Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling

Abstract

Background and Objectives

Controversy exists regarding dose adjustment in patients treated with voriconazole due to the severity of the infections for which it is prescribed. The Dutch Pharmacogenetics Working Group (DPWG) recommends a 50% dose increase or decrease for cytochrome P450 (CYP) 2C19 ultrarapid (UM) or poor (PM) metabolizers, respectively. In contrast, for the previous phenotypes, the Clinical Pharmacogenetics Implementation Consortium (CPIC) voriconazole guideline only recommends a change of treatment. Based on observed data from single-dose bioequivalence studies and steady-state observed concentrations, we aimed to investigate voriconazole dose adjustments by means of physiologically based pharmacokinetic (PBPK) modeling.

Methods

PBPK modeling was used to optimize voriconazole single-dose models for each CYP2C19 phenotype, which were extrapolated to steady state and evaluated for concordance with the therapeutic range of voriconazole. Based on optimized models, dose adjustments were evaluated for better adjustment to the therapeutic range.

Results

Our models suggest that the standard dose may only be appropriate for normal metabolizers (NM), although they would benefit from a 50–100% loading dose increase. Intermediate metabolizers (IMs) and PMs required a daily dose reduction of 50 and 75%, respectively. Rapid metabolizers (RMs) and UMs required a daily dose increase of 100% and 300%, respectively.

Conclusion

The prescription of voriconazole in clinical practice should be personalized according to the CYP2C19 phenotype, followed by therapeutic drug monitoring of plasma concentrations to guide dose adjustment.

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References

  1. 1.

    European Medicines Agency. VFEND, INN voriconazole, Annex I, Summary of Product Characteristics [cited 31 Oct 2019]. 2019. https://www.ema.europa.eu/en/documents/product-information/vfend-epar-product-information_en.pdf.

  2. 2.

    Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet. 2006;45:649–63.

    CAS  Article  Google Scholar 

  3. 3.

    Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK, Thakker DR. In vitro hepatic metabolism explains higher clearance of voriconazole in children versus adults: role of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab Dispos. 2010;38:25–31.

    CAS  Article  Google Scholar 

  4. 4.

    Yanni SB, Annaert PP, Augustijns P, Bridges A, Gao Y, Benjamin DK, et al. Role of flavin-containing monooxygenase in oxidative metabolism of voriconazole by human liver microsomes. Drug Metab Dispos. 2008;36:1119–25.

    CAS  Article  Google Scholar 

  5. 5.

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

    CAS  Article  Google Scholar 

  6. 6.

    Yanni SB, Annaert PP, Augustijns P, Bridges A, Gao Y, Benjamin DK, et al. Role of flavin-containing monooxygenase in oxidative metabolism of voriconazole by human liver microsomes. Drug Metab Dispos Biol Fate Chem. 2008;36:1119–25.

    CAS  Article  Google Scholar 

  7. 7.

    Pascual A, Nieth V, Calandra T, Bille J, Bolay S, Decosterd LA, et al. Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods. Antimicrob Agents Chemother. 2007;51:137–43.

    CAS  Article  Google Scholar 

  8. 8.

    Gastine S, Lehrnbecher T, Müller C, Farowski F, Bader P, Ullmann-Moskovits J, et al. Pharmacokinetic modeling of voriconazole to develop an alternative dosing regimen in children. Antimicrob Agents Chemother. 2017;62:e01194–e1217.

    Article  Google Scholar 

  9. 9.

    Yi WM, Schoeppler KE, Jaeger J, Mueller SW, MacLaren R, Fish DN, et al. Voriconazole and posaconazole therapeutic drug monitoring: a retrospective study. Ann Clin Microbiol Antimicrob. 2017;16:60.

    Article  Google Scholar 

  10. 10.

    Jin H, Wang T, Falcione BA, Olsen KM, Chen K, Tang H, et al. Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis. J Antimicrob Chemother. 2016;71:1772–855.

    CAS  Article  Google Scholar 

  11. 11.

    Kuo IF, Ensom MHH. Role of therapeutic drug monitoring of voriconazole in the treatment of invasive fungal infections. Can J Hosp Pharm. 2009;62(6):469–82.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Dapía I, García I, Martinez JC, Arias P, Guerra P, Díaz L, et al. Prediction models for voriconazole pharmacokinetics based on pharmacogenetics: an exploratory study in Spanish population. Int J Antimicrob Agents. 2019;54(4):463–70.

