinetic parameters after a single oral dose of aprepitant 240 mg were measured in eight patients with end-stage renal disease (ESRD) requiring haemodialysis, eight patients with severe renal insufficiency (SRI [24-hour creatinine clearance <30 mL/min/1.73 m(2)]) and 16 healthy and age-, sex- and weight-matched subjects (controls). RESULTS: In ESRD patients, the area under the plasma concentration-time curve (AUC) from 0 to 48 hours (AUC(48)) for aprepitant was on average approximately 36% lower than that observed in control subjects (ratio [ESRD patients/healthy controls] of geometric means = 0.64), but the 90% confidence interval 0.52, 0.78 for the ratio of true mean AUC(48) fell within the predefined target interval of 0.5, 2.0. Also in ESRD patients, there was no statistically or clinically significant difference in unbound aprepitant AUC (which may be more clinically relevant than total aprepitant AUC) when compared with healthy control subjects. Aprepitant pharmacokinetic parameters in ESRD patients were clinically similar when haemodialysis was initiated at 4 hours or 48 hours after aprepitant administration. In SRI patients, the ratio (SRI patients/healthy controls) of aprepitant AUC from zero to infinity (AUC(infinity)) geometric mean value was 0.79 with a 90% confidence interval of 0.56, 1.10. On average, in SRI patients the principal aprepitant pharmacokinetic parameters (AUC(infinity), initial maximum plasma concentration [C(max)], time to initial C(max), and apparent elimination half-life) were not statistically different from those obtained in healthy control subjects. Aprepitant was generally well tolerated in both ESRD and SRI patients. CONCLUSION: The results of this study demonstrate that ESRD, haemodialysis and SRI have no clinically meaningful effect on aprepitant pharmacokinetics. Therefore, no dosage adjustment of aprepitant is warranted in SRI or ESRD patients.

Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant.

BACKGROUND: Aprepitant is a highly selective substance P (neurokinin 1 [NK(1)] receptor) antagonist that significantly improves the pharmacotherapy of acute and delayed highly emetogenic chemotherapy-induced nausea and vomiting, probably through an action in the brain stem region of the central nervous system. Here, we report the use of positron emission tomography imaging with the NK(1) receptor binding-selective tracer [(18)F]SPA-RQC to determine the levels of central NK(1) receptor occupancy achieved by therapeutically relevant doses of aprepitant in healthy humans. METHODS: Two single-blind, randomized, placebo-controlled studies in healthy subjects were performed. The first study evaluated the plasma concentration-occupancy relationships for aprepitant dosed orally at 10, 30, 100, or 300 mg, or placebo (n = 12). The second study similarly evaluated oral aprepitant 30 mg and placebo (n = 4). In each study, dosing was once daily for 14 consecutive days. Data from both studies were combined for analyses. The ratio of striatal/cerebellar [(18)F]SPA-RQ (high receptor density region/reference region lacking receptors) was used to calculate trough receptor occupancy 24 hours after the last dose of aprepitant. RESULTS: Brain NK(1) receptor occupancy increased after oral aprepitant dosing in both a plasma concentration-related (r =.97; 95% confidence interval [CI] =.94-1.00, p <.001) and a dose-related (r =.94; 95% CI =.86-1.00, p <.001) fashion. High (> or =90%) receptor occupancy was achieved at doses of 100 mg/day or greater. The plasma concentrations of aprepitant that achieved 50% and 90% occupancy were estimated as approximately 10 ng/mL and approximately 100 ng/mL, respectively. CONCLUSIONS: Positron emission tomography imaging with [(18)F]SPA-RQ allows brain NK(1) receptor occupancy by aprepitant to be predicted from plasma drug concentrations and can be used to guide dose selection for clinical trials of NK(1) receptor antagonists in central therapeutic indications.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study. METHODS: In this open-label, randomized, single-period study, 16 healthy male subjects were enrolled. Subjects received one of two oral aprepitant regimens for 5 days (8 subjects per regimen): (1) 125 mg aprepitant on day 1 and then 80 mg/d on days 2 to 5 or (2) 40 mg aprepitant on day 1 and then 25 mg/d on days 2 to 5. All subjects also received a single oral dose of midazolam, 2 mg, at prestudy (3 to 7 days before aprepitant treatment) and on days 1 and 5 (1 hour after aprepitant administration). RESULTS: Coadministration of midazolam and 125/80 mg aprepitant increased the midazolam area under the plasma concentration-time curve by 2.3-fold on day 1 (P <.01) and by 3.3-fold on day 5 (P <.01), as compared with midazolam alone (prestudy). The 125/80-mg regimen of aprepitant also increased the midazolam maximum observed concentration by 1.5-fold on day 1 (P <.05) and by 1.9-fold on day 5 (P <.01). The midazolam half-life values increased from 1.7 hours (prestudy) to 3.3 hours on both day 1 and day 5. Coadministration of 40/25 mg aprepitant and midazolam did not result in significant changes in the midazolam area under the plasma concentration-time curve, maximum observed concentration, and half-life at either day 1 or day 5. CONCLUSIONS: The 5-day 125/80-mg regimen of aprepitant produced moderate inhibition of CYP3A4 activity in humans, as measured with the use of midazolam as a probe drug.

