Skip to main content

Advertisement

SpringerLink
Log in

Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Irinotecan (IR) displays significant PK/PD variability. This study evaluated functional hepatic imaging (HNI) and extensive pharmacogenomics (PGs) to explore associations with IR PK and PD (toxicity and response).

Methods

Eligible patients (pts) suitable for Irinotecan-based therapy. At baseline: (i) PGs: blood analyzed by the Affymetrix-DMET™-Plus-Array (1936 variants: 1931 single nucleotide polymorphisms [SNPs] and 5 copy number variants in 225 genes, including 47 phase I, 80 phase II enzymes, and membrane transporters) and Sanger sequencing (variants in HNF1A, Topo-1, XRCC1, PARP1, TDP, CDC45L, NKFB1, and MTHFR), (ii) HNI: pts given IV 250 MBq-99mTc-IDA, data derived for hepatic extraction/excretion parameters (CLHNI, T1/2-HNI, 1hRET, HEF, Td1/2). In cycle 1, blood was taken for IR analysis and PK parameters were derived by non-compartmental methods. Associations were evaluated between HNI and PGs, with IR PK, toxicity, objective response rate (ORR) and progression-free survival (PFS).

Results

N = 31 pts. The two most significant associations between PK and PD with gene variants or HNI parameters (P < 0.05) included: (1) PK: SN38-Metabolic Ratio with CLHNI, 1hRET, (2) Grade 3+ diarrhea with SLC22A2 (rs 316019), GSTM5 (rs 1296954), (3) Grade 3+ neutropenia with CLHNI, 1hRET, SLC22A2 (rs 316019), CYP4F2 (rs2074900) (4) ORR with ALDH2 (rs 886205), MTHFR (rs 1801133). (5) PFS with T1/2-HNI, XDH (rs 207440), and ABCB11 (rs 4148777).

Conclusions

Exploratory associations were observed between Irinotecan PK/PD with hepatic functional imaging and extensive pharmacogenomics. Further work is required to confirm and validate these findings in a larger cohort of patients.

Australian New Zealand Clinical Trials Registry (ANZCTR) Number

ACTRN12610000897066, Date registered: 21/10/2010.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A (2001) Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7(8):2182–2194

    CAS  PubMed  Google Scholar 

  2. Chu XY, Kato Y, Ueda K, Suzuki H, Niinuma K, Tyson CA, Weizer V, Dabbs JE, Froehlich R, Green CE, Sugiyama Y (1998) Biliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters. Cancer Res 58(22):5137–5143

    CAS  PubMed  Google Scholar 

  3. Nozawa T, Minami H, Sugiura S, Tsuji A, Tamai I (2005) Role of organic anion transporter OATP1B1 (OATP-C) in hepatic uptake of irinotecan and its active metabolite, 7-ethyl-10-hydroxycamptothecin: in vitro evidence and effect of single nucleotide polymorphisms. Drug Metab Dispos 33(3):434–439. https://doi.org/10.1124/dmd.104.001909

    Article  CAS  PubMed  Google Scholar 

  4. Schellens JH, Maliepaard M, Scheper RJ, Scheffer GL, Jonker JW, Smit JW, Beijnen JH, Schinkel AH (2000) Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications. Ann N Y Acad Sci 922:188–194

    Article  CAS  Google Scholar 

  5. de Man FM, Goey AKL, van Schaik RHN, Mathijssen RHJ, Bins S (2018) Individualization of irinotecan treatment: a review of pharmacokinetics, pharmacodynamics, and pharmacogenetics. Clin Pharmacokinet. https://doi.org/10.1007/s40262-018-0644-7

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sugatani J, Sueyoshi T, Negishi M, Miwa M (2005) Regulation of the human UGT1A1 gene by nuclear receptors constitutive active/androstane receptor, pregnane X receptor, and glucocorticoid receptor. Methods Enzymol 400:92–104. https://doi.org/10.1016/S0076-6879(05)00006-6

    Article  CAS  PubMed  Google Scholar 

  7. van der Bol JM, Mathijssen RH, Loos WJ, Friberg LE, van Schaik RH, de Jonge MJ, Planting AS, Verweij J, Sparreboom A, de Jong FA (2007) Cigarette smoking and irinotecan treatment: pharmacokinetic interaction and effects on neutropenia. J Clin Oncol 25(19):2719–2726. https://doi.org/10.1200/JCO.2006.09.6115

