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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.

The NK(1) receptor antagonist aprepitant (EMEND(R)), developed for use in combination with a 5HT(3) receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy-induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(-)-warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4. The time course of induction of CYP2C9 by aprepitant was also evaluated using oral tolbutamide, a probe substrate of CYP2C9. In this double-blind, randomized, placebo-controlled, single-center study, 24 healthy subjects were randomized (12 subjects per group) to receive either an aprepitant 3-day regimen (aprepitant 125 mg p.o. on day 1 and aprepitant 80 mg p.o. on days 2 and 3) or matching placebo. All subjects also received probe drugs (midazolam 2 mg i.v. and tolbutamide 500 mg p.o.) once prior to aprepitant dosing (baseline) and again on days 4, 8, and 15. The ratio (aprepitant/placebo) of the geometric mean area under the plasma concentration curve (AUC) fold-change from baseline for midazolam was 1.25 on day 4 (p < 0.01), 0.81 on day 8 (p < 0.01), and 0.96 on day 15 (p = 0.646). The ratio (aprepitant/placebo) of the geometric mean AUC fold-change from baseline for tolbutamide was 0.77 on day 4 (p < 0.01), 0.72 on day 8 (p < 0.001), and 0.85 on day 15 (p = 0.05). Assessed using intravenous midazolam as a probe, aprepitant 125/80 mg p.o. administered over days 1 to 3 produced clinically insignificant weak inhibition (day 4) and induction (day 8) of CYP3A4 activity and no effect on CYP3A4 activity on day 15. Assessed using oral tolbutamide as a probe, the aprepitant regimen also produced modest induction of CYP2C9 activity on days 4 and 8, which resolved nearly to baseline by day 15. Thus, the aprepitant regimen for CINV results in modest, transient induction of CYPs 3A4 and 2C9 in the 2 weeks following administration.

Precision and accuracy of the quantitative magnetic resonance (QMR) system for measuring fat in phantoms and total body fat (TBF) in humans were investigated. Measurements were made using phantoms: oil, beef with water, beef with oil, and humans with oil and water. TBFQMR in humans was compared with TBF by a four-compartment model (TBF4C). The coefficient of variation (CV) for replicate TBFQMR was 0.437%. QMR fat was lower at 23 °C vs. 37 °C. The fat increase in QMR phantom studies was consistent with the oil increase. When oil was added with humans, the increase in TBFQMR was >250 g for the initial 250 g of oil. With additional oil increments, the increase in TBFQMR was consistent with the amount of oil added. When water was added with humans, the TBFQMR increased independent of the amount of water added. TBFQMR was significantly less (mean ± s.e.) than TBF4C (females: −0.68 ± 0.27 kg, males: −4.66 ± 0.62 kg; P = 0.0001), TBFBV (females: −1.90 ± 0.40 kg; males: −5.68 ± 0.75 kg; P = 0.0001), and TBFD2O for males, but greater for females (1.19 ± 0.43 kg vs. −3.69 ± 0.81 kg for males; P = 0.0003). TBFQMR was lower than TBFiDXA with the difference greater in males (P = 0.001) and decreased with age (P = 0.011). The strong linear relationships between TBFQMR and TBF4C, TBFBV, and TBFD2O with slopes consistent with unity suggest that modifications are required to improve the accuracy. Should the latter be accomplished, QMR holds promise as a highly precise, rapid, and safe, noninvasive method for estimating the amount of and changes in TBF in overweight and severely obese persons.