A pharmacokinetic and pharmacodynamic review of single-dose fosaprepitant 150 mg

Despite noteworthy progress in the prevention of chemotherapy-induced nausea and vomiting (CINV), emesis remains a significant adverse effect of chemotherapy. Several studies have established that addition of a neurokinin- 1 (NK-1) receptor antagonist, such as aprepitant, to a 5-HT3 receptor antagonist and dexamethasone can dramatically improve prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC) during the 120 hours after initiation of chemotherapy. The focus of this article is to review the current information on the pharmacology and clinical uses of single-dose fosaprepitant.

Analog of aprepitant

Fosaprepitant dimeglumine is a water-soluble, phosphorylated analog of aprepitant that is rapidly converted to aprepitant after IV administration. Fosaprepitant (115 mg) has been approved as an alternative to the 125-mg oral aprepitant dose on day 1 of a 3-day regimen. Fosaprepitant has an excellent therapeutic index of aprepitant and the administration of higher doses sufficient to maintain a significant serum level over an extended period of time is attainable. An equally effective, single-dose alternative to the 3-day regimen for aprepitant or fosaprepitant/aprepitant could maintain overall therapeutic benefit with greater convenience and adherence.

Unique mechanism of action

Aprepitant has a unique mode of action; it is a selective, high-affinity antagonist at human substance P NK-1 receptors. Counter-screening assays showed that aprepitant was at least 3,000-fold selective for the NK-1 receptor over other enzyme, transporter, ion channel and receptor sites, including the dopamine and serotonin receptors that are targets for existing CINV therapies.

Tiffany Capouch

NK1-receptor antagonists have been shown preclinically to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Preclinical and human PET studies with aprepitant have shown that it penetrates the brain and occupies brain NK-1 receptors. Preclinical studies show that aprepitant has a long duration of central activity, inhibits both the acute and delayed phases of cisplatin-induced emesis, and augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced emesis.

Pharmacokinetics and pharmacodynamics

Fosaprepitant is rapidly converted to aprepitant in in vitro human hepatic cells. Furthermore, fosaprepitant undergoes rapid and nearly complete conversion to aprepitant in assay preparations from other human tissues, including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple tissues.

In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes after the end of infusion. After a single IV dose of fosaprepitant 150 mg administered as a 20-minute infusion to healthy volunteers, the mean area under the curve of aprepitant was 35.0 mcg/hr/mL and the mean maximal aprepitant concentration was 4.01 mcg/mL.

Aprepitant is highly protein bound, with a mean of 97%. The geometric mean volume of distribution at steady state (Vd_ss) of aprepitant estimated from a single 150-mg IV dose of fosaprepitant is approximately 82 L in humans.

Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19% of the radioactivity in plasma over 72 hours following administration of a single IV 100 mg dose of [14C]- fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19. All metabolites observed in urine, feces and plasma after an IV fosaprepitant dose were also observed after an oral dose of aprepitant.

Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in feces. After a single intravenously administered 100 mg dose of [14C]-fosaprepitant to healthy patients, 57% of the radioactivity was recovered in urine and 45% in feces. The pharmacokinetics of aprepitant is nonlinear across the clinical dose range. The terminal half-life of aprepitant after a 150-mg IV dose of fosaprepitant was approximately 11 hours. The geometric mean plasma clearance of aprepitant after a 150-mg IV dose of fosaprepitant was approximately 73 mL/min.

Non-inferiority study shows promise

In a randomized, parallel, double blind, active-controlled non-inferiority study, fosaprepitant 150 mg (n=1,147) was compared with a 3-day aprepitant regimen (n=1,175) in patients receiving a highly emetogenic chemotherapy regimen that included cisplatin at a dose greater than or equal to 70 mg/m². Other concomitant chemotherapy agents were administered similar to those in prior HEC studies described above. The fosaprepitant regimen consisted of fosaprepitant 150 mg on day 1 in combination with ondansetron 32 mg IV on day 1 and dexamethasone 12 mg on day 1; 8 mg on day 2; and 8 mg twice daily on days 3 and 4. The aprepitant regimen consisted of aprepitant 125 mg on day 1 and 80 mg/day on days 2 and 3, in combination with ondansetron 32 mg IV on day 1 and dexamethasone 12 mg on day 1; and 8 mg daily on days 2 through 4. Fosaprepitant placebo, aprepitant placebo, and dexamethasone placebo (in the evenings on days 3 and 4) were used to maintain blinding. Efficacy was based on the evaluation of the following composite measures: complete response in both the overall and delayed phases and no vomiting in the overall phase.

The prespecified noninferiority margins were as follows: complete response in the overall phase: 7 percentage points; complete response in the delayed phase: 7.3 percentage points; and no vomiting in the overall phase: 8.2 percentage points. Fosaprepitant 150 mg was shown to be noninferior to the standard 3-day aprepitant regimen.

Conclusion

Fosaprepitant is an IV prodrug of aprepitant that offers a new alternative to patients with CINV. Currently, fosaprepitant can substitute for oral aprepitant in day 1 of a 3-day regimen. Current studies show that a single-day fosaprepitant regimen is noninferior to the 3-day aprepitant regimen; this could significantly simplify the care for CINV patients in the future.

Tiffany Capouch, PharmD, is a PGY-2 oncology pharmacy resident, Fairview – University of Minnesota Medical Center and Maple Grove, Maple Grove, Minn. She reported no relevant financial disclosures.

For more information:

• Colon-Gonzalez F. Expert Opin Drug Metab Toxicol. 2010; 6(10):1277-1286.
• Grunberg, S. J Clin Oncol. 2011; 29:1495-1501.
• Lasseter KC. J Clin Pharmacol. 2007;47:834-840.