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© 2000 American Society for Clinical Oncology Pharmacokinetic, Metabolic, and Pharmacodynamic Profiles in a Dose-Escalating Study of Irinotecan and CisplatinFrom the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands; and Rhône-Poulenc Rorer, Antony, France. Address reprint requests to M.J.A. de Jonge, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands.
PURPOSE: To investigate the pharmacokinetics and pharmacodynamics of irinotecan and cisplatin administered once every 3 weeks in a dose-escalating study in patients with solid tumors. PATIENTS AND METHODS: Fifty-two cancer patients were treated with irinotecan administered as a 90-minute infusion at doses ranging from 175 to 300 mg/m2 followed by cisplatin administered as a 3-hour intravenous infusion at doses ranging from 60 to 80 mg/m2. After reaching the maximum-tolerated dose, the sequence of drug administration was revised. For pharmacokinetic analysis, serial plasma samples were obtained on days 1 through 3 of the first cycle. Forty-five patients were assessable for irinotecan pharmacokinetics, and 46 were assessable for cisplatin pharmacokinetics. RESULTS: Irinotecan and cisplatin demonstrated linear pharmacokinetics comparable to that observed with single-agent administration, which suggests an absence of pharmacokinetic interaction. SN-38G constituted the major plasma metabolite of irinotecan, whereas 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC) was only a minor metabolite in plasma, possibly indicating a rapid conversion of NPC to SN-38. The terminal elimination phases of SN-38 and SN-38G were similar and relatively delayed when compared with the elimination of irinotecan. Maximal DNA adduct formation did not significantly differ from that observed with single-agent administration. The percentage decrease in WBC was significantly related to the areas under the plasma concentration-time curve (AUCs) of the lactone form of irinotecan (P = .0245) and SN-38 (P = .0123). The severity of diarrhea was not significantly related to the AUCs of irinotecan and SN-38, nor to the systemic glucuronidation rate of SN-38. CONCLUSION: There was no apparent pharmacokinetic interaction between irinotecan and cisplatin in this study. Reversion of the administration sequence of the drugs did not seem to have any influence on the pharmacokinetics. The incidence and severity of delayed-type diarrhea was not related to any of the studied parameters.
IRINOTECAN AND other camptothecin analogs reversibly inhibit DNA topoisomerase I. The ability of camptothecin analogs to inhibit topoisomerase I–mediated DNA functions suggests that they might interfere with processes that are involved in DNA repair and enhance cytotoxicity when combined with DNA-damaging agents. Several preclinical studies demonstrated a sequence-dependent cytotoxicity for the combination irinotecan/SN-38 and platinum-derivatives in vitro, with synergy increasing when irinotecan was preceded by the platinum-derivative.1 However, the interaction observed was not consistent, which indicates that it may be cell-type dependent.2 Where observed, synergism might at least partly be explained by interference of the topoisomerase I inhibitor in the repair of cisplatin-induced DNA interstrand cross-links.3,4 Until now, phase I studies on the combination of irinotecan and cisplatin focused on fractionated dose schedules.5-14 In all studied schedules, irinotecan administration preceded that of cisplatin. Pharmacokinetic data were only obtained in two phase I trials6,15 involving a limited number of patients, with contradicting results concerning the existence of a drug interaction. After intravenous (IV) administration, irinotecan is converted to its active metabolite SN-38 by a carboxylesterase. Carboxylesterase activity has been characterized in serum,16 liver,17 small intestines,18 and tumor tissues.19,20 SN-38 undergoes further metabolism to an inactive beta-glucuronide derivative,21,22 which is present in significant concentrations in plasma, urine, and bile.21,23 Another pathway of irinotecan metabolism constitutes cytochrome P-450 3A–mediated oxidation of the terminal piperidine group on the C-10 side chain, resulting in the formation of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecine (APC) and 7-ethyl-10-[4-N-(1-piperidino)1-amino]-carbonyloxycamptothecine (NPC)24,25 (Fig 1).
