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Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir

The Pharmacogenomics Journal volume 21, pages 336–345 (2021)Cite this article

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Abstract

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of the tested CYP3A, ABCB1, ABCC2, and SLCO1B3 genotypes and diplotypes showed a significant relation with an altered bioavailability or clearance of either docetaxel or ritonavir. Similarly, no clear effect of CYP1B1 genotype on clinical outcomes was observed in a subgroup of non-small cell lung cancer (NSCLC) patients. Our post hoc power analysis indicated that our pharmacogenetic–pharmacokinetic analysis was only powered for relatively high effect sizes, which were to be expected given the high interpatient variability. This makes it unlikely that future studies will explain the high observed interpatient variability in oral docetaxel pharmacokinetics as a result of any of these separate polymorphisms and diplotypes.

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Fig. 1: Linkage disequilibrium plots.
Fig. 2: Swimmer plot visualizing time on study and best outcome of treatment with oral docetaxel for 51 NSCLC patients grouped by CYP1B1 genotype.
Fig. 3: PPE power curves.

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Code availability

The NONMEM control streams for the oral docetaxel and ritonavir models that were used in our pharmacokinetic–pharmacogenetic analysis and in our trial simulations are available in the supplementary material.

References

  1. Sanofi-Aventis. Summary of Product Characteristics (Taxotere). 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/taxotere

  2. De Weger VA, Stuurman FE, JJMA Hendrikx, Moes JJ, Sawicki E, ADR Huitema, et al. A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir. Eur J Cancer. 2017;86:217–25.

    Article  Google Scholar 

  3. Nieuweboer AJM, de Morrée ES, de Graan AJM, Sparreboom A, de Wit R, Mathijssen RHJ. Inter-patient variability in docetaxel pharmacokinetics: a review. Cancer Treat Rev. 2015;41:605–13.

    Article  CAS  Google Scholar 

  4. Oshiro C, Marsh S, McLeod H, Carrillo MW, Klein T, Altman R. Taxane pathway. Pharmacogenet Genom. 2009;19:979–83.

    Article  CAS  Google Scholar 

  5. Iusuf D, JJMA Hendrikx, Van Esch A, Van De Steeg E, Wagenaar E, Rosing H, et al. Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int J Cancer. 2015;136:225–33.

    Article  CAS  Google Scholar 

  6. De Graan AJM, Lancaster CS, Obaidat A, Hagenbuch B, Elens L, Friberg LE, et al. Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clin Cancer Res. 2012;18:4433–40.

    Article  Google Scholar 

  7. Baker SD, Sparreboom A, Verweij J. Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet. 2006;45:235–52.

    Article  CAS  Google Scholar 

  8. Van Waterschoot RAB, Lagas JS, Wagenaar E, Rosing H, Beijnen JH, Schinkel AH. Individual and combined roles of CYP3A, P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) in the pharmacokinetics of docetaxel. Int J Cancer. 2010;127:2959–64.

    Article  Google Scholar 

  9. Hsu A, Granneman GR, Bertz RJ. Ritonavir: clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet. 1998;35:275–91.

    Article  CAS  Google Scholar 

  10. Huisman MT, Smit JW, Crommentuyn KML, Zelcer N, Wiltshire HR, Beijnen JH, et al. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. Aids 2002;16:2295–301.

    Article  CAS  Google Scholar 

  11. Cerveny L, Ptackova Z, Durisova M, Staud F. Interactions of protease inhibitors atazanavir and ritonavir with ABCB1, ABCG2, and ABCC2 transporters: Effect on transplacental disposition in rats. Reprod Toxicol. 2018;79:57–65.

    Article  CAS  Google Scholar 

  12. Bosch TM, Huitema ADR, Doodeman VD, Jansen R, Witteveen E, Smit WM, et al. Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res. 2006;12:5786–93.

    Article  CAS  Google Scholar 

  13. Baker SD, Verweij J, Cusatis GA, Van Schaik RH, Marsh S, Orwick SJ, et al. Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharm Ther. 2009;85:155–63.

    Article  CAS  Google Scholar 

  14. Vasile E, Tibaldi C, Leon GL, D’Incecco A, Giovannetti E. Cytochrome P450 1B1 (CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer (NSCLC) patients. J Cancer Res Clin Oncol. 2015;141:1189–94.

    Article  CAS  Google Scholar 

  15. Sissung TM, Danesi R, Price DK, Steinberg SM, De Wit R, Zahid M, et al. Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel. Mol Cancer Ther. 2008;7:19–26.

    Article  CAS  Google Scholar 

  16. Pastina I, Giovannetti E, Chioni A, Sissung TM, Crea F, Orlandini C, et al. Cytochrome 450 1B1 (CYP1B1) polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC) patients. BMC Cancer. 2010;10.

  17. Shimada T, Watanabe J, Kawajiri K, Sutter TR, Guengerich FP, Gillam EMJ, et al. Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis. 1999;20:1607–13.

    Article  CAS  Google Scholar 

  18. Hanna IH, Dawling S, Roodi N, Guengerich FP, Parl FF. Cytochrome P450 1B1 (CYP1B1) pharmacogenetics association of polymorphisms with functional differences in estrogen hydroxylation activity. Cancer Res. 2000;60:3440–4.

