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Predicting the Effects of Different Triazole Antifungal Agents on the Pharmacokinetics of Tamoxifen

AAPS PharmSciTech volume 20, Article number: 24 (2019) Cite this article

Abstract

Tamoxifen is an antiestrogen drug that is widely used in the adjuvant chemotherapy of estrogen receptor-α (ERα)-positive breast cancer. Chemotherapy could suppress immune function in breast cancer patients, which may cause invasive fungal infections (IFIs). Triazoles (voriconazole, fluconazole, and itraconazole) were commonly used for IFI. The physiologically based pharmacokinetic (PBPK) models were developed to investigate the influence of different triazoles on tamoxifen pharmacokinetics in this paper. To investigate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on tamoxifen pharmacokinetics. Adjusted physicochemical data and pharmacokinetic parameters of voriconazole, fluconazole, itraconazole, and tamoxifen were obtained from published literatures. PBPK models were built and verified in healthy subjects using GastroPlus™. Voriconazole, itraconazole, and tamoxifen were administered orally. Fluconazole was administered intravenously. Simulated plasma concentration–time curves of the voriconazole, fluconazole, itraconazole, and tamoxifen showed good agreement with the observed profiles, respectively. The DDI simulations showed that the pharmacokinetic parameters of tamoxifen were increased by various degrees when coadministered with different triazoles. In healthy subjects, the area under the plasma concentration–time curve from 0 to t h (AUC0–t) of tamoxifen was increased by 41%, 5%, and1% when coadministrated with voriconazole, fluconazole, and itraconazole, respectively. The PBPK models adequately characterized the pharmacokinetics of tamoxifen and triazoles. Among the three triazoles, voriconazole exhibited the greatest effect on tamoxifen pharmacokinetics. In clinical practice, an effective dosage adjustment of tamoxifen may need to be considered and TDM for tamoxifen is advisable to guide dosing and optimize therapy when coadministered with voriconazole.

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References

  1. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality predictions for the year 2014. Ann Oncol. 2014;25(8):1650–6.

    CAS  Article  Google Scholar 

  2. de Vries Schultink AH, Zwart W, Linn SC, Beijnen JH, Huitema AD. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen. Clin Pharmacokinetic. 2015;54(8):797–810.

    Article  Google Scholar 

  3. Rovati B, Mariucci S, Delfanti S, Grasso D, Torre C, De Amici M, et al. Simultaneous detection of circulating immunological parameters and tumor biomarkers in early stage breast cancer patients during adjuvant chemotherapy. Cell Oncol. 2016;39(3):211–28.

    CAS  Article  Google Scholar 

  4. Scodavolpe S, Quaranta S, Lacarelle B, Solas C. Triazole antifungal agents: practice guidelines of therapeutic drug monitoring and perspectives in treatment optimization. Ann Biol Clin. 2014;72(4):391–404.

    Google Scholar 

  5. Helmestam M, Andersson H, Stavreusevers A, Brittebo E, Olovsson M. Tamoxifen modulates cell migration and expression of angiogenesis-related genes in human endometrial endothelial cells. Am J Pathol. 2012;180(6):2527–35.

    CAS  Article  Google Scholar 

  6. Lass-Flörl C. Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs. 2011;71(18):2405–19.

    Article  Google Scholar 

  7. Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous-to oral-dose escalation regimens. Antimicrob Agents Chemother. 2002;46(8):2546–53.

    CAS  Article  Google Scholar 

  8. Passler NH, Chan HM, Stewart AJ, Duran SH, Welles EG, Lin HC, et al. Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing. J Vet Pharmacol Ther. 2010;33(1):35–41.

    CAS  Article  Google Scholar 

  9. Saari TI, Laine K, Neuvonen M, Neuvonen PJ, Olkkola KT. Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. Eur J Clin Pharmacol. 2008;64(1):25–30.

    CAS  Article  Google Scholar 

  10. Mikus G, Scholz IM, Weiss J. Pharmacogenomics of the triazole antifungal agent voriconazole. Pharmacogenomics. 2011;12(6):861–72.