In the present report, we present a comprehensive analysis of the plasma pharmacokinetics of the lactone and total forms of irinotecan and its four major metabolites and cisplatin in cancer patients, who were treated in a phase I dose-finding study with IV irinotecan and cisplatin administered once every 3 weeks.
Patient Population The patients, from whom pharmacokinetic curves were obtained, participated in a phase I study. Eligibility criteria included a histologically or cytologically confirmed diagnosis of a malignant solid tumor that was refractory to standard forms of therapy. All patients had adequate hematopoietic (absolute neutrophil count  2.0 x 109/L and platelet count 100 x 109/L), renal (serum creatinine concentration  135 µmol/L or creatinine clearance 60 mL/min), and hepatic function (total serum bilirubin 1.25 x upper normal limit and serum AST and ALT 3.0 x upper normal limits; in case of liver metastasis, total serum bilirubin was 1.5 x upper normal limit and serum AST and ALT 5.0 x upper normal limits). All patients gave written informed consent before study entry. Results of the clinical part of this study will be reported separately.26
Treatment Plan and Drug Administration Irinotecan (CPT-11, Campto; Rhône-Poulenc Rorer, Antony, France) was provided as a concentrated sterile solution (20 mg/mL) in a 5-mL vial. This was diluted before use with 250 mL of 0.9% NaCl solution. The drug was administered IV over 90 minutes. Cisplatin (Platosin; Pharmachemie, Haarlem, the Netherlands) was supplied as a powder and was dissolved in 250 mL of 3.0% saline and was administered as a 3-hour IV infusion. Premedication consisted of a 5-hydroxytryptamine-3 receptor antagonist administered IV (ondansetron 8 mg) combined with dexamethasone 10 mg IV administered 30 minutes before the start of the chemotherapy. The administration of the chemotherapy was followed by the infusion of 2,000 mL of dextrose/saline applied over 8 hours and another 1,000 mL of dextrose/saline infused over the following 8 hours to avoid cisplatin-induced renal damage.
Experimental Studies Plasma samples were assayed for lactone and total drug forms of irinotecan and SN-38 according to a validated reversed-phase high-performance liquid chromatographic method as reported previously.27 Briefly, for measurement of the lactones, aliquots of plasma were spiked with the internal standard, camptothecin, and extracted with a mixture of acetonitrile-n-butyl chloride (1:4, volume-to-volume ratio [v/v]). After centrifugation, the clear supernatant was evaporated to dryness under nitrogen and reconstituted in mobile phase. Sample clean-up for total drug forms was achieved via a simple-protein precipitation with aqueous perchloric acid-methanol (1:1, v/v), which results in quantitative conversion of the carboxylate to lactone forms. Chromatography was performed on a column packed with Hypersil ODS material (5 µm particle size, 100 x 4.6 mm internal diameter, Applied Science Group, Breda, the Netherlands) using isocratic elution with methanol (0.1 mol/L ammonium acetate containing 0.01 mol/L tetrabutylammonium sulfate [35:65, v/v; pH 5.5]). The flow rate was set at 1 mL/min, and the eluent was monitored fluorometrically at excitation and emission wavelengths of 355 and 515 nm, respectively. For quantitative determination of total concentrations of SN-38G, APC, and NPC, samples were reanalyzed using a modified mobile phase with decreased organic modifier content to ensure sufficient selectivity and analyte separation.28 The determination of each compound was based on chromatographic retention times and peak area measurements in comparison with injected standards, typically over a range of 0.5 to 200 ng/mL. Calibration curves were prepared in drug-free plasma and fitted by a least-squares regression function with proportional weighting using Lotus (Version 2.4, Lotus, New York, NY). The mean overall extraction efficiencies for irinotecan and the metabolites ranged between 83.0% and 99.1%. The percentage deviation from nominal values and the inter- and intra-assay precision for each compound were always less than 12%. Non–protein-bound and total cisplatin concentrations in plasma, in addition to cisplatin DNA-adduct levels in leukocytes, were determined by flameless atomic absorption spectrometry according to the method of Reed et al,29 with modifications as described.30,31
Pharmacokinetic and Pharmacodynamic Analysis Kinetic profiles of cisplatin were obtained similarly using a one- or two-compartment model with extended least-squares regression analysis as reported earlier.34 The AUC of cisplatin was calculated to the last sampling period (Clast) by the linear trapezoid method and extended to infinity by addition of Clast/kterm, where kterm is the slope obtained by log-linear regression of the final plasma concentration values. The cisplatin DNA-adduct levels in leukocytes were expressed as picogram of platinum per microgram of DNA (pg Pt/µg DNA).
