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S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults.

Methods

In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >−5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%.

Results

S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R2, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE.

Conclusions

Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.

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References

  1. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, Gelboin HV, Gonzalez FJ, Trager WF (1992) Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 5(1):54–59

    Article  CAS  Google Scholar 

  2. Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO, Birkett DJ (1991) Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res Commun 175(3):1112–1118

    Article  CAS  Google Scholar 

  3. Zanger UM, Turpeinen M, Klein K, Schwab M (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392(6):1093–1108

    Article  CAS  Google Scholar 

  4. Food and Drug Adminstration. Drug development and drug interactions: table of substrates, inhibitors and inducers. Available from: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm (Accessed 05 January 2021).

  5. Tucker GT, Houston JB, Huang SM (2001) Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential--towards a consensus. Br J Clin Pharmacol 52(1):107–117

    Article  CAS  Google Scholar 

  6. Kim JS, Nafziger AN, Gaedigk A, Dickmann LJ, Rettie AE, Bertino JS Jr (2001) Effects of oral vitamin K on S- and R-warfarin pharmacokinetics and pharmacodynamics: enhanced safety of warfarin as a CYP2C9 probe. J Clin Pharmacol 41(7):715–722

    Article  CAS  Google Scholar 

  7. Ma JD, Nafziger AN, Kashuba AD, Kim MJ, Gaedigk A, Rowland E, Kim JS, Bertino JS Jr (2004) Limited sampling strategy of S-warfarin concentrations, but not warfarin S/R ratios, accurately predicts S-warfarin AUC during baseline and inhibition in CYP2C9 extensive metabolizers. J Clin Pharmacol 44(6):570–576

    Article  CAS  Google Scholar 

  8. Chang AT, Bertino JS Jr, Nafziger AN, Kashuba AD, Turpault S, Lewis LD, Ma JD (2016) S-Warfarin limited sampling models to estimate area under the concentration versus time curve for cytochrome P450 2C9 baseline activity and after induction. Ther Drug Monit 38(3):383–387

    Article  CAS  Google Scholar 

  9. Wu JC, Nafziger AN, Bertino JS Jr, Ma JD (2012) Limitations of S-warfarin truncated area under the concentration-time curve to predict cytochrome P450 2c9 activity. Drug Metab Lett 6(2):94–101

    Article  CAS  Google Scholar 

  10. Burger D, Ewings F, Kabamba D, L’Homme R, Mulenga V, Kankasa C, Thomason M, Gibb DM, Chintu C, Walker AS (2010) Limited sampling models to predict the pharmacokinetics of nevirapine, stavudine, and lamivudine in HIV-infected children treated with pediatric fixed-dose combination tablets. Ther Drug Monit 32(3):369–372

    Article  CAS  Google Scholar 

  11. Ting LS, Villeneuve E, Ensom MH (2006) Beyond cyclosporine: a systematic review of limited sampling strategies for other immunosuppressants. Ther Drug Monit 28(3):419–430

    Article  CAS  Google Scholar 

  12. van Rijn SP, Zuur MA, van Altena R, Akkerman OW, Proost JH, de Lange WC, Kerstjens HA, Touw DJ, van der Werf TS, Kosterink JG, Alffenaar JW (2017) Pharmacokinetic modeling and limited sampling strategies based on healthy volunteers for monitoring of ertapenem in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 61(4)

  13. David O, Johnston A (2000) Limited sampling strategies. Clin Pharmacokinet 39(4):311–313

    Article  CAS  Google Scholar 

  14. David OJ, Johnston A (2001) Limited sampling strategies for estimating cyclosporin area under the concentration-time curve: review of current algorithms. Ther Drug Monit 23(2):100–114

    Article  CAS  Google Scholar 

  15. Yang J, Patel M, Nikanjam M, Capparelli EV, Tsunoda SM, Greenberg HE, Penzak SR, Aubrey Stoch S, Bertino JS Jr, Nafziger AN, Ma JD (2018) Midazolam single time point concentrations to estimate exposure and cytochrome P450 (CYP) 3A constitutive activity utilizing limited sampling strategy with a population pharmacokinetic approach. J Clin Pharmacol 58(9):1205–1213

    Article  CAS  Google Scholar 

  16. Johnson BM, Song IH, Adkison KK, Borland J, Fang L, Lou Y, Berrey MM, Nafziger AN, Piscitelli SC, Bertino JS Jr (2006) Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail. J Clin Pharmacol 46(5):577–587

    Article  CAS  Google Scholar 

  17. Lee, L.S., Effect of azithromycin, levofloxacin, and telithromycin on the activities of cytochrome P450 1A2, 2C9, 2C19, 2D6, 3A, N-acetyltransferase-2, and xanthine oxidase as assessed by the Cooperstown 5+1 Cocktail in 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. 2005: Washington DC