    CAS  Article  Google Scholar 

  11. Pieper JB, Dirikolu L, Campbell KL, Li Z, Mitchell MA. Evaluation of the effect of fluconazole on the pharmacokinetics of cyclosporin A in healthy dogs after a single dose and at steady-state. J Vet Pharmacol Ther. 2017;40(3):304–8.

    CAS  Article  Google Scholar 

  12. Jezequel SG. Fluconazole: interspecies scaling and allometric relationships of pharmacokinetic properties. J Pharm Pharmacol. 2011;46(3):196–9.

    Article  Google Scholar 

  13. Holmes AR, Lin YH, Niimi K, Lamping E, Keniya M, Niimi M, et al. ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates. Antimicrob Agents Chemother. 2008;52(11):3851–62.

    CAS  Article  Google Scholar 

  14. Chen Y, Ma F, Lu T, Budha N, Jin JY, Kenny JR, et al. Development of a physiologically based pharmacokinetic model for itraconazole pharmacokinetics and drug–drug interaction prediction. Clin Pharmacokinetic. 2016;55(6):735–49.

    CAS  Article  Google Scholar 

  15. Roffey SJ, Cole S, Comby P, Gibson D, Jezequel SG, Nedderman AN, et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos. 2003;31(6):731–41.

    CAS  Article  Google Scholar 

  16. Grant SM, Clissold SP. Itraconazole. Drugs. 1989;37(3):310–44.

    CAS  Article  Google Scholar 

  17. Nivoix Y, Levêque D, Herbrecht R, Koffel JC, Beretz L, Ubeaud-Sequier G. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet. 2008;47(12):779–92.

    CAS  Article  Google Scholar 

  18. Rama Raju KS, Taneja I, Singh SP, Tripathi A, Mishra DP, Hussain KM, et al. Simultaneous determination of centchroman and tamoxifen along with their metabolites in rat plasma using LC-MS/MS. Bioanalysis. 2015;7(8):967–79.

    CAS  Article  Google Scholar 

  19. Lien EA, Solheim E, Ueland PM. Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res. 1991;51(18):4837–44.

    CAS  PubMed  Google Scholar 

  20. Sutiman N, Lim JSL, Muerdter TE, Singh O, Cheung YB, Ng RCH, et al. Pharmacogenetics of UGT1A4, UGT2B7, and UGT2B15, and their influence on tamoxifen disposition in Asian breast cancer patients. Clin Pharmacokinet. 2016;55(10):1239–50.

    CAS  Article  Google Scholar 

  21. Starlard-Davenport A, Lyn-cook B, Beland FA, Pogribny IP. The role of UDP-glucuronosyltransferases and drug transporters in breast cancer drug resistance. Exp Oncol. 2010;32(3):172–80.

    CAS  PubMed  Google Scholar 

  22. Kiyotani K, Mushiroda T, Nakamura Y, Zembutsu H, et al. Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet. 2012;27(1):122–31.

    CAS  Article  Google Scholar 

  23. Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM. Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4′-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos. 2002;30(8):869–74.

    CAS  Article  Google Scholar 

  24. Zhu L, Yang J, Zhang Y, Wang Y, Zhang J, Zhao Y, et al. Prediction of pharmacokinetics and penetration of moxifloxacin in human with intra-abdominal infection based on extrapolated PBPK model. Korean J Physiol Pharmacol. 2015;19(2):99–104.

    CAS  Article  Google Scholar 

  25. Poirier A, Funk C, Scherrmann JM, Lavé T. Mechanistic modeling of hepatic transport from cells to whole body: application to napsagatran and fexofenadine. Mol Pharm. 2009;6(6):1716–33.

    CAS  Article  Google Scholar 

  26. Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95(6):1238–57.

    CAS  Article  Google Scholar 

  27. Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94(6):1259–76.

    CAS  Article  Google Scholar 

  28. Damle B, Varma MV, Wood N. Pharmacokinetics of voriconazole administered concomitantly with fluconazole and population-based simulation for sequential use. Antimicrob Agents Chemother. 2011;55(11):5172–7.

