Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism

被引:51
作者
de Jonge, ME
Huitema, ADR
Holtkamp, MJ
van Dam, SM
Beijnen, JH
Rodenhuis, S
机构
[1] Slotervaart Hosp, Netherlands Canc Inst, Dept Pharm & Pharmacol, NL-1066 EC Amsterdam, Netherlands
[2] Netherlands Canc Inst, Dept Med Oncol, NL-1066 CX Amsterdam, Netherlands
关键词
aprepitant; cyclophosphamide; thiotepa; pharmacokinetic drug-drug interaction; nausea; vomiting;
D O I
10.1007/s00280-005-1005-4
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Patients and methods: Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide ( 1,500 mg/m(2)/day), thiotepa ( 120 mg/m(2)/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 mu g/ml) and thiotepa (IC50 = 0.27 mu g/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). Conclusion: 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.
引用
收藏
页码:370 / 378
页数:9
相关论文
共 32 条
[1]  
BEAL SL, 1998, USERS GUIDES NONMEM
[2]  
CHANG TKH, 1993, CANCER RES, V53, P5629
[3]  
CRAIG AW, 1995, BRIT J PHARMACOL, V10, P321
[4]   Aprepitant - A review of its use in the prevention of chemotherapy-induced nausea and vomiting [J].
Dando, TM ;
Perry, CM .
DRUGS, 2004, 64 (07) :777-794
[5]   Integrated population pharmacokinetic model of both cyclophosphamide and thiotepa suggesting a mutual drug-drug interaction [J].
de Jonge, ME ;
Huitema, ADR ;
Rodenhuis, S ;
Beijnen, JH .
JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2004, 31 (02) :135-156
[6]   Simultaneous quantification of cyclophosphamide, 4-hydroxycyclophosphamide, N,N′,N"-triethylenethiophosphoramide (thiotepa) and N,N′,N"-triethylenephosphoramide (tepa) in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry [J].
de Jonge, ME ;
van Dam, SM ;
Hillebrand, MJX ;
Rosing, H ;
Huitema, ADR ;
Rodenhuis, S ;
Beijnen, JH .
JOURNAL OF MASS SPECTROMETRY, 2004, 39 (03) :262-271
[7]   The oral NK1 antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy:: a combined analysis of two randomised, placebo-controlled phase III clinical trials [J].
de Wit, R ;
Herrstedt, J ;
Rapoport, B ;
Carides, AD ;
Guoguang-Ma, J ;
Elmer, M ;
Schmidt, C ;
Evans, JK ;
Horgan, KJ .
EUROPEAN JOURNAL OF CANCER, 2004, 40 (03) :403-410
[8]   Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy [J].
de Wit, R ;
Herrstedt, J ;
Rapoport, B ;
Carides, AD ;
Carides, G ;
Elmer, M ;
Schmidt, C ;
Evans, JK ;
Horgan, KJ .
JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (22) :4105-4111
[9]   Human CYP2B6: expression, inducibility and catalytic activities [J].
Gervot, L ;
Rochat, B ;
Gautier, JC ;
Bohnenstengel, F ;
Kroemer, H ;
de Berardinis, V ;
Martin, H ;
Beaune, P ;
de Waziers, I .
PHARMACOGENETICS, 1999, 9 (03) :295-306
[10]  
HEIDEMAN RL, 1989, CANCER RES, V49, P736