Download PDF
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
Preeti Ahlawat
1   Global Drug Development, ClinTec (India) International Pvt Ltd., Bangalore, (India)
,
Nuggehally R Srinivas
1   Global Drug Development, ClinTec (India) International Pvt Ltd., Bangalore, (India)
1   New address: Suramus Biopharm, Bangalore, (India)
› Author Affiliations
Further Information

Publication History

Publication Date:
13 December 2011 (online)

    Permissions and Reprints

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, Vss) 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 (8.9641W1 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
 

  • References

  • 1 Liew ST, Yang LX. Design, synthesis and development of novel camptothecin drugs. Curr Pharm Des. 2008; 14: 1078-1097
    CrossrefPubMedSearch in Google Scholar
  • 2 Rothenberg ML. Irinotecan (CPT-11): Recent developments and future directions-colorectal cancer and beyond. Oncol. 2001; 6: 65
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 6 Schaeppi U, Fleischman RW, Cooney DA. Toxicity of camptothecin (NSC-100880). Cancer Chemother Report. 1974; 5: 25-36
    PubMedSearch in Google Scholar
  • 7 Creemers GJ, Lund B, Verweij J. Topoisomerase I inhibitors. Topotecan and irinotecan. Cancer Treat Rev. 1994; 20: 73-96
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 25 Teh-Min Hu, William LH. Allometric Scaling of Xenobiotic Clearance: Uncertainty versus Universality. AAPS Pharm Sci. 2001; 3 (29)
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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)
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 30 Robert J, Rivory L. Pharmacology of Irinotecan. Drugs Today. 1998; 34: 777
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 37 Gupta E, Safa AR, Wang X, Ratain MJ. Pharmacokinetic Modulation of Irinotecan and Metabolites by Cyclosporin A. Cancer Res. 1996; 56: 1309-1314
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 42 Kaneda N, Yokokura T. Nonlinear Pharmacokinetics of CPT-11 in Rats. Cancer Res. 1990; 50: 1721-1725
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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.
    PubMedSearch in Google Scholar