Determination of a suitable voriconazole pharmacokinetic model for personalised dosing

  • David A. J. McDougall
  • Jennifer Martin
  • E. Geoffrey Playford
  • Bruce Green
Original Paper

Abstract

Model based personalised dosing (MBPD) is a sophisticated form of individualised therapy, where a population pharmacokinetic (PK) or pharmacodynamic model is utilised to estimate the dose required to reach a target exposure or effect. The choice of which model to implement in MBPD is a subjective decision. By choosing one model, information from the remaining models is ignored, as well as the rest of the literature base. This manuscript describes a methodology to develop a ‘hybrid’ model for voriconazole that incorporated information from prior models in a biologically plausible manner. Voriconazole is a triazole antifungal with difficult to predict PK, although it does have a defined exposure–response relationship. Nine population PK models of voriconazole were identified from the literature. The models differed significantly in structural components. The hybrid model contained a two-compartment disposition model with mixed linear and nonlinear time-dependent clearance. The parameters for the hybrid model were determined using simulation techniques. Validation of the hybrid model was assessed via visual predictive checks, which indicated the majority of the variability in the literature models was captured by the hybrid model. The predictive performance was assessed using four different sampling strategies of limited concentrations from ten richly PK sampled subjects to predict future concentrations. Overall, the hybrid model predicted future concentrations with good precision. Further prospective and retrospective validation of the hybrid model is required before it could be used in clinical practice.

Keywords

Personalised medicine Voriconazole Bayesian dose forecasting Model based personalised dosing Dose individualisation 

Supplementary material

10928_2015_9462_MOESM1_ESM.docx (366 kb)
Supplementary material 1 (DOCX 366 kb)

References

  1. 1.
    Sheiner LB (1969) Computer-aided long-term anticoagulation therapy. Comput Biomed Res Int Journal 2(6):507–518CrossRefGoogle Scholar
  2. 2.
    Jelliffe R, Neely M, Schumitzky A, Bayard D, Van Guilder M, Botnen A, Bustad A, Laing D, Yamada W, Bartroff J, Tatarinova T (2011) Nonparametric population modeling and Bayesian analysis. Pharmacol Res Off J Ital Pharmacol Soc 64(4):426Google Scholar
  3. 3.
    Jelliffe RW, Schumitzky A, Bayard D, Milman M, Van Guilder M, Wang X, Jiang F, Barbaut X, Maire P (1998) Model-based, goal-oriented, individualised drug therapy. Linkage of population modelling, new ‘multiple model’ dosage design, Bayesian feedback and individualised target goals. Clin Pharmacokinet 34(1):57–77CrossRefPubMedGoogle Scholar
  4. 4.
    Jelliffe RW, Schumitzky A, Van Guilder M, Liu M, Hu L, Maire P, Gomis P, Barbaut X, Tahani B (1993) Individualizing drug dosage regimens: roles of population pharmacokinetic and dynamic models, Bayesian fitting, and adaptive control. Ther Drug Monit 15(5):380–393CrossRefPubMedGoogle Scholar
  5. 5.
    Upton RN, Mould DR (2014) Basic concepts in population modeling, simulation, and model-based drug development: part 3-introduction to pharmacodynamic modeling methods. CPT Pharmacomet Syst Pharmacol 3:e88CrossRefGoogle Scholar
  6. 6.
    Mould DR, Upton RN (2012) Basic concepts in population modeling, simulation, and model-based drug development. CPT Pharmacomet Syst Pharmacol 1:e6CrossRefGoogle Scholar
  7. 7.
    Mould DR, Upton RN (2013) Basic concepts in population modeling, simulation, and model-based drug development-part 2: introduction to pharmacokinetic modeling methods. CPT Pharmacomet Syst Pharmacol 2:e38CrossRefGoogle Scholar
  8. 8.
    Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, Hope WW, Farkas A, Neely MN, Schentag JJ, Drusano G, Frey OR, Theuretzbacher U, Kuti JL, on behalf of The International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases (2014) Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 14 (6):498–509Google Scholar
  9. 9.
    Lepak AJ, Andes DR (2011) Antifungal PK/PD considerations in fungal pulmonary infections. Semin Respir Crit Care Med 32(6):783–794CrossRefPubMedGoogle Scholar
  10. 10.
    Han K, Capitano B, Bies R, Potoski BA, Husain S, Gilbert S, Paterson DL, McCurry K, Venkataramanan R (2010) Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients. Antimicrob Agents Chemother 54(10):4424–4431CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hope WW (2012) Population pharmacokinetics of voriconazole in adults. Antimicrob Agents Chemother 56(1):526–531CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ (2012) Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother 56(9):4793–4799CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pascual A, Csajka C, Buclin T, Bolay S, Bille J, Calandra T, Marchetti O (2012) Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. Clin Infect Dis 55(3):381–390CrossRefPubMedGoogle Scholar
  14. 14.
    Hamada Y, Seto Y, Yago K, Kuroyama M (2012) Investigation and threshold of optimum blood concentration of voriconazole: a descriptive statistical meta-analysis. J Infect Chemother 18(4):501–507CrossRefPubMedGoogle Scholar
  15. 15.
    Miyakis S, van Hal SJ, Ray J, Marriott D (2010) Voriconazole concentrations and outcome of invasive fungal infections. Clin Microbiol Infect 16(7):927–933CrossRefPubMedGoogle Scholar
  16. 16.
    Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O (2008) Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 46(2):201–211CrossRefPubMedGoogle Scholar
  17. 17.
    Retout S, Mentré F (2003) Further developments of the Fisher information matrix in nonlinear mixed effects models with evaluation in population pharmacokinetics. J Biopharm Stat 13(2):209–227CrossRefPubMedGoogle Scholar
  18. 18.
    Dolton MJ, Mikus G, Weiss J, Ray JE, McLachlan AJ (2014) Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing. J Antimicrob Chemother 69(6):1633–1641CrossRefPubMedGoogle Scholar
  19. 19.
    Wang T, Chen S, Sun J, Cai J, Cheng X, Dong H, Wang X, Xing J, Dong W, Yao H, Dong Y (2013) Identification of factors influencing the pharmacokinetics of voriconazole and the optimization of dosage regimens based on Monte Carlo simulation in patients with invasive fungal infections. J Antimicrob Chemother 69(2):463–470CrossRefPubMedGoogle Scholar
  20. 20.
    Friberg LE, Ravva P, Karlsson MO, Liu P (2012) Integrated population pharmacokinetic analysis of voriconazole in children, adolescents, and adults. Antimicrob Agents Chemother 56(6):3032–3042CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Karlsson MO, Lutsar I, Milligan PA (2009) Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother 53(3):935–944CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Han K, Bies R, Johnson H, Capitano B, Venkataramanan R (2011) Population pharmacokinetic evaluation with external validation and Bayesian estimator of voriconazole in liver transplant recipients. Clin Pharmacokinet 50(3):201–214CrossRefPubMedGoogle Scholar
  23. 23.
    Nomura K, Fujimoto Y, Kanbayashi Y, Ikawa K, Taniwaki M (2008) Pharmacokinetic–pharmacodynamic analysis of voriconazole in Japanese patients with hematological malignancies. Eur J Clin Microbiol Infect Dis 27(11):1141–1143CrossRefPubMedGoogle Scholar
  24. 24.
    Bonate PL (2005) Pharmacokinetic–pharmacodynamic modeling and simulation. Springer, New YorkGoogle Scholar
  25. 25.
