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Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose

  • Manuel Ibarra
  • Marta VázquezEmail author
  • Pietro Fagiolino
Original Paper

Abstract

Nevirapine (NVP) extensive data obtained after oral single dose administration of 200 mg in a crossover study involving 16 healthy subjects was used to develop a descriptive population pharmacokinetic model including drug recirculation, since secondary peaks were observed in plasma concentration-time profiles for all subjects. Through implementation of model event time feature in NONMEM 7.3.0, a simple mechanistic model physiologically consistent with the process of drug cycling was able to describe multiple peaks phenomena and quantify its pharmacokinetic parameters, achieving a better performance than its analogue conventional one. Absorption process, between subject and-between occasion variability of pharmacokinetic parameters was also assessed. Estimated mean fraction of NVP bioavailable dose undergoing recirculation process was 51.6 %, a magnitude which could hardly be explained by enterohepatic cycling. In this work we propose an alternative disposition process to explain NVP drug recirculation: gastric secretion with posterior intestinal reabsorption. Due to physicochemical and pharmacokinetic properties of the drug, this neglected phenomenon is more likely to explain the results obtained, and might be present in disposition of several basic drugs.

Keywords

Drug recirculation Nevirapine Population pharmacokinetic modelling 

Notes

Acknowledgments

We acknowledge the scientific support given by Uppsala Pharmacometric Summer School event held on August 5–16, 2013.

Conflict of interest

Authors have no conflict of interest to declare.