    Article  Google Scholar 

  13. 13.

    Moriyama B, Obeng AO, Barbarino J, Penzak S, Henning S, Scott S, et al. Clinical pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2C19 and Voriconazole therapy. Clin Pharmacol Ther. 2017;102:45–51.

    CAS  Article  Google Scholar 

  14. 14.

    Dutch Pharmacogenetics Working Group. Pharmacogenetic Recommendations. 2020. https://www.knmp.nl/@@search.

  15. 15.

    Willmann S, Lippert J, Sevestre M, Solodenko J, Fois F, Schmitt W. PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model. BIOSILICO. 2003;1:121–4.

    CAS  Article  Google Scholar 

  16. 16.

    Dodds Ashley ES, Zaas AK, Fang AF, Damle B, Perfect JR. Comparative pharmacokinetics of voriconazole administered orally as either crushed or whole tablets. Antimicrob Agents Chemother. 2007;51:877–80.

    CAS  Article  Google Scholar 

  17. 17.

    Australian Register of Therapeutic Goods. Australian Product Information. Australia Voriconazole Apotex Powder for Injection [Internet]. 2020. https://medicines.org.au/files/txpvoriv.pdf.

  18. 18.

    Zane NR, Thakker DR. A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children. Clin Pharmacokinet. 2014;53:1171–82.

    CAS  Article  Google Scholar 

  19. 19.

    Medicines Evaluation Board. Public Assessment Report. Voriconazole Apotex 50 mg and 200 mg, film-coated tablets [scientific discussion]. 2020. https://mri.cts-mrp.eu/human/downloads/NL_H_3067_001_PAR.pdf.

  20. 20.

    Thelen K, Coboeken K, Willmann S, Burghaus R, Dressman JB, Lippert J. Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. J Pharm Sci. 2011;100:5324–45.

    CAS  Article  Google Scholar 

  21. 21.

    Schmitt W. General approach for the calculation of tissue to plasma partition coefficients. Toxicol In Vitro. 2008;22:457–67.

    CAS  Article  Google Scholar 

  22. 22.

    Zhou L, Sharma P, Yeo KR, Higashimori M, Xu H, Al-Huniti N, et al. Assessing pharmacokinetic differences in Caucasian and East Asian (Japanese, Chinese and Korean) populations driven by CYP2C19 polymorphism using physiologically-based pharmacokinetic modelling. Eur J Pharm Sci. 2019;139:105061.

    CAS  Article  Google Scholar 

  23. 23.

    European Medicines Agency. Questions and answers on the supply shortage of Vfend (voriconazole) [Internet]. 2012. https://www.ema.europa.eu/en/documents/medicine-qa/questions-answers-supply-shortage-vfend-voriconazole_en.pdf.

  24. 24.

    Brüggemann RJM, Donnelly JP, Aarnoutse RE, Warris A, Blijlevens NMA, Mouton JW, et al. Therapeutic drug monitoring of voriconazole. Ther Drug Monit. 2008;30(4):403–11.

    PubMed  Google Scholar 

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Corresponding author

Correspondence to Francisco Abad-Santos.

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Funding

Dora Koller is financed by the H2020 Marie Skłodowska Curie Innovative Training Network 721236 grant. Irene García García is financed by Instituto de Salud Carlos III by the Rio Hortega grant. Marcos Navares-Gomez is co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo. No funds were received for the current research.

Conflict of Interest

Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. Pablo Zubiaur, Lisa A. Kneller, Gina Mejía, Miriam Saiz-Rodríguez, Alberto M. Borobia, Dora Koller, Irene García García, Marcos Navares-Gómez, and Georg Hempel declare no conflicts of interest.

Ethics Approval

Study protocols were approved by an independent Research Ethics Committee. In addition, the protocols were duly authorized by the Spanish Medicines Agency (AEMPS) and were carried out under the guidelines of Good Clinical Practices, complying with current Spanish legislation on clinical research in humans and with the Declaration of Helsinki. EUDRA-CT numbers: 2012–004029-26, 2014–001964-36, and 2014–005342-22.

Consent for Participation

All subjects provided informed consent to participate in the present research.

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Data are available from the corresponding author upon reasonable request.

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Zubiaur, P., Kneller, L.A., Ochoa, D. et al. Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling. Clin Pharmacokinet (2020). https://doi.org/10.1007/s40262-020-00941-8

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