    Article  CAS  PubMed  Google Scholar 

  8. Mathijssen RH, Verweij J, de Jonge MJ, Nooter K, Stoter G, Sparreboom A (2002) Impact of body-size measures on irinotecan clearance: alternative dosing recommendations. J Clin Oncol 20(1):81–87. https://doi.org/10.1200/JCO.2002.20.1.81

    Article  CAS  PubMed  Google Scholar 

  9. Hahn RZ, Antunes MV, Verza SG, Perassolo MS, Suyenaga ES, Schwartsmann G, Linden R (2018) Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity. Curr Med Chem. https://doi.org/10.2174/0929867325666180622141101

    Article  Google Scholar 

  10. US Food and Drug Administration (2014) Irinotecan hydrochloride. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e98886aa-933c-430f-bb56-f1eb3862aae4#boxedwarning

  11. Association RDP (2014) Dutch Pharmacogenetics Working Group (DPWG). Pharmacogenetic Guidelines. Netherlands. Irinotecan-UGT1A1. http://kennisbank.knmp.nl

  12. Michael M, Thompson M, Hicks RJ, Mitchell PL, Ellis A, Milner AD, Di Iulio J, Scott AM, Gurtler V, Hoskins JM, Clarke SJ, Tebbut NC, Foo K, Jefford M, Zalcberg JR (2006) Relationship of hepatic functional imaging to irinotecan pharmacokinetics and genetic parameters of drug elimination. J Clin Oncol 24(26):4228–4235. https://doi.org/10.1200/JCO.2005.04.8496

    Article  CAS  PubMed  Google Scholar 

  13. Affymetrix I (2008) DMETTM plus array. https://assets.thermofisher.com/TFS-Assets/LSG/manuals/dmet_plus_array_insert.pdf

  14. Deeken J (2009) The Affymetrix DMET platform and pharmacogenetics in drug development. Curr Opin Mol Ther 11(3):260–268

    CAS  PubMed  Google Scholar 

  15. Horita Y, Yamada Y, Hirashima Y, Kato K, Nakajima T, Hamaguchi T, Shimada Y (2010) Effects of bevacizumab on plasma concentration of irinotecan and its metabolites in advanced colorectal cancer patients receiving FOLFIRI with bevacizumab as second-line chemotherapy. Cancer Chemother Pharmacol 65(3):467–471. https://doi.org/10.1007/s00280-009-1051-4

    Article  CAS  PubMed  Google Scholar 

  16. Gupta E, Mick R, Ramirez J, Wang X, Lestingi TM, Vokes EE, Ratain MJ (1997) Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients. J Clin Oncol 15(4):1502–1510. https://doi.org/10.1200/JCO.1997.15.4.1502

    Article  CAS  PubMed  Google Scholar 

  17. Toffoli G, Sharma MR, Marangon E, Posocco B, Gray E, Mai Q, Buonadonna A, Polite BN, Miolo G, Tabaro G, Innocenti F (2017) Genotype-guided dosing study of FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer. Clin Cancer Res 23(4):918–924. https://doi.org/10.1158/1078-0432.CCR-16-1012

    Article  CAS  PubMed  Google Scholar 

  18. Innocenti F, Schilsky RL, Ramirez J, Janisch L, Undevia S, House LK, Das S, Wu K, Turcich M, Marsh R, Karrison T, Maitland ML, Salgia R, Ratain MJ (2014) Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer. J Clin Oncol 32(22):2328–2334. https://doi.org/10.1200/JCO.2014.55.2307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. van der Bol JM, Mathijssen RH, Creemers GJ, Planting AS, Loos WJ, Wiemer EA, Friberg LE, Verweij J, Sparreboom A, de Jong FA (2010) A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan. Clin Cancer Res 16(2):736–742. https://doi.org/10.1158/1078-0432.CCR-09-1526

