Allometric Scaling of a Metabolically Complex Camptothecin Analog

Preeti Ahlawat; Nuggehally R Srinivas

doi:10.1055/s-0031-1296402

Arzneimittelforschung, Table of Contents

Arzneimittelforschung 2009; 59(6): 311-317
DOI: 10.1055/s-0031-1296402

Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics

Editio Cantor Verlag Aulendorf (Germany)

Allometric Scaling of a Metabolically Complex Camptothecin Analog

Differences in scaling of irinotecan and its active metabolite, SN-38

Authors

Preeti Ahlawat

¹Global Drug Development, ClinTec (India) International Pvt Ltd., Bangalore, (India)
Nuggehally R Srinivas

¹Global Drug Development, ClinTec (India) International Pvt Ltd., Bangalore, (India)

¹New address: Suramus Biopharm, Bangalore, (India)

Abstract

Allometry has been extensively used in the modern day drug development scenario to predict the human relevant parameters (clearance, CI, and volume of distribution at steady state, V_ss) from animal data. The applicability of allometry in the prediction of human parameters for irinotecan (CAS 97682-44-5), an important topoisomerase I inhibitor, has been retrospectively investigated. Literature pharmacokinetic data has been gathered for both irinotecan and its main metabolite, SN-38 (CAS 86639-52-3), from several animal species. The corresponding human parameters were predicted using allometry (Cl and Vss for irinotecan; Cl/F for SN-38). Although irinotecan has a complex metabolism and disposition profile, it appeared that simple allometry predicted satisfactorily the human values for Cl (1.7648W⁰’⁶⁶⁹) and Vss (3.1277W⁰’⁹⁰⁴⁴) for irinotecan. On the contrary, Cl/F for SN-38 was over predicted by simple allometry (53.389W¹’²⁷⁷³); and the applicability of bile correction factor rendered Cl/F of SN-38 to be closer to the observed human value (8.9641W^{1 3108}). The investigation suggests that prospective allometric approaches may aid in the development of future compounds in this important pharmacological and chemical class of cytotoxics.

Key words

Allometry - Camptothecin analog, clearance, pharmacokinetics, volume of distribution - CAS 7689-03-4 - CAS 86639-52-3 - CAS 97682-44-5 - Irinotecan - SN-38 - Toposiomerase I inhibitors

