In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype

British Journal of Clinical Pharmacology

Volumn 71, Issue 4, 2011, Pages 536-543

  Rekić, Dinko ^a   Röshammar, Daniel ^a,d   Mukonzo, Jackson ^b,c   Ashton, Michael ^a  

^a UNIVERSITY OF GOTHENBURG   (Sweden)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^c MAKERERE UNIVERSITY   (Uganda)

^d ASTRAZENECA R AND D   (Sweden)

Author keywords

Drug drug interaction; Efavirenz; HIV AIDS; In vitro in vivo extrapolation; Rifampicin; Simcyp

Indexed keywords

CYTOCHROME P450 1A2; CYTOCHROME P450 2A6; CYTOCHROME P450 2B6; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; EFAVIRENZ; GLUCURONOSYLTRANSFERASE 2B7; RIFAMPICIN;

AREA UNDER THE CURVE; ARTICLE; BODY WEIGHT; COMPUTER MODEL; DRUG ABSORPTION; DRUG METABOLISM; HUMAN; HUMAN CELL; MAXIMUM PLASMA CONCENTRATION; PHENOTYPE; PHYSICAL CHEMISTRY; PLASMA CONCENTRATION-TIME CURVE; PREDICTION; PRIORITY JOURNAL; SIMULATOR; TIME TO MAXIMUM PLASMA CONCENTRATION;

ANTI-HIV AGENTS; ANTIBIOTICS, ANTITUBERCULAR; ARYL HYDROCARBON HYDROXYLASES; BENZOXAZINES; BODY WEIGHT; COMPUTER SIMULATION; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INTERACTIONS; DRUG THERAPY, COMBINATION; FORECASTING; HIV INFECTIONS; HUMANS; MODELS, THEORETICAL; OXIDOREDUCTASES, N-DEMETHYLATING; PHENOTYPE; RIFAMPIN; TUBERCULOSIS;

EID: 79952607777     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/j.1365-2125.2010.03883.x     Document Type: Article

References (40)

