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 [(18)F]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 (T(max); ~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 (T(max) ~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.

Enalapril in RAPIDISC (wafer formulation): pharmacokinetic evaluation of a novel, convenient formulation.

BACKGROUND: Enalapril in RAPIDISC* (wafer), a new easy-to-administer formulation of enalapril, may improve the convenience of enalapril therapy, thereby helping patients adhere to antihypertensive treatment. SUBJECTS AND METHODS: To determine whether 20 mg enalapril wafer is bioequivalent to the conventional 20 mg enalapril tablet, an open-label, two-period crossover study was performed in 16 healthy male volunteers. Cumulative urinary recovery of free enalaprilat (active metabolite of enalapril) and the serum maximum concentration of free enalaprilat (Cmax) were the primary pharmacokinetic parameters used to determine bioequivalence in this study. Bioequivalence was defined as the geometric mean ratio (wafer: tablet) falling within the equivalence limits of 0.80 to 1.25 for both parameters. RESULTS: Cumulative urinary recovery of free enalaprilat (0 - 72 hours) was similar between the wafer and conventional tablet formulations (arithmetic mean 5.13 vs. 5.03 mg, about 36% of dose). The geometric mean ratio of the urinary recovery of free enalaprilat (wafer: tablet) was 1.03 (90% CI: 0.93, 1.15). Cmax of serum enalaprilat was also similar between the wafer and conventional tablet formulations (arithmetic mean 85.7 vs. 76.3 ng/ml). The geometric mean Cmax ratio (wafer: tablet) was 1. 10 (90% CI: 1.00, 1.22). Both enalapril formulations were well tolerated. CONCLUSION: This study demonstrates that 20 mg enalapril in RAPIDISC is bioequivalent to 20 mg enalapril conventional tablet.

A double-blind, placebo-controlled evaluation of the effect of oral doses of rizatriptan 10 mg on oral contraceptive pharmacokinetics in healthy female volunteers.

Rizatriptan (MAXALT), a potent, oral 5-HT1B/1D agonist with a rapid onset of action, is available now for the acute treatment of migraine. This study examined the pharmacokinetic and clinical interaction between rizatriptan 10 mg and the components (ethinyl estradiol [EE] 35 micrograms and norethindrone [NET] 1.0 mg) of a well-established oral contraceptive combination product, ORTHO-NOVUM 1/35. Levels of sex hormone binding globulin (SHBG), a protein increased by EE to which NET binds, were also examined. In this two-period crossover study, 20 healthy young female subjects received a coadministration of 8 days of rizatriptan treatment (6 days of single-dose 10 mg rizatriptan and 2 days of multiple-dose rizatriptan, 10 mg q 4 hours for three doses, giving a total daily dose of 30 mg on Days 7 and 8) or matching placebo along with their daily dose (one tablet) of ORTHO-NOVUM 1/35 within their oral contraceptive cycle. Plasma was sampled for EE, NET, and SHBG concentrations. Safety evaluations included routine laboratory safety studies, physical examinations, and monitoring for ECG, vital signs, and adverse events. There were no statistically significant differences in any of the pharmacokinetic parameters of EE or NET between the rizatriptan and placebo treatment periods, thus indicating that rizatriptan had no meaningful effect on the disposition of either the EE or the NET component of ORTHO-NOVUM 1/35. The SHBG concentration did not change throughout the entire study. Clinically, coadministration of rizatriptan with ORTHO-NOVUM 1/35 was well tolerated. Blood pressure, heart rate, and temperature showed no consistent trend or clinically important changes. Adverse events following coadministration of rizatriptan with ORTHO-NOVUM 1/35 were similar to those reported when placebo was given with ORTHO-NOVUM 1/35. The findings of this study indicate that there is little potential for dosages as high as 30 mg/day, the maximum recommended dosing schedule, of rizatriptan to alter the plasma concentrations of oral contraceptives.

Rizatriptan, a novel 5-HT1B/1D agonist for migraine: single- and multiple-dose tolerability and pharmacokinetics in healthy subjects.

Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma.

Lack of pharmacokinetic and pharmacodynamic interaction between rizatriptan and paroxetine.

Rizatriptan is a potent, oral 5-HT(1B/1D) agonist with a rapid onset of action being investigated for the acute treatment of migraine. This study examined the clinical and pharmacolinetic interaction between rizatriptan and the selective serotonin reuptake inhibitor, paroxetine. In this two-period crossover study, 12 healthy young subjects (6 males and 6 females) received 1 mg rizatriptan following 14 days of treatment with placebo or paroxetine (20 mg once daily). Plasma was sampled for rizatriptan and N-monodesmethyl rizatriptan, a minor but active metabolite of rizatriptan. Safety evaluations included monitoring for adverse events, vital signs, and visual analog scale assessment of mood. Plasma levels of rizatriptan and N-monodesmethyl rizatriptan were not altered when rizatriptan was administered with paroxetine compared to the placebo. Clinically, coadministration of rizatriptan with paroxetine was well tolerated. Blood pressure, heart rate, and temperature changes during the observation period did not differ to a clinically significant degree when rizatriptan was administered with paroxetine compared to the placebo. No effects on mood occurred following treatment with the combination compared to rizatriptan alone. Adverse events following rizatriptan administration with paroxetine were similar to those reported when rizatriptan was given with the placebo.