Kinetic-dynamic relationships were evaluated using the SIPHAR and NCSS (Version 5.X; Jerry Hintze, MD, Kaysville, UT) programs and were rated for goodness of fit by minimization of sums of squared residuals and by construction of the estimated coefficient of variation for fitted parameters. Significance of the relationships was assessed by construction of contingency tables with subsequent
Statistical Considerations
Patient Characteristics and Toxicity A total of 52 patients (18 female and 33 male) with a median age of 52 years (range, 37 to 69 years) and a median performance status of 0 (range, 0 to 1) were entered onto the pharmacologic part of the phase I study. The predominant tumor type was colorectal cancer (22 patients). One patient was not eligible for study. Forty-five patients were assessable for the complete pharmacokinetics of irinotecan and metabolites, and 46 patients were assessable for pharmacokinetics of cisplatin. Thirty-nine patients were assessable for the pharmacokinetic-pharmacodynamic analysis. In all patients, the main hematologic toxicity was neutropenia with both sequences of drug administration. No indications of cumulative myelotoxicity were noted. Gastrointestinal toxicity, including nausea, vomiting, and diarrhea, was the most prominent nonhematologic side effect. Grade 1-2 diarrhea was observed in 61% of the cycles, and grade 3-4 diarrhea occurred in 4%. The percentage of patients experiencing diarrhea increased with the irinotecan dose. Other side effects included fatigue, mucositis, alopecia, and acute cholinergic syndrome. No significant sequence-dependent differences in side effects were observed. Response could be evaluated in 49 patients. Three complete responses were observed, and eight patients exhibited a partial response. Disease stabilization was noted in 28 patients. Results of the full phase I study are reported in full separately.26
Pharmacokinetics
Over the total dose range studied, the AUC of irinotecan increased from 17.2 ± 7.08 µmol/L·h (mean ± SD) to 32.1 ± 8.69 µmol/L·h, and the peak plasma concentration of irinotecan increased from 3.94 ± 1.25 µmol/L to 6.55 ± 1.91 µmol/L, which is consistent with linear and dose-independent pharmacokinetic behavior. The AUC of the lactone forms of irinotecan and SN-38 were significantly correlated to their respective total drug AUCs (CPT-11, r = 0.86, P < .001; SN-38, r = 0.92, P < .001). Substantial interpatient variability in pharmacokinetic parameters was apparent, with a greater than two-fold variation in irinotecan AUC, although mean values were strongly correlated to dose (Spearman’s r = 0.78). No significant differences in dose-normalized pharmacokinetic parameters were observed between the irinotecan dose levels (P > .05; Kruskal-Wallis). Alternation of the administration sequence of irinotecan and cisplatin did not seem to have any influence on the pharmacokinetic data (Tables 1 and 2). The average REC of irinotecan to SN-38 ranged from 0.01 to 0.07. Over the dose range studied, no significant correlation between REC and irinotecan dose could be established. No dose dependence of the extent of metabolism of irinotecan to APC, as estimated from the REM, was observed. The elimination phases of irinotecan and APC were consistently parallel. Also, no significant dose dependence of the REG of SN-38, which ranged from 4.5 to 32.0, was noted. The elimination phases of SN-38 and SN-38G were also consistently parallel and the terminal half-lives of these compounds were significantly correlated. Cisplatin pharmacokinetics could best be described with a two-compartment model. The kinetic parameters obtained by means of this model are presented in Table 4. The plasma clearance of unbound cisplatin was 1.05 ± 0.27 L/min (mean ± SD, n = 46; range, 0.526 to 2.42 L/min). The pharmacokinetic behavior of cisplatin across all irinotecan dose levels was highly