title: Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism.
abstract: BACKGROUND
  Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist aprepitant in addition to standard anti-emetic therapy. As aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of aprepitant in the CTC regimen are reported.
  
  
  METHODS
  Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m2/day), thiotepa (120 mg/m2/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without aprepitant. Inhibitory activity of aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes.
  
  
  RESULTS
  In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC50) of aprepitant for inhibition of cyclophosphamide (IC50=1.3 microg/ml) and thiotepa (IC50=0.27 microg/ml) metabolism were within the therapeutic range. Patients receiving aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001).
  
  
  CONCLUSIONS
  Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands. apmil@slz.nl
authors.forename: Milly E
authors.initials: ME
authors.lastname: de Jonge
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Marjo J
authors.initials: MJ
authors.lastname: Holtkamp
authors.forename: Selma M
authors.initials: SM
authors.lastname: van Dam
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
mesh_terms: D000932:Antiemetics / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000077608:Aprepitant; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000378:metabolism*; D013852:Thiotepa / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D000932:Antiemetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D009025:Morpholines; D000077608:Aprepitant; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin