Abstract. Background: The present study was designed to investigate whether a combination of irinotecan and the monoclonal antibody cetuximab shows ...
ANTICANCER RESEARCH 26: 1337-1342 (2006)
In Vivo Disposition of Irinotecan (CPT-11) and its Metabolites in Combination with the Monoclonal Antibody Cetuximab DAGMAR E. ETTLINGER1,2, MARKUS MITTERHAUSER2, WOLFGANG WADSAK2, EVA OSTERMANN3, ANDRÉ FARKOUH1, JOHANN SCHUELLER3,4 and MARTIN CZEJKA1,4 1Department
of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna; 2Department of Nuclear Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna; 3Department of Internal Medicine and Oncology, Hospital Rudolfstiftung, Boerhaavegasse 13, A-1030 Vienna; 4Austrian Society of Applied Pharmacokinetics, Krottenbachstrasse 184, A-1190 Vienna, Austria
Abstract. Background: The present study was designed to investigate whether a combination of irinotecan and the monoclonal antibody cetuximab shows potential to modulate the pharmacokinetics of irinotecan and its metabolites. Patients and Methods: All patients, suffering from advanced colorectal cancer, received irinotecan (350 mg/m2) every third week and cetuximab as a loading dose (400 mg/m2) on day 2, followed by a weekly maintenance dose (250 mg/m2). Plasma samples were analysed after the first (MONO) and second (CMAB) irinotecan infusions. Results: No significant alterations in the plasma concentrations and pharmacokinetics of irinotecan and its metabolites were observed after combination with cetuximab. Only differentiation of irinotecan into lactone and carboxylate plasma concentrations resulted in a distinctly lower cmax of the active lactone in the CMAB and a significantly higher AUClast in the MONO schedule (p80%) entered the pharmacokinetic study. The preceding chemotherapy was oxaliplatin (FOLFOX, 1st line) and irinotecan (2nd line). The mean age was 61±9 years (range 45 – 72 years), mean weight was 78±12 kg (60 – 99 kg), mean height 172±6 cm (165– 180 cm) and the mean body surface area was 1.91±0.16 m2 (1.67 – 2.19 m2). Written informed consent was obtained from each patient according to the specifications of the ethics committee of Vienna, Austria. Study design and treatment. The study had a prospective crossover design with patients serving as their own controls. Irinotecan (Campto®) was supplied as a sterile solution containing 100 mg in 5ml vials (Pfizer, Vienna, Austria) and was infused through a central venous catheter at a constant rate for 60 min every third week (350 mg/m2, the mean dose was 669±56 mg with a range 584.5 – 766.5 mg and a mean infusion rate of 11.15±0.94 mg/min with a range 9.74 – 12.78). The patients received pre-medication with tropisetron and atropine 1 h before irinotecan infusion and ranitidine and dimetinden before cetuximab infusion. Cetuximab (Erbitux®) was supplied as a sterile infusion containing 2 mg/ml cetuximab in 50-ml vials (Merck, Vienna, Austria) and was administered through a central venous catheter at a constant rate (400 mg/m2) for 120 min as a loading dose on day 2 (the day after the first irinotecan infusion), followed by a weekly infusion at a constant rate of 250 mg/m2 for 60 min. Blood samples. Blood samples were drawn from the cubital vein at 0, 60, 70, 90, 105, 120, 180, 240 and 300 min after the start of the infusion into sodium-heparinised vacutubes and were centrifuged immediately for 3 min at 3000 rpm to separate blood cells. Sample clean-up was performed by vortexing 1.0 ml plasma with 2.0 ml ice-cold methanol for 1 min followed by 4 min of centrifugation at 10,000 rpm to remove the precipitated proteins. The obtained supernatant was frozen immediately at –80ÆC until HPLC analysis. Blood samples during the first cycle (day 1, MONO) were taken as their own controls versus the second cycle of irinotecan therapy (day 21, CMAB). Analytical procedure. After thawing, each plasma sample was first analysed under neutral conditions (to obtain the sum of lactone and carboxylate concentrations) and second acidified with phosphoric acid (1.0 ml supernatant with 40 Ìl phosphoric acid 8.5%) to obtain total lactone amounts. Irinotecan, SN-38, SN-38gluc and APC were quantified by isocratic reversed phase HPLC using fluorimetic detection, described previously (16, 17). Biometric calculation. WinNonlin® Professional Version 4.0.1 (Pharsight Corporation, USA) was used for curve fitting of plasma concentrations of irinotecan. Therefore, non-compartmental and 2-compartmental models were chosen. The analysed PK parameters included:
cmax: maximum plasma concentration [ng/ml] time to reach maximum plasma concentration [min] tmax: AUClast: area under the concentration time curve from 0-300 min [min*ng/ml] AUCinf: area under the concentration time curve towards infinitesimal [min*ng/ml] elimination half-life [min] t1/2el: Vd: volume of distribution [ml] Vss: volume of distribution at steady state [ml] Cl: clearance [ml/min] MRTlast: mean residence time from 0 to tlast [min] PK Solutions 2.0, Summit Research Services, Pharmacokinetics and Metabolism Software, was used for the pharmacokineticcalculation of SN-38, APC and SN-38gluc. Analysed PK parameters included: maximum plasma concentration [ng/ml] cmax: time to reach maximum plasma concentration [min] tmax: AUClast: area under the concentration time curve from 0-300 min [min*ng/ml] AUCinf: area under the concentration time curve towards infinitesimal [min*ng/ml] t1/2appin: apparent half-life of formation [min] The statistical evaluation of differences in plasma concentrations and PK parameters was performed by paired, two-sided Student’s t-test using GraphPad Prism® Version 3.00, GraphPad Software, Incorporation and Microsoft® Excel 2000, Microsoft Corporation.
Results Plasma concentrations. The mean plasma concentration-time curves for irinotecan, SN-38, APC and SN-38gluc differed insignificantly in the CMAB group (Figure 1). For irinotecan, SN-38 and APC, the plasma concentrations were comparable during MONO and CMAB treatment, whereas the plasma concentrations of the phase-II conjugate SN38gluc were distinctly higher in the MONO schedule, especially at 180 min (MONO: 168.8±48.0 ng/ml; CMAB: 116.9±37.7 ng/ml; p