    Article  CAS  PubMed  Google Scholar 

  20. Denlinger CS, Blanchard R, Xu L, Bernaards C, Litwin S, Spittle C, Berg DJ, McLaughlin S, Redlinger M, Dorr A, Hambleton J, Holden S, Kearns A, Kenkare-Mitra S, Lum B, Meropol NJ, O’Dwyer PJ (2009) Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors. Cancer Chemother Pharmacol 65(1):97–105. https://doi.org/10.1007/s00280-009-1008-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chabot GG (1997) Clinical pharmacokinetics of irinotecan. Clin Pharmacokinet 33(4):245–259. https://doi.org/10.2165/00003088-199733040-00001

    Article  CAS  PubMed  Google Scholar 

  22. Conti JA, Kemeny NE, Saltz LB, Huang Y, Tong WP, Chou TC, Sun M, Pulliam S, Gonzalez C (1996) Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14(3):709–715. https://doi.org/10.1200/JCO.1996.14.3.709

    Article  CAS  PubMed  Google Scholar 

  23. Sissung TM, Rajan A, Blumenthal GM, Liewehr DJ, Steinberg SM, Berman A, Giaccone G, Figg WD (2019) Reproducibility of pharmacogenetics findings for paclitaxel in a heterogeneous population of patients with lung cancer. PLoS One 14(2):e0212097. https://doi.org/10.1371/journal.pone.0212097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ravegnini G, Urbini M, Simeon V, Genovese C, Astolfi A, Nannini M, Gatto L, Saponara M, Ianni M, Indio V, Brandi G, Trino S, Hrelia P, Biasco G, Angelini S, Pantaleo MA (2018) An exploratory study by DMET array identifies a germline signature associated with imatinib response in gastrointestinal stromal tumor. Pharmacogenomics J. https://doi.org/10.1038/s41397-018-0050-4

    Article  PubMed  Google Scholar 

  25. Uchiyama T, Kanno H, Ishitani K, Fujii H, Ohta H, Matsui H, Kamatani N, Saito K (2012) An SNP in CYP39A1 is associated with severe neutropenia induced by docetaxel. Cancer Chemother Pharmacol 69(6):1617–1624. https://doi.org/10.1007/s00280-012-1872-4

    Article  CAS  PubMed  Google Scholar 

  26. Nieuweboer AJ, Smid M, de Graan AM, Elbouazzaoui S, de Bruijn P, Eskens FA, Hamberg P, Martens JW, Sparreboom A, de Wit R, van Schaik RH, Mathijssen RH (2016) Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics. Pharmacogenomics J 16(6):519–524. https://doi.org/10.1038/tpj.2015.66

    Article  CAS  PubMed  Google Scholar 

  27. Rumiato E, Boldrin E, Amadori A, Saggioro D (2013) DMET (drug-metabolizing enzymes and transporters) microarray analysis of colorectal cancer patients with severe 5-fluorouracil-induced toxicity. Cancer Chemother Pharmacol 72(2):483–488. https://doi.org/10.1007/s00280-013-2210-1

    Article  CAS  PubMed  Google Scholar 

  28. Harris M, Bhuvaneshwar K, Natarajan T, Sheahan L, Wang D, Tadesse MG, Shoulson I, Filice R, Steadman K, Pishvaian MJ, Madhavan S, Deeken J (2014) Pharmacogenomic characterization of gemcitabine response—a framework for data integration to enable personalized medicine. Pharmacogenet Genomics 24(2):81–93. https://doi.org/10.1097/FPC.0000000000000015

    Article  CAS  PubMed  Google Scholar 

  29. Thompson P, Wheeler HE, Delaney SM, Lorier R, Broeckel U, Devidas M, Reaman GH, Scorsone K, Sung L, Dolan ME, Berg SL (2014) Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group. Cancer Chemother Pharmacol 74(4):831–838. https://doi.org/10.1007/s00280-014-2535-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, Sparreboom A, McLeod HL (2003) Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 9(9):3246–3253

    CAS  PubMed  Google Scholar 

  31. Li M, Seiser EL, Baldwin RM, Ramirez J, Ratain MJ, Innocenti F, Kroetz DL (2018) ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia. Pharmacogenomics J 18(1):35–42. https://doi.org/10.1038/tpj.2016.75