consistent with previously published values obtained with cisplatin administered as a single agent. In addition, the total body clearance and Vss data of unbound cisplatin and the AUC of total cisplatin in plasma indicate no significant influence of irinotecan on the protein binding of cisplatin. The platinum DNA-adduct levels in leukocytes peaked consistently at 1 hour after the end of the cisplatin infusion and showed wide interpatient variability. Mean values of 2.60 ± 1.59 pg Pt/µg DNA (n = 9) and 8.13 ± 7.87 pg Pt/µg DNA (n = 29) were observed at the cisplatin doses of 60 and 80 mg/m2, respectively, and were not significantly altered by an increase in the irinotecan dose. Administration of cisplatin before irinotecan resulted in a mean value of 9.04 ± 5.38 pg Pt/µg DNA (n = 6); this was not significantly different from that observed in the reversed schedule (6.77 ± 6.47 pg Pt/µg DNA [n = 6]). The number of responses was too limited to establish a meaningful relationship between platinum DNA-adduct formation in leukocytes and the likelihood of tumor response.
Pharmacodynamics The pharmacokinetic data obtained from 39 patients were plotted against the percentage decrease in WBC count, PLT, and ANC at nadir relative to the pretreatment value. Four different models, based on linear, log-linear, maximum effect (Emax), and sigmoidal Emax fitting, were compared for their ability to describe the data. The percentage decrease in ANC and PLT was not significantly related to the AUC of any compound (neither lactone nor total drug) in any of the models tested. The percentage decrease in WBC, however, was significantly related using a sigmoidal Emax model to the AUC of irinotecan lactone (EC50 = 2.77 µmol/L [CV = 36.2%];  = 0.90 [CV = 39.6%]; P = .0245), the AUC of SN-38 lactone (EC50 = 0.182 µmol/L [CV = 31.5%]; = 0.85 [CV = 32.8%]; P = .0123), and also, to a lesser extent, to the AUC of irinotecan total drug (EC50 = 8.04 µmol/L [CV = 44.1%]; = 0.82 [CV = 43.5%]; P = .0442) and the AUC of SN-38 total drug (EC50 = 0.157 µmol/L [CV = 69.6%]; = 0.49 [CV = 41.9%]; P = .0317) (Fig 3).38 These data indicate that the hematologic toxicity was mainly related to the pharmacologic active lactone form of both irinotecan and SN-38.
The severity of diarrhea was not significantly related to the AUC of irinotecan lactone (P = .467), the AUC of irinotecan total drug (P = .680), the AUC of SN-38 lactone (P = .683), or the AUC of SN-38 total drug (P = .613). Biliary index in patients with diarrhea CTC grade 0-2 (2,033 ± 1,124; n = 32) or CTC grade 3-4 (1917 ± 577.8; n = 3) were also not significantly different (P = .519; Mann-Whitney U test).
This is the first pharmacokinetic study of irinotecan to incorporate the analysis of the plasma pharmacokinetics of cisplatin and the four major metabolites of irinotecan that have been identified to date (namely SN-38, SN-38G, APC, and NPC) in cancer patients who were treated in a phase I dose-finding study with irinotecan and cisplatin administered IV once every 3 weeks. Over the total dose range studied, the AUC and the peak plasma concentrations of irinotecan demonstrated linear and dose-independent behavior similar to that achieved with single-agent administration, indicating no apparent pharmacokinetic interaction. The ratio of irinotecan and SN-38 AUC of lactone to total drug agree quite well with data of a previous study in which irinotecan was administered as a single agent in a small patient population (36.8% ± 3.5% and 64.0% ± 3.4% for irinotecan and SN-38, respectively39). Reversion of the administration sequence of irinotecan and cisplatin did not seem to have any influence on the pharmacokinetic data for both compounds. However, our data are limited, and the impact of the sequence of drug administration on the pharmacokinetic or metabolic interaction between irinotecan and cisplatin should be further evaluated.