    CAS  PubMed  Google Scholar 

  19. Bournique B, Lemarié A. Docetaxel (Taxotere) is not metabolized by recombinant human CYP1B1 in vitro, but acts as an effector of this isozyme. Drug Metab Dispos. 2002;30:1149–52.

    Article  CAS  Google Scholar 

  20. De Weger VA, Stuurman FE, Koolen SLW, Moes JJ, JJMA Hendrikx, Sawicki E, et al. A phase I dose escalation study of once-weekly oral administration of docetaxel as ModraDoc001 capsule or ModraDoc006 tablet in combination with ritonavir. Clin Cancer Res. 2019;25:5466–74.

    Article  Google Scholar 

  21. Yu H, Janssen JM, Sawicki E, van Hasselt JGC, de Weger VA, Nuijen B, et al. A population pharmacokinetic model of oral docetaxel coadministered with ritonavir to support early clinical development. J Clin Pharm. 2020;60:340–50.

    Article  CAS  Google Scholar 

  22. Keizer RJ, Zandvliet AS, Beijnen JH, Schellens JHM, Huitema ADR. Performance of methods for handling missing categorical covariate data in population pharmacokinetic analyses. AAPS J. 2012;14:601–11.

    Article  CAS  Google Scholar 

  23. Jonsson EN, Karlsson MO. Automated covariate model building within NONMEM. Pharm Res. 1998;15:1463–8.

    Article  CAS  Google Scholar 

  24. Lindbom L, Pihlgren P, Jonsson N. PsN-Toolkit - A collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed. 2005;79:241–57.

    Article  Google Scholar 

  25. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.

    Article  CAS  Google Scholar 

  26. Ueckert S, Karlsson MO, Hooker AC. Accelerating Monte Carlo power studies through parametric power estimation. J Pharmacokinet Pharmacodyn. 2016;43:223–34.

    Article  Google Scholar 

  27. Sherry ST, Ward M, Sirotkin K. dbSNP—database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res. 1999;9:677–9.

    CAS  PubMed  Google Scholar 

  28. Fung KL, Gottesman MM. A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta—Proteins Proteom. 2009;1794:860–71.

    Article  CAS  Google Scholar 

  29. Smith NF, Marsh S, Scott-Horton TJ, Hamada A, Mielke S, Mross K, et al. Variants in the SLCO1B3 gene: interethnic distribution and association with paclitaxel pharmacokinetics. Clin Pharm Ther. 2007;81:76–82.

    Article  CAS  Google Scholar 

  30. Lepper ER, Baker SD, Permenter M, Ries N, Van Schaik RHN, Schenk PW, et al. Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients. Clin Cancer Res. 2005;11:7398–404.

    Article  CAS  Google Scholar 

  31. Lian G, Yuan J, Gao Y. In vitro transport ability of ABCC2 (G1249A) polymorphic variant towards anticancer drugs. Onco Targets Ther. 2020;13:1413–9.

    Article  CAS  Google Scholar 

  32. Daly AK. Significance of the minor cytochrome P450 3A isoforms. Clin Pharmacokinet. 2006;45:13–31.

    Article  CAS  Google Scholar 

  33. Elens L, Van Gelder T, Hesselink DA, Haufroid V, Van Schaik RHN. CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics. 2013;14:47–62.

    Article  CAS  Google Scholar 

  34. Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharm Toxicol. 2006;98:79–85.

    Article  CAS  Google Scholar 

  35. Hossain MA, Tran T, Chen T, Mikus G, Greenblatt DJ. Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat. J Pharm Pharm. 2017;69:1786–93.

    Article  CAS  Google Scholar 

  36. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, et al. Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): Influence of protein expression on drug-drug interactions. J Med Chem. 2012;55:4740–63.

    Article  CAS  Google Scholar 

  37. Drewe J, Gutmann H, Fricker G, Török M, Beglinger C. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharm. 1999;57:1147–52.

    Article  Google Scholar 

  38. Ye ZW, Camus S, Augustijns P, Annaert P. Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes. Biopharm Drug Dispos. 2010;31:178–88.

    CAS  PubMed  Google Scholar 

  39. Kobayashi Y, Ohshiro N, Sakai R, Ohbayashi M, Kohyama N, Yamamoto T. Transport mechanism and substrate specificity of human organic anion transporter 2 (hOat2 [SLC22A7]). J Pharm Pharm. 2005;57:573–8.

    Article  CAS  Google Scholar 

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Acknowledgements

JHB has received a grant for translational research (ZonMw code 40-41200-98-004).

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Authors and Affiliations

  1. Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands

    Maarten van Eijk, Dick Pluim, Thomas P. C. Dorlo, Alwin D. R. Huitema & Jos H. Beijnen

  2. Division of Clinical Pharmacology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek, Amsterdam, The Netherlands

    Serena Marchetti

  3. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Alwin D. R. Huitema

  4. Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Alwin D. R. Huitema

  5. Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

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Correspondence to Maarten van Eijk.

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Conflict of interest

JHB holds a patent on oral taxane formulations and is a (part-time) employee and (indirect) shareholder of Modra Pharmaceuticals, a spin-off company that develops oral taxane formulations. The other authors declare that they have no conflict of interest.

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van Eijk, M., Pluim, D., Dorlo, T.P.C. et al. Investigating the influence of relevant pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of orally administered docetaxel combined with ritonavir. Pharmacogenomics J 21, 336–345 (2021). https://doi.org/10.1038/s41397-021-00213-z

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