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References

References
1 Liew ST, Yang LX. Design, synthesis and development of novel camptothecin drugs. Curr Pharm Des. 2008; 14: 1078-1097
2 Rothenberg ML. Irinotecan (CPT-11): Recent developments and future directions-colorectal cancer and beyond. Oncol. 2001; 6: 65
3 Mathijssen RHJ, Verweij J, Loos WJ, de Bruijn P, Nooter K, Sparreboom A. Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38. Br J Cancer. 2002; 144-150
4 Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS. Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother. Report. 1972; 56: 515-521
5 Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Report. 1972; 56: 95-101
6 Schaeppi U, Fleischman RW, Cooney DA. Toxicity of camptothecin (NSC-100880). Cancer Chemother Report. 1974; 5: 25-36
7 Creemers GJ, Lund B, Verweij J. Topoisomerase I inhibitors. Topotecan and irinotecan. Cancer Treat Rev. 1994; 20: 73-96
8 Slatter JG, Schaaf LJ, Sams JP, Feenstra KL, Johnson MG, Bombardt PA et al Pharmacokinetics, metabolism and excretion of irinotecan(CPT-11) following I.V. infusion of [(14)C] CPT-11 in cancer patients. Drug Metab Dispos. 2000; 28: 423-433
9 Farabos C, Haaz MC, Gires P, Robert J. Hepatic extraction, metabolism and biliary excretion of irinotecan in the isolated perfused rat liver. J Pharm Sci. 2001; 90: 722-731
10 Sparreboom A, de Jonge MJ, de Bruijn P, Brouwer E, Nooter K, Loos WJ et al Irinotecan (CPT-11) metabolism and disposition in cancer patients. Clin Cancer Res. 1998; 4: 2247-2254
11 Itoh T, Takemoto I, Itagaki S, Sasaki K, Hirano T, Iseki K. Biliary excretion of irinotecan and its metabolites. J Pharm Sci. 2004; 7: 13-18
12 Sai K, Kaniwa N, Ozawa S, Sawada JI. A new metabolite of irinotecan in which formation is mediated by human hepatic Cytochrome P-450 3A4. Drug Metab Dispos. 2001; 29: 1505-1513
13 Iyer L, Ramirez J, Shepard DR, Bingam CM, Hossfeld DK, Ratain MJ et al Biliary transport of irinotecan and metabolites in normal and P-glycoprotein-deficient mice. Cancer Chemother Pharmacol. 2002; 49: 336-341
14 Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusi H, Sugiya-ma Y. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther. 1997; 281: 304-314
15 Atsumi R, Suzuki W, Hakusui H. Identification of the metabolites of irinotecan, a new derivative of camptothecin, in rat bile and its biliary excretion. Xenobiotica. 1991; 21: 1159-1169
16 Araki E, Ishikawa M, Iigo M, Koide T, Itabashi M, Hoshi A. Relationship between development of diarrhea and the concentration of SN-38, an active metabolite of CPT-11, in the intestine and the blood plasma of athymic mice following intraperitoneal administration of CPT-11. Jpn J Cancer Res. 1993; 84: 697-702
17 Carbonero RG, Supko JG. Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res. 2002; 8: 641-661
18 Tallman MN, Ritter JK, Smith PC. Differential rates of glu-curonidation for 7-ethly-10-hydroxy-camptothecin (SN-38) lactone and Carboxylate in human and rat microsomes and recombinant UDP-glucuronosyltransferase isoforms. Drug Metab Dispos. 2005; 33: 977-983
19 Girard H, Villeneuve L, Court MH, Fortier LC, Caron P, Hao Q et al The novel UGT1A9 intronic 1399 polymorphism appears as a predictor of 7-ethyl-10-hydroxycamp-tothecin glucuronidation in the liver. Drug Metab Dispos. 2006; 34: 1220-1228
20 Luo FR, Paranjpe PV, Guo A, Rubin E, Sinko P. Intestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters PgP, cMOAT, and MRP1. Drug Metab Dispos. 2002; 30: 763-70
21 Ando Y, Saka H, Asai G, Sugiura S, Shimokata K, Kamataki T. UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol. 1998; b 845-847
22 Chu XY, Kato Y, Niinuma K, Sudo KI, Hakusui H, Sugiyama Y. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J. Pharmacol Exp Ther. 1997; 281: 304-14
23 Stewart CF, Zamboni WC, Crom WR, Hougton PJ. Disposition of Irinotecan and SN-38 following oral and intravenous irinotecan dosing in mice. Cancer Chemother Pharmacol. 1997; 40: 259-265
24 Kirman CR, Sweeney LM, Meek ME, Gargas ML. Assessing the dose dependency of allometric scaling performance using physiologically based pharmacokinetic modeling. Reg Tox Pharmacol. 2003; 345-367
25 Teh-Min Hu, William LH. Allometric Scaling of Xenobiotic Clearance: Uncertainty versus Universality. AAPS Pharm Sci. 2001; 3 (29)
26 Mahmood I, Yuan R. A Comparative Study of Allometric Scaling with Plasma Concentrations Predicted by Species-invariant Time Methods. Biopharm Drug Dispos. 1999; 20: 137-144
27 Sinha VK, De Buck SS, Fenu LA, Smit JW, Nijsen M, Gilis-sen RA et al Predicting oral clearance in humans: how close can we get with allometry. Clin Parmacokinet. 2008; 47: 35-45