    McLeay SC, Morrish GA, Kirkpatrick CMJ, Green B (2012) The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007. Clin Pharmacokinet 51(5):319–330CrossRefPubMedGoogle Scholar
  26. 26.
    Holford N (2005) The Visual Predictive Check Superiority to Standard Diagnostic (Rorschach) Plots. Paper presented at the PAGE 14, Pamplona, Spain. http://www.page-meeting.org/?abstract=738. Accessed 1 Dec 2015
  27. 27.
    Continuous National Health and Nutrition Examination Survey. National Center for Health Statistics Center for Disease Control and Prevention. http://wwwn.cdc.gov/nchs/nhanes/search/nhanes_continuous.aspx. Accessed 29 April 2015
  28. 28.
    Brüggemann RJM, Blijlevens NMA, Burger DM, Franke B, Troke PF, Donnelly JP (2010) Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother 65(1):107–113CrossRefPubMedGoogle Scholar
  29. 29.
    Anderson BJ, Holford NHG (2008) Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol 48:303–332CrossRefPubMedGoogle Scholar
  30. 30.
    Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B (2005) Quantification of lean bodyweight. Clin Pharmacokinet 44(10):1051–1065CrossRefPubMedGoogle Scholar
  31. 31.
    (CDC). CfDCaP (2014) National Health and Nutrition Examination Survey Data. National Center for Health Statistics (NCHS), Hyattsville, MDGoogle Scholar
  32. 32.
    Al-Sallami H, Goulding A, Taylor R, Grant A, Williams S, Duffull S (2011) A semi-mechanistic model for estimating fat free mass in children. Paper presented at the Population Analysis Group Europe, Athens. http://www.page-meeting.org/page/page2011/PAGEPosters.pdf. Accessed 1 Dec 2015
  33. 33.
    Development Core Team R (2014) R: a language and environment for statistical computing. R Found Stat Comput, ViennaGoogle Scholar
  34. 34.
    Damle B, Varma MV, Wood N (2011) Pharmacokinetics of voriconazole administered concomitantly with fluconazole and population-based simulation for sequential use. Antimicrob Agents Chemother 55(11):5172–5177CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Green B, Duffull SB (2004) What is the best size descriptor to use for pharmacokinetic studies in the obese. Br J Clin Pharmacol 58(2):119–133CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Gilbert DN The Sanford guide to antimicrobial therapy 2011. Antimicrobial Therapy, Inc., SperryvilleGoogle Scholar
  37. 37.
    Rengelshausen J, Banfield M, Riedel K-D, Burhenne J, Weiss J, Thomsen T, Walter-Sack I, Haefeli WE, Mikus G (2005) Opposite effects of short-term and long-term St John’s wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 78(1):25–33CrossRefPubMedGoogle Scholar
  38. 38.
    Alffenaar J-WC, van der Elst KCM, Uges DRA, Kosterink JGW, Daenen SMGJ (2009) Phenytoin-induced reduction of voriconazole serum concentration is not compensated by doubling the dosage. Br J Clin Pharmacol 68(3):462–463CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Purkins L, Wood N, Ghahramani P, Love ER, Eve MD, Fielding A (2003) Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol 56(Suppl 1):37–44CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Spriet I, Meersseman P, Meersseman W, de Hoon J, Willems L (2010) Increasing the dose of voriconazole compensates for enzyme induction by phenytoin. Br J Clin Pharmacol 69(6):701–702CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Verweij PE, de Pauw BE, Meis JF (1999) Voriconazole (Pfizer ltd). IDrugs 2(9):925–937PubMedGoogle Scholar
  42. 42.
    Hyland R, Jones BC, Smith DA (2003) Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 31(5):540–547CrossRefPubMedGoogle Scholar
  43. 43.
    Koselke E, Kraft S, Smith J, Nagel J (2012) Evaluation of the effect of obesity on voriconazole serum concentrations. J Antimicrob Chemother 67(12):2957–2962CrossRefPubMedGoogle Scholar
  44. 44.
    Hoenigl M, Duettmann W, Raggam RB, Seeber K, Troppan K, Fruhwald S, Prueller F, Wagner J, Valentin T, Zollner-Schwetz I, Wölfler A, Krause R (2013) Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies. Antimicrob Agents Chemother 57(7):3262–3267CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Han PY, Duffull SB, Kirkpatrick CM, Green B (2007) Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther 82(5):505–508CrossRefPubMedGoogle Scholar
  46. 46.
    Pai MP, Lodise TP (2011) Steady-state plasma pharmacokinetics of oral voriconazole in obese adults. Antimicrob Agents Chemother 55(6):2601–2605CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Theuretzbacher U, Ihle F, Derendorf H (2006) Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 45(7):649–663CrossRefPubMedGoogle Scholar
  48. 48.
    Purkins L, Wood N, Kleinermans D, Greenhalgh K, Nichols D (2003) Effect of food on the pharmacokinetics of multiple-dose oral voriconazole. Br J Clin Pharmacol 56(Suppl 1):17–23CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK Jr, Thakker DR (2010) In vitro hepatic metabolism explains higher clearance of voriconazole in children versus adults: role of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab Dispos 38(1):25–31CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.School of PharmacyUniversity of QueenslandBrisbaneAustralia
  2. 2.Model Answers Pty LimitedBrisbaneAustralia
  3. 3.School of Medicine and Public HealthUniversity of NewcastleNewcastleAustralia
  4. 4.Infection Management ServicesPrincess Alexandra HospitalBrisbaneAustralia
  5. 5.School of MedicineUniversity of QueenslandBrisbaneAustralia

Personalised recommendations