References

  1. 1.
    World Health Organization (2010) Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress ReportGoogle Scholar
  2. 2.
    World Health Organization (2013) Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approachGoogle Scholar
  3. 3.
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 1 Jan 2014
  4. 4.
    Hawi A, Bell G (1994) Preformulation studies of nevirapine, a reverse transcriptase inhibitor. Pharm Res 11:236Google Scholar
  5. 5.
    VIRAMUNE® prescribing information (2012) Boehringer Ingelheim Pharmaceuticals IncGoogle Scholar
  6. 6.
    Lamson MJ, Sabo JP, MacGregor TR, Pav JW, Rowland L, Hawi A, Cappola M, Robinson P (1999) Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers. Biopharm Drug Dispos 20:285–291PubMedCrossRefGoogle Scholar
  7. 7.
    Cheesman SH, Hattox SE, McLaughlin MM, Koup RA, Andrews C, Bova CA, Pav JW, Roy T, Sullivan JL, Keirns JJ (1993) Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob Agents Chemother 37(2):178–182CrossRefGoogle Scholar
  8. 8.
    Murphy RL, Montaner J (1996) Nevirapine: a review of its development, pharmacological profile and potential for clinical use. Exp Opin Investig Drugs 5(9):1183–1199CrossRefGoogle Scholar
  9. 9.
    Antinori A, Perno CF, Giancola ML, Forbici F, Ippolito G, Hoetelmans RM, Piscitelli SC (2005) Efficacy of cerebrospinal fluid (CSF)-penetrating antiretroviral drugs against HIV in the neurological compartment: different patterns of phenotypic resistance in CSF and plasma. Clin Infect Dis 41:1789–1793Google Scholar
  10. 10.
    van Praag RM, van Weert EC, van Heeswijk RP, Zhou XJ, Sommadossi JP, Jurriaans S, Lange JM, Hoetelmans RM, Prins JM (2002) Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob Agents Chemother 46(3):889–896Google Scholar
  11. 11.
    Störmer E, von Moltke LL, Perloff MD, Greenblatt DJ (2002) Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture. Pharm Res 19(7):1038–1045PubMedCrossRefGoogle Scholar
  12. 12.
    Glynn SL, Mehran Y (1998) In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. J Pharm Sci 87(3):306–310PubMedCrossRefGoogle Scholar
  13. 13.
    Janneh O, Chandler B, Hartkoorn R, Kwan WS, Jenkinson C, Evans S, Back DJ, Owen A, Khoo SH (2009) Intracellular accumulation of efavirenz and nevirapine is independent of P-glycoprotein activity in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother 64:1002–1007PubMedCrossRefGoogle Scholar
  14. 14.
    Almond LM, Edirisinghe D, Dalton M, Bonington A, Back DJ, Khoo SH (2005) Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals. Clin Pharmacol Ther 78(2):132–142PubMedCrossRefGoogle Scholar
  15. 15.
    Riska P, Lamson M, MacGregor T, Sabo J, Hattox S, Pav J, Keirns J (1999) Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos 27(8):895–901PubMedGoogle Scholar
  16. 16.
    Erickson DA, Mather G, Trager WF, Levy RH, Keirns J (1999) Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 27(12):1488–1495PubMedGoogle Scholar
  17. 17.
    Fan-Harvard P, Liu Z, Chou M, Ling Y, Barrail-Tran A, Haas DW, Taburet AM (2013) Pharmacokinetics of phase I nevirapine metabolites following single dose and at steady state. Antimicrob Agents Chemother 57(5):2154–2160CrossRefGoogle Scholar
  18. 18.
    Havlir D, Cheesman SH, Mclaughlin M, Murphy R, Erice A, Spector SA, Greenough TC, Sullivan JL, Hall D, Myers M, Lamson M, Richman DD (1995) High-dose nevirapine: safety, pharmacokinetics, and antiretroviral effect in patients with human immunodeficiency virus infection. J Infect Dis 171(3):537–545PubMedCrossRefGoogle Scholar
  19. 19.
    Zhou XJ, Sheiner LB, D’Aquila RT, Hughes MD, Hirsch MS, Fischl MA, Johnson VA, Myers M, Sommadossi JP (1999) Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 43(1):121–128PubMedCentralPubMedGoogle Scholar
  20. 20.
    de Maat MM, Huitema AD, Mulder JW, Meenhorst PL, van Gorp EC, Beijnen JH (2002) Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals. Br J Clin Pharmacol 54:378–385PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Chou M, Bertrand J, Segeral O, Verstuyft C, Borand L, Comets E, Le Tiec C, Becquemont L, Ouk V, Mentre F, Taburet AM (2010) Population pharmacokinetic-pharmacogenetic study of nevirapine in HIV-infected Cambodian patients. Antimicrob Agents Chemother 54:4432–4439PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Kappelhoff BS, van Leth F, MacGregor TR, Lange JM, Beijnen JH, Huitema AD (2005) Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antivir Ther 10:145–155PubMedGoogle Scholar
  23. 23.
    Schipani A, Wyen C, Mahungu T, Hendra H, Egan D, Siccardi M, Davies G, Khoo S, Fatkenheuer G, Youle M, Rockstroh J, Brockmeyer NH, Johnson MA, Owen A, Back DJ (2011) Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals. J Antimicrob Chemother 66:1332–1339PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Svensson E, van der Walt JF, Barnes KI, Cohen K, Kredo T, Huitema A, Nachega JB, Karlsson MO, Denti P (2012) Integration of data from multiple sources for simultaneous modelling analysis: experience from nevirapine population pharmacokinetics. Br J Clin Pharmacol 74(3):465–476PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Hamrapurkar P, Phale M, Patil P, Shah N (2010) Determination of nevirapine in plasma by high performance liquid chromatography with ultraviolet detection. Int J Pharm Tech Res 2(2):1316–1324Google Scholar
  26. 26.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ (1989–2011) NONMEM user’s guides. Ellicott City,MD, USA: Icon Development SolutionsGoogle Scholar
  27. 27.
    Lindbom L, Pihlgren P, Jonsson EN (2005) PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 79(3):241–257PubMedCrossRefGoogle Scholar
  28. 28.
    Keizer RJ, van Benten M, Beijnen JH, Schellens JHM, Huitema ADR (2011) Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed 101(1):72–79PubMedCrossRefGoogle Scholar
  29. 29.
    Jonsson EN, Karlsson MO (1999) Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58:51–64PubMedCrossRefGoogle Scholar
  30. 30.
    Petricoul O, Cosson V, Fuseau E, Marchand M (2007) Population models for drug absorption and enterohepatic recycling. In: Ette EI, Williams PJ (eds) Pharmacometrics: the science of quantitative pharmacology. Wiley, Hoboken, pp 345–382CrossRefGoogle Scholar
  31. 31.
    Savic RM, Jonker DM, Kerbusch T, Karlsson MO (2007) Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 34:711–726PubMedCrossRefGoogle Scholar
  32. 32.
    Boeckmann A, Sheiner LB, Beal SL (2011) NONMEM user’s guide part V. Ellicott City,MD, USA: Icon Development SolutionsGoogle Scholar
  33. 33.
    Holford NH (1996) A size standard for pharmacokinetics. Clin Pharmacokinet 30(5):329–332PubMedCrossRefGoogle Scholar
  34. 34.
    Ibarra M, Vázquez M, Fagiolino P, Derendorf H (2013) Sex related differences on valproic acid pharmacokinetics after oral single dose. J Pharmacokinet Pharmacodyn 40:479–486PubMedCrossRefGoogle Scholar
  35. 35.
    Davies NM, Takemoto JK, Brocks DR, Yáñez JA (2010) Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet 49(6):351–377PubMedCrossRefGoogle Scholar
  36. 36.
    Shore PA, Brodie BB, Hogben CA (1957) The gastric secretion of drugs: a pH partition hypothesis. J Pharmacol Exp Ther 119(3):361–369PubMedGoogle Scholar
  37. 37.
    Furuta T, Ohashi K, Kosuge K, Zhao XJ, Takashima M, Kimura M, Nishimoto M, Hanai H, Kaneko E, Ishizaki T (1999) CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 65(5):552–561PubMedCrossRefGoogle Scholar
  38. 38.
    Hall JE (2010) Guyton and Hall textbook of medical physiology, 12th edn. Saunders, PhiladelphiaGoogle Scholar
  39. 39.
    Padowski JM, Pollack GM (2012) Influence of enterohepatic recycling on the time course of brain-to-blood partitioning of valproic acid in rats. Drug Metab Dispos 40(9):1846–1853PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Fagiolino P, Vázquez M, Eiraldi R (2013) Clearance and bioavailability study through arterio-venous drug concentrations relationship. Eur J Pharm Sci 48:825–829PubMedCrossRefGoogle Scholar
  41. 41.
    Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F, Uip DE, Thompson MA, Russel DB, Lange JM, Beijnen JH, Huitema AD (2005) Are adverse effects of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 10:489–498PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Manuel Ibarra
    • 1
  • Marta Vázquez
    • 1
    Email author
  • Pietro Fagiolino
    • 1
  1. 1.Pharmaceutical Sciences Department, Faculty of ChemistryUniversidad de la RepúblicaMontevideoUruguay

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