28 Zamboni WC, Stewart CF, Thompson J, Santsna VM, Cheshire PJ, Richmond LB et al Relationship Between Topo-tecan Systemic Exposure and Tumor Response in Human Neuroblastoma Xenografts. NCI. 1998; 90 (7)
29 Mahmood I, Martinez M, Hunter RP. Interspecies allometric scaling. Part I: prediction of clearance in large animals. J Vet Pharmacol Ther. 2006; 29: 415-423
30 Robert J, Rivory L. Pharmacology of Irinotecan. Drugs Today. 1998; 34: 777
31 Bhamidipati RK, Dravid PV, Mullangi R, Srinivas NR. Prediction of clinical pharmacokinetic parameters of linezolid using animal data by allometric scaling: applicability for the development of novel oxazolidinones. Xenobiotica. 2004; 34 (6) 571-9
32 Shim HJ, Kim YC, Lee JH, Kwon JW, Kim WB, Kim YG et al Interspecies pharmacokinetic scaling of DA-8159, a new erectogenic, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics. Biopharm Drug Dispos. 2005; 26 (7) 269-77
33 Gao W, Johnston JS, Miller DD, Dalton JT. Interspecies differences in pharmacokinetics and metabolism of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N- (4-nitro-3-trifluoromethylphenyl)-propionamide: the role of N-ace-tyltransferase. Drug Metab Dispos. 2006; 34 (2) 254-60
34 Blaney SM, Takimoto C, Murry DJ, Kuttesch N, McCully C, Cole DE et al Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates. Cancer Chemother Pharmacol. 1998; 41: 464-468
35 Balram C, Zhou QY, Cheung YB, Lee EJ. Influence of multiple dose activated charcoal on the disposition kinetics of irinotecan in rats. Drug Metab Drug Inter. 2002; 19: 137-148
36 Chu XY, Kato Y, Sugiyama Y. Multiplicity of Biliary Excretion Mechanisms for Irinotecan, CPT-11, and its metabolites in Rats. Cancer Res. 1997; 57: 1934-1938
37 Gupta E, Safa AR, Wang X, Ratain MJ. Pharmacokinetic Modulation of Irinotecan and Metabolites by Cyclosporin A. Cancer Res. 1996; 56: 1309-1314
38 Nagilla R, Ward KW. A Comprehensive Analysis of the Role of Correction factors in the Allometric Predictivity of Clearance from Rat, Dog, and Monkey to Humans. J Pharm. Sci. 2004; 93: 2522-2534
39 Pavankumar VV, Vinu CA, Mullangi R, Srinivas NR. Preclinical pharmacokinetics and interspecies scaling of ragagli-tazar, a novel biliary excreted PPAR dual activator. Eu J Drug Metab Pharmacol. 2007; 32: 29-37
40 Kaneda N, Nagata H, Furuta T, Yokokura T. Metabolism and Pharmacokinetics of the Camptothecin Analogue CPT-11 in the mouse. Cancer Res. 1990; 50: 1715-1720
41 Zamboni WC, Hougton PJ, Thompson J, Cheshire PJ, Hanna SK, Richmond LB et al Altered Irinotecan and SN-38 Disposition after Intravenous Administration of Irinotecan in mice Bearing Human Neuroblastoma Xenografts. Clin Cancer Res. 1998; 4: 455-462
42 Kaneda N, Yokokura T. Nonlinear Pharmacokinetics of CPT-11 in Rats. Cancer Res. 1990; 50: 1721-1725
43 Inaba M, Ohnishi Y, Ishii H, Tanioka Y, Yoshida Y, Sudoh K et al Pharmacokinetics of CPT-11 in rhesus monkeys. Cancer Chemother Pharmacol. 1998; 41: 103-108
44 Van Groeningen CJ, Van der Vijgh WJF, Baars JJ, Stieltjes H, Huibregtse K, Pinedo H. Altered Pharmacokinetics and Metabolism of CPT-11 in liver Dysfunction: A need for Guidelines. Clin Cancer Res. 2000; 6: 1342-1346
45 Kehrer DFS, Yamamoto W, Verweij J, de Jonge MJA, de Bruijn P, Sparreboom A. Factors involved in the Prolongation of the terminal disposition Phase of SN-38: Clinical and experimental studies. Clin Cancer Res. 2000; 6: 3451-3458
46 Xie R, Mathijssen RHJ, Sparreboom A, Verweij J, Karlsson MO. Clinical Pharmacokinetics of Irinotecan and its metabolites: A population analysis. J Clin Oncol. 2002; a 20: 3293-3301
47 Poujol S, Bressolle F, Duffour J, Abderrahim AG, Astre C, Ychou M et al Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen. Cancer Chemother Pharmacol. 2006; 58: 292-305
48 Klein CE, Gupta E, Reid JM, Atherton PJ, Sloan JA, Pitot HC et al Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide. Clin Pharmacol Ther. 2002; 72: 638-647
49 Xie R, Mathijssen RHJ, Sparreboom A, Verweij J, Karlsson MO. Clinical Pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther. 2002; b 72: 265-275
50 Pitot HC, Goldberg RM, Reid JM, Sloan JA, Skaff PA, Erlich-man C et al Phase I Dose-finding and Pharmacokinetic Trial of Irinotecan Hydrochloride (CPT-11) Using a Once-Every-Three-Week Dosing Schedule for Patients with Advanced Solid Tumor Malignancy. Clin Cancer Re.s. 2000; 6: 2236-2244
51 Vassal G, Santos A, Deroussent A, Doz F, Frappaz D, Pein F et al Clinical Pharmacology of Irinotecan (CPT-11) in children (Meeting abstract). 1998 Abstract No. 720; ASCO Annual Meeting.