  18. Ma JD, Nafziger AN, Villano SA, Gaedigk A, Bertino JS Jr (2006) Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults. Antimicrob Agents Chemother 50(4):1130–1135

    Article  CAS  Google Scholar 

  19. Shelepova T, Nafziger AN, Victory J, Kashuba AD, Rowland E, Zhang Y, Sellers E, Kearns G, Leeder JS, Gaedigk A, Bertino JS Jr (2005) Effect of a triphasic oral contraceptive on drug-metabolizing enzyme activity as measured by the validated Cooperstown 5+1 cocktail. J Clin Pharmacol 45(12):1413–1421

    Article  CAS  Google Scholar 

  20. Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, Boulenc X (2009) Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 68(6):928–935

    Article  CAS  Google Scholar 

  21. Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ Jr, Klein CE, Rublein JC, Kashuba AD (2006) Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr 42(1):52–60

    Article  CAS  Google Scholar 

  22. Lim ML, Min SS, Eron JJ, Bertz RJ, Robinson M, Gaedigk A, Kashuba AD (2004) Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr 36(5):1034–1040

    Article  CAS  Google Scholar 

  23. Karnes JH, Rettie AE, Somogyi AA, Huddart R, Fohner AE, Formea CM, Lee MTM, Llerena A, Whirl-Carrillo M, Klein TE, Phillips EJ, Mintzer S, Gaedigk A, Caudle KE, Callaghan JT (2021) Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and HLA-B genotypes and phenytoin dosing: 2020 update. Clin Pharmacol Ther 109(2):302–309

    Article  Google Scholar 

  24. Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB, Clinical Pharmacogenetics C (2011) Implementation, Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 90(4):625–629

    Article  CAS  Google Scholar 

  25. Kamali F, Khan TI, King BP, Frearson R, Kesteven P, Wood P, Daly AK, Wynne H (2004) Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 75(3):204–212

    Article  CAS  Google Scholar 

  26. Lindh JD, Holm L, Andersson ML, Rane A (2009) Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. Eur J Clin Pharmacol 65(4):365–375

    Article  CAS  Google Scholar 

  27. Arab-Alameddine M, Di Iulio J, Buclin T, Rotger M, Lubomirov R, Cavassini M, Fayet A, Decosterd LA, Eap CB, Biollaz J, Telenti A, Csajka C, H.I.V.Cohort Study (2009) Swiss, Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals. Clin Pharmacol Ther 85(5):485–494

    Article  CAS  Google Scholar 

  28. Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9:503–512

    Article  CAS  Google Scholar 

  29. Mahmood I (2003) Center specificity in the limited sampling model (LSM): can the LSM developed from healthy subjects be extended to disease states? Int J Clin Pharmacol Ther 41(11):517–523

    Article  CAS  Google Scholar 

  30. Chaobal HN, Kharasch ED (2005) Single-point sampling for assessment of constitutive, induced, and inhibited cytochrome P450 3A activity with alfentanil or midazolam. Clin Pharmacol Ther 78(5):529–539

    Article  CAS  Google Scholar 

  31. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287(13):1690–1698

    Article  CAS  Google Scholar 

  32. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106(7):2329–2333

    Article  CAS  Google Scholar 

  33. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R (2002) Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 72(6):702–710

    Article  CAS  Google Scholar 

  34. Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12(3):251–263

    Article  CAS  Google Scholar 

  35. D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105(2):645–649

    Article  Google Scholar 

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Funding

Dr. Tran was a post-doctoral fellow with funding supported by the University of North Carolina at Chapel Hill and Pharmaceutical Product Development. Funding support was provided by a Research in Pediatric and Developmental Pharmacology NIH grant (1U54HD090259-01 to E.V.C.)

Author information

Authors and Affiliations

  1. Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Lana Tran & Angela D.M. Kashuba

  2. Division of Hematology-Oncology, University of California San Diego, San Diego, CA, USA

    Mina Nikanjam

  3. Division of Host-Microbe Systems, University of California San Diego, San Diego, CA, USA

    Edmund V. Capparelli

  4. Bertino Consulting, Schenectady, NY, USA

    Joseph S. Bertino Jr & Anne N. Nafziger

  5. Sanofi US, Bridgewater, NJ, USA

    Sandrine Turpault

  6. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0657, La Jolla, CA, 92093-0657, USA

    Joseph D. Ma

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  1. Lana Tran
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Contributions

LT, MN, EVC, and JDM contributed to the study design. LT, MN, and JDM were involved in data collection. LT, MN, EVC, JSB, ANN, and JDM contributed to data interpretation and statistical analysis. All authors reviewed, edited, and approved the final version of the manuscript.

Corresponding author

Correspondence to Joseph D. Ma.

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Tran, L., Nikanjam, M., Capparelli, E.V. et al. S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults. Eur J Clin Pharmacol 77, 1349–1356 (2021). https://doi.org/10.1007/s00228-021-03123-y

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  • DOI: https://doi.org/10.1007/s00228-021-03123-y

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