Pharmacokinetics of Aprepitant After Single and Multiple Oral Doses in Healthy Volunteers

Abstract

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.

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

“…earlier studies with various doses of aprepitant indicated some nonlinearity in the disposition of aprepitant, reflecting saturation of metabolism and decreased clearance with an increasing dose. 4,10,18) The low oral bioavailability of aprepitant was also reported to be attributed to its slow dissolution rate, poor permeability across the intestinal mucosa, or first-pass metabolism in the gut and liver. 5) Higher T-Bil was correlated with a higher plasma exposure to aprepitant in a univariate analysis.…”

“…4) There are no restrictions in the administration of aprepitant with regard to feeding conditions. 4,5) Aprepitant penetrates the blood-brain barrier and binds to a high degree with brain NK 1 receptors, inhibiting emesis via the central nervous system.…”

“…4) There are no restrictions in the administration of aprepitant with regard to feeding conditions. 4,5) Aprepitant penetrates the blood-brain barrier and binds to a high degree with brain NK 1 receptors, inhibiting emesis via the central nervous system. [6][7][8][9] A population pharmacokinetics study of aprepitant in Japan found that body weight, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and age affected the oral clearance of aprepitant.…”

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

“…During one study period (i.e., the treatment period), subjects received a supratherapeutic dose of 375 mg of aprepitant after the morning session (T max ϭ 4 h) (Patel and Lindley, 2003;Majumdar et al, 2006), which is known to achieve a level of Ն90% neurokinin-1 receptor occupancy in the central nervous system of humans (Patel and Lindley, 2003;Bergström et al, 2004;Majumdar et al, 2006). During the other period (i.e., control period), no treatment was given.…”

Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

“…Of note, however, the clinically available NK 1 receptor antagonist aprepitant is administered for the prevention of CINV but not for the treatment of nausea and vomiting, which is possibly due to its relatively slow distribution to the brain. 32,33) Here, we showed the immediate antiemetic activity of the oral administration of FK886 against cisplatin-induced delayed emesis. This is consistent with previous reports of the rapid and efficient distribution of FK886 into the brain in several species other than ferrets.…”