Top

Clinical Pharmacokinetics

Published in:

01-05-2017 | Original Research Article

Evaluation of Concomitant Antiretrovirals and CYP2C9/CYP2C19 Polymorphisms on the Pharmacokinetics of Etravirine

Authors: Bruce Green, Herta Crauwels, Thomas N. Kakuda, Simon Vanveggel, Anne Brochot

Published in: Clinical Pharmacokinetics | Issue 5/2017

Abstract

Background

Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine.

Methods

We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model. The presence of atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, tenofovir disoproxil fumarate, or enfuvirtide together with the CYP2C9 and CYP2C19 phenotype and other demographics were evaluated.

Results

A one-compartment model with first-order input and a lag-time best described the data. Estimates of apparent total clearance (CL/F), apparent central volume of distribution (V _c/F), first-order absorption rate constant (k _a), and absorption lag-time were 41.7 L/h, 972 L, 1.16 h, and 1.32 h, respectively. Estimates of between-subject variability on CL/F, V _c/F, and relative bioavailability (F) were 39.4 %CV (percentage coefficient of variation), 35.9 %CV and 35.5 %CV, respectively. Between-occasion variability on F was estimated to be 30.0 %CV. CL/F increased non-linearly with body weight and creatinine clearance (CL_CR), and also varied based on CYP2C9/CYP2C19 phenotype.

Conclusions

In this analysis, body weight, CL_CR, and CYP2C9/CYP2C19 phenotype were found to describe some of the variability in CL/F. It was not possible to show an impact of concomitant antiretrovirals on the pharmacokinetics of etravirine for adults predominantly taking coadministered boosted protease inhibitors as a background antiretroviral regimen.

Available only for authorised users

Andries K, Azijn H, Thielemans T, et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Society. 2004;48(12):4680–6. doi:10.1128/AAC.48.12.4680.

Yanakakis LJ, Bumpus NN. Biotransformation of the antiretroviral drug etravirine: metabolite identification, reaction phenotyping, and characterization of autoinduction of cytochrome P450-dependent metabolism. Drug Metab Dispos. 2012;40(4):803–14. doi:10.1124/dmd.111.044404.CrossRefPubMedPubMedCentral

Kakuda TN, Schöller-Gyüre M, Hoetelmans RMW. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet. 2011;50(1):25–39. doi:10.2165/11534740-000000000-00000.CrossRefPubMed

Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Clinical perspective on antiretroviral drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor etravirine. Antivir Ther. 2010;15(6):817–29. doi:10.3851/IMP1652.CrossRefPubMed

Kakuda TN, Wade JR, Snoeck E, et al. Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients. Clin Pharmacol Ther. 2010;88(5):695–703. doi:10.1038/clpt.2010.181.CrossRefPubMed

Schöller-Gyüre M, Boffito M, Pozniak AL, et al. Effects of different meal compositions and fasted state on the oral bioavailability of etravirine. Pharmacotherapy. 2008;28(10):1215–22. doi:10.1592/phco.28.10.1215.CrossRefPubMed

Lubomirov R, Arab-Alameddine M, Rotger M, et al. Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals. Pharmacogenet Genomics. 2013;23(1):9–18. doi:10.1097/FPC.0b013e32835ade82.CrossRefPubMed

Kakuda TN, Brochot A, Green B, et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of etravirine in HIV-1-infected, treatment-experienced children and adolescents in PIANO. J Clin Pharmacol. Epub. 2016;. doi:10.1002/jcph.746.

Di Perri G, Green B, Morrish G, et al. Pharmacokinetics and pharmacodynamics of etravirine 400 mg once daily in treatment-naïve patients. HIV Clin Trials. 2013;14(3):92–8. doi:10.1310/hct1403-92.CrossRefPubMed

10.

Scholler-Gyure M, Kakuda TN, Raoof A, et al. Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet. 2009;48(9):561–74. doi:10.2165/10895940-000000000-00000.CrossRefPubMed

11.

Song I, Borland J, Min S, et al. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrob Agents Chemother. 2011;55(7):3517–21. doi:10.1128/AAC.00073-11.CrossRefPubMedPubMedCentral

12.

Kakuda TN, Abel S, Davis J, et al. Pharmacokinetic interactions of maraviroc with darunavir-ritonavir, etravirine, and etravirine-darunavir-ritonavir in healthy volunteers: results of two drug interaction trials. Antimicrob Agents Chemother. 2011;55(5):2290–6. doi:10.1128/AAC.01046-10.CrossRefPubMedPubMedCentral

13.

14.

Scholler-Gyure M, Kakuda TN, De Smedt G, et al. A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers. Br J Clin Pharmacol. 2008;66(4):508–16. doi:10.1111/j.1365-2125.2008.03214.x.CrossRefPubMedPubMedCentral

15.

Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504. doi:10.1023/A:1012299115260.CrossRefPubMed

16.

Wählby U, Bouw MR, Jonsson EN, et al. Assessment of type I error rates for the statistical sub-model in NONMEM. J Pharmacokinet Pharmacodyn. 2002;29(3):251–69. doi:10.1023/A:1020254823597.CrossRefPubMed

17.