1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Washington DC: Department of Health and Human Services, 2009; 1-161. Available at (last accessed December 2009).
2. Josephson F, Albert J, Flamholc L, Gisslen M, Karlstrom O, Lindgren SR, Naver L, Sandstrom E, Svedhem-Johansson V, Svennerholm B, Sonnerborg A. Antiretroviral treatment of HIV infection: Swedish recommendations 2007. Scand J Infect Dis 2007; 39: 486-507.
3. Keiser P, Nassar N, White C, Koen G, Moreno S. Comparison of nevirapine- and efavirenz-containing antiretroviral regimens in antiretroviral-naive patients: a cohort study. HIV Clin Trials 2002; 3: 296-303.
4. Lucas GM, Chaisson RE, Moore RD. Comparison of initial combination antiretroviral therapy with a single protease inhibitor, ritonavir and saquinavir, or efavirenz. AIDS 2001; 15: 1679-86.
5. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 2003; 306: 287-300.
6. Ogburn E, Jones D, Masters A, Xu C, Guo Y, Desta Z. Efavirenz primary and secondary metabolism in vitro and in vivo: identification of novel metabolic pathways and cytochrome P450 2A6 as the principal catalyst of efavirenz 7-hydroxylation. Drug Metab Dispos 2010; 38: 1218.
7. Belanger AS, Caron P, Harvey M, Zimmerman PA, Mehlotra RK, Guillemette C. Glucuronidation of the antiretroviral drug efavirenz by UGT2B7 and an in vitro investigation of drug-drug interaction with zidovudine. Drug Metab Dispos 2009; 37: 1793-6.
8. Kwara A, Lartey M, Sagoe KW, Kenu E, Court MH. CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients. AIDS 2009; 23: 2101-6.
9. Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski CJ, LeCluyse EL, Negishi M, Wang H. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007; 320: 72-80.
10. Hariparsad N, Nallani SC, Sane RS, Buckley DJ, Buckley AR, Desai PB. Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol 2004; 44: 1273-81.
11. Approval documentation for Sustiva™ (Efavirenz) NDA no 020972. 2009, Avalable at (last accessed December 2009).
12. Backman JT, Granfors MT, Neuvonen PJ. Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol 2006; 62: 451-61.
13. Huang SM, Temple R, Throckmorton DC, Lesko LJ. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther 2007; 81: 298-304.
14. Lopez-Cortes LF, Ruiz-Valderas R, Viciana P, Alarcon-Gonzalez A, Gomez-Mateos J, Leon-Jimenez E, Sarasanacenta M, Lopez-Pua Y, Pachon J. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin Pharmacokinet 2002; 41: 681-90.
15. Pozniak AL, Miller RF, Lipman MC, Freedman AR, Ormerod LP, Johnson MA, Collins S, Lucas SB. BHIVA treatment guidelines for tuberculosis (TB)/HIV infection 2005. HIV Med 2005; 6: (Suppl. 2): 62-83.
16. Brennan-Benson P, Lyus R, Harrison T, Pakianathan M, Macallan D. Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all. AIDS 2005; 19: 1541-3.
17. DiGiacinto JL, Chan-Tack KM, Robertson SM, Reynolds KS, Struble KA. Are literature references sufficient for dose recommendations? An FDA case study of efavirenz and rifampin. J Clin Pharmacol 2008; 48: 518-23.
18. Manosuthi W, Sungkanuparph S, Thakkinstian A, Vibhagool A, Kiertiburanakul S, Rattanasiri S, Prasithsirikul W, Sankote J, Mahanontharit A, Ruxrungtham K. Efavirenz levels and 24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin. AIDS 2005; 19: 1481-6.
19. Centers for Disease Control and Prevention. Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis [online]. 2007. Available at (last accessed December 2009).
20. Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A. The simcyp population-based ADME simulator. Expert Opin Drug Metab Toxicol 2009; 5: 211-23.
21. Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov 2007; 6: 140-8.
22. Turner D. SimCYP User Manual Version 8. Sheffield: SimCYP Inc, 2008.
23. Jansson R, Bredberg U, Ashton M. Prediction of drug tissue to plasma concentration ratios using a measured volume of distribution in combination with lipophilicity. J Pharm Sci 2008; 97: 2324-39.
24. Proctor N, Tucker G, Rostami-Hodjegan A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica 2004; 34: 151-78.
25. Austin RP, Barton P, Cockroft SL, Wenlock MC, Riley RJ. The influence of nonspecific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties. Drug Metab Dispos 2002; 30: 1497-503.
26. Shou M, Hayashi M, Pan Y, Xu Y, Morrissey K, Xu L, Skiles G. Modeling, prediction, and in vitro in vivo correlation of CYP3A4 induction. Drug Metab Dispos 2008; 36: 2355.
27. Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL. Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos 2004; 32: 348-58.
28. *6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans. Br J Clin Pharmacol 2009; 68: 690-9.
29. *6) variant and effect on the population pharmacokinetics of efavirenz in HIV/AIDS outpatients in Zimbabwe. Eur J Clin Pharmacol 2008; 64: 357-65.
30. Josephson F, Andersson MC, Flamholc L, Gisslen M, Hagberg L, Ormaasen V, Sonnerborg A, Vesterbacka J, Bottiger Y. The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naive HIV-1 infected patients. Eur J Clin Pharmacol 2009; 66: 349-57.
31. Csajka C, Marzolini C, Fattinger K, Decosterd LA, Fellay J, Telenti A, Biollaz J, Buclin T. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther 2003; 73: 20-30.
32. Turner DB, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. Prediction of non-specific hepatic microsomal binding from readily available physicochemical properties. Drug Metab Rev 2006; 38: 162.
33. Matteelli A, Regazzi M, Villani P, De Iaco G, Cusato M, Carvalho A, Caligaris S, Tomasoni L, Manfrin M, Capone S. Multiple-dose pharmacokinetics of efavirenz with and without the use of rifampicin in HIV-positive patients. Curr HIV Res 2007; 5: 349-53.
34. Itoh M, Nakajima M, Higashi E, Yoshida R, Nagata K, Yamazoe Y, Yokoi T. Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor- coactivator 1. J Pharmacol Exp Ther 2006; 319: 693.
35. Barrett JS, Joshi AS, Chai M, Ludden TM, Fiske WD, Pieniaszek HJ Jr Population pharmacokinetic meta-analysis with efavirenz. Int J Clin Pharmacol Ther 2002; 40: 507-19.
36. Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, Clifford DB, Hulgan T, Marzolini C, Acosta EP. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. AIDS 2004; 18: 2391-400.
37. Haas DW, Smeaton LM, Shafer RW, Robbins GK, Morse GD, Labbe L, Wilkinson GR, Clifford DB, D'Aquila RT, De Gruttola V, Pollard RB, Merigan TC, Hirsch MS, George AL Jr, Donahue JP, Kim RB. Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. J Infect Dis 2005; 192: 1931-42.
38. Rowe SM, Fontalbert L, Rabel SR, Maurin MB. Physical chemical properties of efavirenz. AAPS annual meeting and exposition. AAPS PharmSci Supplement 1999.
39. Balani SK, Kauffman LR, deLuna FA, Lin JH. Nonlinear pharmacokinetics of efavirenz (DMP-266), a potent HIV-1 reverse transcriptase inhibitor, in rats and monkeys. Drug Metab Dispos 1999; 27: 41-5.
40. Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, Yamashita S. Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test. Pharm Res 2006; 23: 1144-56.