    Article  CAS  PubMed  Google Scholar 

  32. Wong M, Balleine RL, Blair EY, McLachlan AJ, Ackland SP, Garg MB, Evans S, Farlow D, Collins M, Rivory LP, Hoskins JM, Mann GJ, Clarke CL, Gurney H (2006) Predictors of vinorelbine pharmacokinetics and pharmacodynamics in patients with cancer. J Clin Oncol 24(16):2448–2455. https://doi.org/10.1200/JCO.2005.02.1295

    Article  CAS  PubMed  Google Scholar 

  33. Di Martino MT, Arbitrio M, Leone E, Guzzi PH, Rotundo MS, Ciliberto D, Tomaino V, Fabiani F, Talarico D, Sperlongano P, Doldo P, Cannataro M, Caraglia M, Tassone P, Tagliaferri P (2011) Single nucleotide polymorphisms of ABCC5 and ABCG1 transporter genes correlate to irinotecan-associated gastrointestinal toxicity in colorectal cancer patients: a DMET microarray profiling study. Cancer Biol Ther 12(9):780–787. https://doi.org/10.4161/cbt.12.9.17781

    Article  CAS  PubMed  Google Scholar 

  34. Hoskins JM, Marcuello E, Altes A, Marsh S, Maxwell T, Van Booven DJ, Pare L, Culverhouse R, McLeod HL, Baiget M (2008) Irinotecan pharmacogenetics: influence of pharmacodynamic genes. Clin Cancer Res 14(6):1788–1796. https://doi.org/10.1158/1078-0432.CCR-07-1472

    Article  CAS  PubMed  Google Scholar 

  35. Glimelius B, Garmo H, Berglund A, Fredriksson LA, Berglund M, Kohnke H, Bystrom P, Sorbye H, Wadelius M (2011) Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer. Pharmacogenomics J 11(1):61–71. https://doi.org/10.1038/tpj.2010.10

    Article  CAS  PubMed  Google Scholar 

  36. Marcuello E, Altes A, Menoyo A, Rio ED, Baiget M (2006) Methylenetetrahydrofolate reductase gene polymorphisms: genomic predictors of clinical response to fluoropyrimidine-based chemotherapy? Cancer Chemother Pharmacol 57(6):835–840. https://doi.org/10.1007/s00280-005-0089-1

    Article  CAS  PubMed  Google Scholar 

  37. Li P, Chen Q, Wang YD, Ha MW (2014) Effects of MTHFR genetic polymorphisms on toxicity and clinical response of irinotecan-based chemotherapy in patients with colorectal cancer. Genet Test Mol Biomarkers 18(5):313–322. https://doi.org/10.1089/gtmb.2013.0494

    Article  CAS  PubMed  Google Scholar 

  38. Dias MM, McKinnon RA, Sorich MJ (2012) Impact of the UGT1A1*28 allele on response to irinotecan: a systematic review and meta-analysis. Pharmacogenomics 13(8):889–899. https://doi.org/10.2217/pgs.12.68

    Article  CAS  PubMed  Google Scholar 

  39. Dias MM, Pignon JP, Karapetis CS, Boige V, Glimelius B, Kweekel DM, Lara PN, Laurent-Puig P, Martinez-Balibrea E, Paez D, Punt CJ, Redman MW, Toffoli G, Wadelius M, McKinnon RA, Sorich MJ (2014) The effect of the UGT1A1*28 allele on survival after irinotecan-based chemotherapy: a collaborative meta-analysis. Pharmacogenomics J 14(5):424–431. https://doi.org/10.1038/tpj.2014.16

    Article  CAS  PubMed  Google Scholar 

  40. Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL (2007) UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst 99(17):1290–1295. https://doi.org/10.1093/jnci/djm115

    Article  CAS  PubMed  Google Scholar 

  41. Liu D, Li J, Gao J, Li Y, Yang R, Shen L (2017) Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis. BMC Cancer 17(1):437. https://doi.org/10.1186/s12885-017-3406-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramirez J, Relling M, Chen P, Das S, Rosner GL, Ratain MJ (2009) Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 27(16):2604–2614. https://doi.org/10.1200/JCO.2008.20.6300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen S, Villeneuve L, Jonker D, Couture F, Laverdiere I, Cecchin E, Innocenti F, Toffoli G, Levesque E, Guillemette C (2015) ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients. Pharmacogenet Genomics 25(12):573–583. https://doi.org/10.1097/FPC.0000000000000168