Stram DO, Lee JW, Kee J. Variance components testing in the longitudinal mixed effects model. Biometrics. 1994;50(4):1171–7. doi:10.2307/2533455.CrossRefPubMed

18.

Green B, Holford NH. Critical values for rejecting the null involving mixture models—identification of poor metabolizers and non-responders [poster]. AAPS Annual Meeting; 6–10 Nov 2005; Nashville.

19.

Ette E, Sun H, Ludden T. Balanced designs in longitudinal population pharmacokinetic studies. J Clin Pharmacol. 1998;38(5):417–23.CrossRefPubMed

20.

Karlsson MMO, Savic RMRM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007;82(1):17–20. doi:10.1038/sj.clpt.2007.6100241.CrossRefPubMed

21.

Bonate PL. Pharmacokinetic-pharmacodynamic modeling and simulation. New York: Springer; 2006.

22.

Han PY, Kirkpatrick CM, Green B. Informative study designs to identify true parameter-covariate relationships. J Pharmacokinet Pharmacodyn. 2009;36(2):147–63. doi:10.1007/s10928-009-9115-y.CrossRefPubMed

23.

Hamberg A-K, Dahl M-L, Barban M, et al. A PK-PD model for predicting the impact of age, CYP2C9, and VKORC1 genotype on individualization of warfarin therapy. Clin Pharmacol Ther. 2007;81(4):529–38. doi:10.1038/sj.clpt.6100084.CrossRefPubMed

24.

Wright DFB, Duffull SB. Development of a bayesian forecasting method for warfarin dose individualization. Pharm Res. 2011;28(5):1100–11. doi:10.1007/s11095-011-0369-x.CrossRefPubMed

25.

Wright DFB, Duffull SB. A Bayesian dose-individualization method for warfarin. Clin Pharmacokinet. 2013;52(1):59–68. doi:10.1007/s40262-012-0017-6.CrossRefPubMed

26.

Scott SA, Sangkuhl K, Stein CM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317–23. doi:10.1038/clpt.2013.105.CrossRefPubMedPubMedCentral

27.

Kleiber M. Body size and metabolism. Hilgardia. 1932;6:315–53.CrossRef

28.

Rubner M. Uber den Einfluss der Korpergrosse auf Stoff- und Kraftwechsel. Zeitscrift fur Biol. 1883;19:535–62.

29.

Miller AJ, Blyth C. Lean body mass as a metabolic reference standard. J Appl Physiol. 1953;5(7):311–6.PubMed

30.

White CR, Seymour RS. Mammalian basal metabolic rate is proportional to body mass^2/3. Proc Natl Acad Sci USA. 2003;100(7):4046–9. doi:10.1073/pnas.0436428100.CrossRefPubMedPubMedCentral

31.

Janmahasatian S, Janmahasatian S, Duffull SB, et al. Quantification of lean body weight. Master Philos. 2005;44(10):1051–65. doi:10.2165/00003088-200544100-00004.

32.

McLeay S, Morrish G, Kirkpatrick C, et al. The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007. Clin Pharmacokinet. 2012;51(5):319–30. doi:10.2165/11598930-000000000-00000.CrossRefPubMed

33.

Han PPY, Kirkpatrick CMC, Green B, et al. Informative study designs to identify true parameter-covariate relationships. J Pharmacokinet Pharmacodyn. 2009;36(2):147–63. doi:10.1007/s10928-009-9115-y.CrossRefPubMed

34.

Orrell C, Felizarta F, Nell A, et al. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, HIV-1-infected patients. AIDS Res Treat. 2015;2015:938628. doi:10.1155/2015/938628.PubMedPubMedCentral

35.

Arathoon E, Bhorat A, Silaghi R, et al. Week 48 results of a phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults. J Int AIDS Soc. 2014;4(Suppl 3):19783.

36.

AutoGenomics. INFINITI CYP450 2C19+ assay. http://www.autogenomics.com/?q=node/152. Accessed 12 Sept 2016.

37.

AutoGenomics. INFINITI CYP450 2C9-VKORC1 assay. http://www.autogenomics.com/?q=node/153. Accessed 12 Sept 2016.

Title: Evaluation of Concomitant Antiretrovirals and CYP2C9/CYP2C19 Polymorphisms on the Pharmacokinetics of Etravirine
Authors: Bruce Green
Herta Crauwels
Thomas N. Kakuda
Simon Vanveggel
Anne Brochot
Publication date: 01-05-2017
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 5/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-016-0454-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Evaluation of Concomitant Antiretrovirals and CYP2C9/CYP2C19 Polymorphisms on the Pharmacokinetics of Etravirine

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2017

A Pooled Analysis of Clinical Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes

Clinical Pharmacokinetics and Pharmacodynamics of Febuxostat

A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Clinical Pharmacokinetics and Pharmacodynamics of Insulin Glargine 300 U/mL

Pharmacokinetics and Pharmacodynamics of Lurasidone Hydrochloride, a Second-Generation Antipsychotic: A Systematic Review of the Published Literature