Cyclobenzaprine pharmacokinetics, including the effects of age, gender, and hepatic insufficiency.

The pharmacokinetics and bioavailability of cyclobenzaprine, a widely used muscle relaxant, were investigated in four clinical studies, and the effects of age, gender, and hepatic insufficiency were characterized. Cyclobenzaprine plasma clearance was 689 ml/min, and the bioavailability of a 5 mg oral dose was 0.55. Following oral doses of 2.5 to 10 mg tid in healthy young subjects, cyclobenzaprine pharmacokinetics were linear, and plasma concentrations generally increased proportional to dose. There was about a fourfold accumulation of the drug in plasma on multiple dosing, corresponding to an effective half-life of 18 hours. Steady-state plasma concentrations of cyclobenzaprine in elderly subjects were twice as high as in young subjects following oral doses of 5 mg tid. Steady-state plasma concentration also appeared to be up to twofold higher in subjects with mild hepatic insufficiency compared to healthy controls. The magnitude of any difference in steady-state plasma concentration between males and females appears to be small relative to intersubject variability. A reduction in dose or dosing frequency should be considered in the elderly and in patients with liver disease.

Bioavailability of alendronate and vitamin D(3) in an alendronate/vitamin D(3) combination tablet.

These studies were designed to demonstrate that the alendronate (ALN) component of an ALN/vitamin D(3) combination tablet was bioequivalent to the 70-mg ALN tablet and that the pharmacokinetic parameters of vitamin D(3) were similar with or without ALN. These were open-label, randomized, 2-part, 2-period, crossover studies. In part I, participants received either a single combination tablet or ALN 70 mg. In part II, participants received either a single combination tablet or vitamin D(3) alone. Results from part I showed that the geometric mean ratio (GMR) for total urinary excretion of ALN for both studies fell within the prespecified bioequivalence bounds. Results from part II showed that the pharmacokinetic profiles of vitamin D(3) with or without ALN were also similar. The combination tablets are bioequivalent to the ALN 70-mg tablet with respect to ALN bioavailability. The bioavailability of vitamin D(3) is similar in the combination tablets and when administered alone. No serious adverse experiences were reported.

Determination of sitagliptinin human plasma using protein precipitation and tandem mass spectrometry.

A simple offline LC-MS/MS method for the quantification of sitagliptin in human plasma is described. Samples are prepared using protein precipitation. Filtration of the supernatants through a Hybrid-SPE-PPT plate was found to be necessary to reduce ionization suppression caused by co-elution of phospholipids with sitagliptin. The sitagliptin and its stable isotope labeled internal standard (IS) were chromatographed under hydrophilic interaction chromatography conditions on a Waters Atlantis HILIC Silica column (2.1 mm x 50 mm, 3 microm) using a mobile phase of ACN/H(2)O (80/20, v/v) containing 10 mM NH(4)Ac (pH 4.7). The sample drying after protein precipitation due to high organic content in the sample is not necessary, because HILIC column was used. The analytes were detected with a tandem mass spectrometer employing a turbo ion spray (TIS) interface in positive ionization mode. The multiple reaction monitoring (MRM) transitions were m/z 408-->235 for sitagliptin and m/z 412-->239 for IS. The lower limit of quantitation (LLOQ) for this method is 1 ng/mL when 100 microL of plasma is processed. The linear calibration range is 1-1000 ng/mL for sitagliptin. Intra-day precision and accuracy were assessed based on the analysis of six sets of calibration standards prepared in six lots of human control plasma. Intra-day precision (RSD%, n=6) ranged from 1.2% to 6.1% and the intra-day accuracy ranged from 97.6% to 103% of nominal values.