    Article  CAS  PubMed  Google Scholar 

  44. Hahn RZ, Antunes MV, Verza SG, Perassolo MS, Suyenaga ES, Schwartsmann G, Linden R (2019) Pharmacokinetic and pharmacogenetic markers of irinotecan toxicity. Curr Med Chem 26(12):2085–2107. https://doi.org/10.2174/0929867325666180622141101

    Article  CAS  PubMed  Google Scholar 

  45. Hahn RZ, Arnhold PC, Andriguetti NB, Schneider A, Kluck HM, Dos Reis SL, Bastiani MF, Kael I, da Silva ACC, Schwartsmann G, Antunes MV, Linden R (2018) Determination of irinotecan and its metabolite SN-38 in dried blood spots using high-performance liquid-chromatography with fluorescence detection. J Pharm Biomed Anal 150:51–58. https://doi.org/10.1016/j.jpba.2017.11.079

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funded by the Australian National Health and Medical Research Council Grant 628564.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia

    Michael Michael & Michael Jefford

  2. Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia

    Emma Link & Annetta Matera

  3. Division of Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia

    Michael Thompson & Rod J. Hicks

  4. Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia

    Carleen Cullinane & Athena Hatzimihalis

  5. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia

    Ian G. Campbell & Simone Rowley

  6. Department of Medical Oncology, St. George’s Hospital, Sydney, Australia

    Winston Liauw

  7. Department of Medical Oncology, St. Vincent’s Hospital, Melbourne, Australia

    Sue-Anne McLachlan

  8. Department of Medical Oncology, Royal Prince Alfred Hospital, Sydney, Australia

    Phillip J. Beale

  9. Department of Medical Oncology, Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Adelaide, Australia

    Christos S. Karapetis

  10. Department of Medical Oncology, The Queen Elizabeth Hospital, Adelaide, Australia

    Timothy Price

  11. Department of Medical Oncology, Royal Brisbane and Women’s Hospital, Brisbane, Australia

    Mathew E. Burge

Authors
  1. Michael Michael
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Winston Liauw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sue-Anne McLachlan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annetta Matera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Jefford
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rod J. Hicks
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carleen Cullinane
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Athena Hatzimihalis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ian G. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Simone Rowley
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Phillip J. Beale
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Christos S. Karapetis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Timothy Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Mathew E. Burge
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Wrote Manuscript, M Michael, W Liauw, S-A McLachlan, E Link, A Matera, M Thompson, M Jefford, RJ Hicks, C Cullinane, A Hatzimihalis, IG Campbell, S Rowley, PJ Beale, CS Karapetis, T Price, ME. Burge. Designed Research, M Michael, E Link, A Matera, M Thompson, RJ Hicks, C Cullinane, A Hatzimihalis, IG Campbell, S Rowley, Performed Research, M Michael, W Liauw, S-A McLachlan, E Link, A Matera, M Thompson, M Jefford, RJ Hicks, C Cullinane, A Hatzimihalis, IG Campbell, S Rowley, PJ Beale, CS Karapetis, T Price, ME. Burge. Analysed Data, and Contributed Analytical Tools. M Michael, E Link, M Thompson, RJ Hicks, C Cullinane, A Hatzimihalis, IG Campbell, S Rowley.

Corresponding author

Correspondence to Michael Michael.

Ethics declarations

Conflicts of interest

All contributing authors have no competing financial interests in relation to the work described.

Ethics approval

The study was approved by the Peter MacCallum Cancer Centre Ethics Committee on the 3rd Sept 2010, followed shortly after the Institutional Ethics Committees at all other study sites. This study was to be carried out in compliance with the protocol and with adherence to Good Clinical Practice, as described in the following documents: ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 91/507/EEC, Rules Governing Medicinal Products in the European Community. Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Patients, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996, Edinburgh 2000, Washington 2002; Appendix 11).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 68 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Michael, M., Liauw, W., McLachlan, SA. et al. Pharmacogenomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: the predict IR study. Cancer Chemother Pharmacol 88, 39–52 (2021). https://doi.org/10.1007/s00280-021-04264-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-021-04264-8

Keywords

Search

Navigation