Quantitatively, the major plasma metabolite of irinotecan was SN-38G. This observation is different from the data reported by Rivory et al,33 who observed that APC was the major plasma metabolite. This difference may be explained partly by the prolonged sampling time applied in the present study. By obtaining samples at 24, 32, 48, and 56 hours after the end of the infusion of irinotecan, the t1/2( The parallel decline of NPC and APC with the parent drug suggest that their elimination is rate limited by the formation of the metabolites. We observed that NPC was only a minor metabolite of irinotecan in plasma of our patients and accounted for only approximately one thirtieth of total circulating drug. Also, the metabolite was only detectable in plasma during times of relatively high concomitant parent compound concentrations. This finding sharply contrasts with recent in vitro observations by Dodds et al.25 Furthermore, when pooled human hepatic microsomes were incubated with irinotecan, NPC was identified to be the prevailing biotransformation product of the oxidative metabolism of irinotecan,25 which is catalyzed by cytochrome P-450 3A. From these data, one would expect a large fraction of irinotecan to be metabolized to NPC in vivo. In vitro incubations of NPC with both human liver microsomes or hepatic carboxylesterase revealed, however, that NPC may be a possible precursor of SN-38 through enzymatic cleavage of the 4-N-(1-piperidino)-1-amino group at C10 (Fig 1).25 Thus the low plasma AUC of NPC observed in our patient population might indicate a rapid and virtually complete conversion of NPC to SN-38. Obviously, we cannot exclude other possible explanations. In this respect, it is noteworthy that the terminal disposition phases of SN-38 and SN-38G were quite similar and relatively delayed compared with the elimination of irinotecan and the cytochrome P-450–mediated metabolites. Hence, the conversion of NPC to SN-38 may be partly responsible for the prolonged terminal half-lives of SN-38 and SN-38G, aside from the enterohepatic recirculation of these metabolites. In addition, after hepatobiliary and/or intestinal secretion of irinotecan and NPC, the reabsorption of both compounds and their subsequent conversion to SN-38 may also contribute to the extended disposition phases of SN-38 and its glucuronide conjugate. Cisplatin pharmacokinetics were comparable to those achieved with single-agent administration.34 Although preclinical studies indicated that the reversal of cisplatin-induced DNA interstrand cross-links was delayed by concomitant incubation with a topoisomerase I inhibitor,3,4 maximal DNA adduct formation did not differ from single-agent data with the method used.34 The pharmacodynamic analysis revealed only a significant correlation between the percentage decrease in WBC and the AUC of the active lactone form of irinotecan and SN-38. Surprisingly, no correlation was found between the percentage decrease of the ANC and the AUC of any compound. Previous studies have shown a correlation between the systemic SN-38 glucuronidation rates, expressed as the biliary index, and the incidence of delayed-type diarrhea.36,37 Although biliary index data for our patients with diarrhea graded 0-2 are similar to those reported recently (median, 2,228), values for patients experiencing grade 3 or 4 diarrhea were lower (median, 5,499).36,37 A similar discrepancy has been reported recently by Canal et al38 in a large group of patients receiving single-agent irinotecan at a dose of 350 mg/m2. The relatively low incidence of grade 3 and 4 diarrhea during our phase I study and the substantial interpatient variability in plasma pharmacokinetic parameters may partly be responsible for this discrepancy. Recently, however, in a study on the metabolism and urinary and fecal excretion of irinotecan, we observed an unexpectedly high fecal concentration of SN-38 accompanied by a virtual disappearance of SN-38G32 in patients treated at a dose level of 200 mg/m2. These findings may reflect the conversion of SN-38G to SN-38 under influence of endogenous and bacterial beta-glucuronidase in the intestines. Although the exact mechanism of the observed delayed-type diarrhea after administration of irinotecan is still unknown, it is thought to be related to the exposition of the intestinal tract to SN-38. Interindividual differences in fecal beta-glucuronidase activity could play a role in the observed variation in irinotecan-induced intestinal side effects and may result in the potential to modulate the experienced toxicity. This concept is presently under further investigation at our institute.