    CAS  Article  Google Scholar 

  29. Harding VD. Pharmaceutical formulations containing voriconazole. US Patent 6,632,803. 2003.

  30. Frechen S, Junge L, Saari TI, Suleiman AA, Rpkitta D, Neuvonen PJ, et al. A semiphysiological population pharmacokinetic model for dynamic inhibition of liver and gut wall cytochrome P450 3A by voriconazole. Clin Pharmacokinet. 2013;52(9):763–81.

    CAS  Article  Google Scholar 

  31. Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwenbergh G. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol. 1989;36(4):423–6.

    Article  Google Scholar 

  32. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis. 1990;12(Suppl 3):S318–26.

    Article  Google Scholar 

  33. Dickschen K, Willmann S, Thelen K, Lippert J, Hempel G, Eissing T. Physiologically based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance. Front Pharmacol. 2012;3:92.

    CAS  Article  Google Scholar 

  34. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, et al. Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002;30(8):883–91.

    CAS  Article  Google Scholar 

  35. Kisanga ER, Mellgren G, Lien EA. Excretion of hydroxylated metabolites of tamoxifen in human bile and urine. Anticancer Res. 2005;25(6C):4487–92.

    CAS  PubMed  Google Scholar 

  36. Sun F, Lee L, Zhang Z, Wang X, Yu Q, Duan X, et al. Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™. Eur J Pharm Sci. 2015;77:290–302.

    CAS  Article  Google Scholar 

  37. Li GF, Wang K, Chen R, Zhao HR, Yang J, Zheng QS. Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. Acta Pharmacol Sin. 2012;33(11):1359–71.

    CAS  Article  Google Scholar 

  38. Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos. 2003;31(5):540–7.

    CAS  Article  Google Scholar 

  39. Ripa S, Ferrante L, Prenna M. Pharmacokinetics of fluconazole in normal volunteers. Chemotherapy. 1993;39(1):6–12.

    CAS  Article  Google Scholar 

  40. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005;28(9):1805–8.

    CAS  Article  Google Scholar 

  41. Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver SD. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol. 2003;56 Suppl 1:10–6.

    Article  Google Scholar 

  42. Grabinski JL, Smith LS, Chisholm GB, Drengler R, Rodriguer GI, Lang AS, et al. Relationship between CYP2D6 and estrogen receptor alpha polymorphisms on tamoxifen metabolism in adjuvant breast cancer treatment. J Clin Oncol. 2006;24(18 Suppl):505.

    Google Scholar 

  43. Hynninen VV, Olkkola KT, Bertilsson L, Kurkinen KJ, Korhonen T, Neuvonen PJ. Voriconazole increases while itraconazole decreases plasma meloxicam concentrations. Antimicrob Agents Chemother. 2009;53(2):587–92.

    CAS  Article  Google Scholar 

  44. Shin SC, Choi JS. Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. Anti-Cancer Drugs. 2009;20(7):584–8.

    CAS  Article  Google Scholar 

  45. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328–32.

    CAS  Article  Google Scholar 

  46. Van Schaik RH, Kok M, Sweep FC, Van Vliet M, Van Fessem M, Meijer-van Gelder, et al. The CYP2C19*2 genotype predicts tamoxifen treatment outcome in advanced breast cancer patients. Pharmacogenomics. 2011;12(8):1137–46.

    Article  Google Scholar 

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Affiliations

  1. Pharmaceutical College, Tianjin Medical University, Tianjin, China

    Lu Chen, Liqin Zhu, Mengxue Li, Na Li & Fang Qi

  2. Department of Pharmacy, Tianjin First Central Hospital, 24#Fukang Road, Nankai District, Tianjin, 300192, China

    Liqin Zhu

  3. Department of Pharmacy, Tianjin Third Central Hospital, Tianjin, China

    Nan Wang

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Chen, L., Zhu, L., Li, M. et al. Predicting the Effects of Different Triazole Antifungal Agents on the Pharmacokinetics of Tamoxifen. AAPS PharmSciTech 20, 24 (2019). https://doi.org/10.1208/s12249-018-1219-5

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  • DOI: https://doi.org/10.1208/s12249-018-1219-5

KEY WORDS

  • voriconazole
  • fluconazole
  • itraconazole
  • tamoxifen
  • drug–drug interactions