1. De Jonge MJA, Sparreboom A, Verweij J: The development of combination therapy involving camptothecins: A review of preclinical and early clinical studies. Cancer Treat Rev 24:205-220, 1998[Medline] 2. Raymond E, Djelloul S, Buquet-Fagot C, et al: Oxaliplatin (LOHP) and cisplatin (CDDP) in combination with 5FU, specific thymidylate synthase (TS) inhibitors (AG337, ZD1694) and topoisomerase I (Topo-I) inhibitors (SN38, CPT-11), in human colonic, ovarian and breast cancers. Assoc Cancer Res 37:291, 1996 (abstr 1981) 3. Goldwasser F, Bozec L, Zeghari-Squalli N, et al: Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line. Anticancer Drugs 10:195-201, 1999[Medline] 4. Goldwasser F, Valenti M, Torres R, et al: Potentiation of cisplatin cytotoxicity by 9-aminocamptothecin. Clin Cancer Res 2:687-693, 1996[Abstract] 5. Masuda N, Fukuoka M, Takada M, et al: CPT-11 in combination with cisplatin for advanced non-small-cell lung cancer. Oncol 10:1775-1780, 1992 6. Masuda N, Fukuoka M, Kudoh S, et al: Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer. Br J Cancer 68:777-782, 1993[Medline] 7. Sugiyama T, Takeuchi S, Noda K, et al: Phase I study of irinotecan (CPT-11) in combination with cisplatin (CDDP) on cervical carcinoma. Proc Natl Acad Sci U S A 13:268, 1994 (abstr 856) 8. Kobayashi K, Soma T, Shinbara A, et al: Phase I study of irinotecan (CPT-11) and cisplatin (CDDP) by divided administration in patients with non-small cell lung cancer (NSCLC). Proc Natl Acad Sci U S A 15:388, 1996 (abstr 1169)
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Saltz LB, Spriggs D, Schaaf LJ, et al: Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors. J Clin Oncol 16:3858-3865, 1998 13. Masuda N, Fukuoka M, Kudoh S, et al: Phase I study of irinotecan and cisplatin with granulocyte colony-stimulating factor support for advanced non-small-cell lung cancer. J Clin Oncol 12:90-96, 1994[Abstract] 14. Mori K, Hirose T, Machida S, et al: A phase I study of irinotecan and infusional cisplatin with recombinant human granulocyte colony-stimulating factor support in the treatment of advanced non-small cell lung cancer. Eur J Cancer 33:503-505, 1997 15. Sumiyoshi H, Fujiwara Y, Ohoshi N, et al: Clinical pharmacological evaluation of CPT-11 and cisplatin (CDDP) in patients with small cell lung cancer (SCLC). Proc Natl Acad Sci U S A 14:457, 1995 (abstr 1470) 16. Tsuji T, Kaneda N, Kado N, et al: CPT-11 converting enzyme from rat serum: Purification and some properties. J Pharmacobiodyn 14:341-349, 1991[Medline] 17. Rivory LP, Bowles MR, Robert J, et al: Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 52:1103-1111, 1996[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, ß, and 
2 analysis. Within individual patients, hematologic toxicity was described as a continuous variable defined as a percentage decrease at nadir in WBC count, absolute neutrophil count (ANC), and platelet count (PLT), whereas diarrhea was a discontinuous variable defined by a National Cancer Institute common toxicity criteria (CTC) grade. The pharmacodynamics of hematologic toxicity was evaluated by four different models, based on linear, log-linear, maximum effect (Emax), and sigmoidal Emax modeling of irinotecan or metabolite AUC values based on a modified Hill equation, as described.
) and total drug (
) and of SN-38 lactone (
) and total drug (•) and (B) irinotecan (
), and NPC (
) in a single patient given irinotecan at 200 mg/m2.
