Skip to main content
SpringerLink
Log in

Simultaneous Population Pharmacokinetic Model for Lopinavir and Ritonavir in HIV-Infected Adults

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background: Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients.

Objective: To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds.

Methods: HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques.

Results: A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as α1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the Imax [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision.

Conclusion: A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1
Fig. 2
Table II
Table III
Table IV
Fig. 3
Fig. 4
Fig. 5
Table V

Similar content being viewed by others

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References:

  1. Walmsley S. Protease inhibitor-based regimens for HIV therapy: safety and efficacy. J Acquir Immune Defic Syndr 2007; 45 Suppl. 1: S5–S13

    Article  PubMed  CAS  Google Scholar 

  2. Sham HL, Kempf DL, Molla A, et al. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 1998; 42: 3218–24

    PubMed  CAS  Google Scholar 

  3. Hicks C, King MS, Gulick RM, et al. Long-term safety and durable antiretroviral activity of lopinavir/ritonavir in treatment-naive patients: 4 year follow-up study. AIDS 2004; 18: 775–9

    Article  PubMed  CAS  Google Scholar 

  4. Kempf DJ, Isaacson JD, King MS, et al. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir Ther 2002; 7: 165–74

    PubMed  CAS  Google Scholar 

  5. Olson DP, Scadden DT, D’Aquila RT, et al. The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1). AIDS 2002; 16: 1743–7

    Article  PubMed  CAS  Google Scholar 

  6. Cooper CL, van Heeswijk RPG, Gallicano K, et al. A review of low-dose ritonavir in protease inhibitor combination therapy. Clin Infect Dis 2003; 36: 1585–92

    Article  PubMed  CAS  Google Scholar 

  7. King JR, Wynn H, Brundage R, et al. Pharmacokinetic enhancement of protease inhibitor therapy. Clin Pharmacokinet 2004; 43: 291–310

    Article  PubMed  CAS  Google Scholar 

  8. la Porte C, Back D, Blaschke T, et al. Updated guideline to perform therapeutic drug monitoring for antiretroviral agents. Reviews in Antiviral Therapy 2006; 3: 4–14

    Google Scholar 

  9. Moltó J, Blanco A, Miranda C, et al. Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practice. Br J Clin Pharmacol 2006; 62: 560–6

    Article  PubMed  Google Scholar 

  10. van der Leur MR, Burger DM, la Porte CJL, et al. A retrospective TDM database analysis of interpatient variability in the pharmacokinetics of lopinavir in HIV-infected adults. Ther Drug Monit 2006; 28: 650–3

    Article  PubMed  Google Scholar 

  11. Masquelier B, Breilh D, Neau D, et al. Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir containing therapy in protease inhibitor-experienced patients. Antimicrob Agents Chemother 2002; 46: 2926–32

    Article  PubMed  CAS  Google Scholar 

  12. Boffito M, Arnaudo I, Raiteri R, et al. Clinical use of lopinavir/ritonavir in a salvage therapy setting: pharmacokinetics and pharmacodynamics. AIDS 2002; 16: 2081–3

    Article  PubMed  Google Scholar 

  13. Hoefnagel JGM, Koopmans PP, Burger DM, et al. Role of the inhibitory quotient in HIV therapy. Antivir Ther 2005; 10: 879–92

    PubMed  CAS  Google Scholar 

  14. Gonzalez de Requena D, Gallego O, Valer L, et al. Prediction of virological response to lopinavir/ritonavir using the genotypic inhibitory quotient. AIDS Research Human Retroviruses 2004; 20: 275–8

    Article  Google Scholar 

  15. Castagna A, Gianotti N, Galli L, et al. The NIQ of lopinavir is predictive of a 48-week virological response in highly treatment-experienced HIV-1-infected subjects treated with a lopinavir/ritonavir-containing regimen. Antivir Ther 2004; 9: 537–43

    PubMed  CAS  Google Scholar 

  16. Marcelin AG, Cohen-Codar I, King MS, et al. Virological and pharmacological parameters predicting the response to lopinavir-ritonavir in heavily protease inhibitors-experienced patients. Antimicrob Agents Chemother 2005; 49: 1720–6

    Article  PubMed  CAS  Google Scholar 

  17. Hsu A, Isaacson J, Bran S, et al. Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2003; 47: 350–9

    Article  PubMed  CAS  Google Scholar 

  18. Best BM, Goicoechea M, Witt MD, et al. A randomized controlled trial of therapeutic drug monitoring in treatment-naive and -experienced HIV-1-infected patients. J Acquir Immune Defic Syndr 2007; 46: 433–42

    Article  PubMed  CAS  Google Scholar 

  19. Kaletra® (lopinavir/ritonavir) [US prescribing information]. North Chicago (IL): Abbott Laboratories, 2003

  20. Sterling R, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 6: 1317–25

    Article  Google Scholar 

  21. Droste JAH, Aarnoutse RE, Koopmans PP, et al. Evaluation of antiretroviral drug measurements by an interlaboratory quality control program. J Acquir Immune Defic Syndr 2003; 32: 287–91

    Article  PubMed  Google Scholar 

  22. Beal SL, Sheiner LB. NONMEM user’s guide. Ellicott City (MD): Icon Development Solutions, 1989–98

    Google Scholar 

  23. Jonsson EN, Karlsson MO. Xpose: an S-Plus based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58: 51–64

    Article  PubMed  CAS  Google Scholar 

  24. Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 9: 503–12

    PubMed  CAS  Google Scholar 

  25. Sale M, Sadler BM, Stein DS. Pharmacokinetic modeling and simulations of interaction of amprenavir and ritonavir. Antimicrob Agents Chemother 2002; 46: 746–54

    Article  PubMed  CAS  Google Scholar 

  26. Lu JF, Blaschke TF, Flexner C, et al. Model-based analysis of the pharmacokinetic interactions between ritonavir, nelfinavir, and saquinavir after simultaneous and staggered oral administration. Drug Metab Dispos 2002; 30: 1455–61

    Article  PubMed  CAS  Google Scholar 

  27. Kappelhoff BS, Huitema AD, Crommentuyn KM, et al. Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients. Br J Clin Pharmacol 2004; 59: 174–84

    Article  Google Scholar 

  28. Moltó J, Valle M, Blanco A, et al. Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis. Clin Pharmacokinet 2007; 46: 85–92

    Article  PubMed  Google Scholar 

  29. Vrijens B, Tousset E, Rode R, et al. Successful projection of the time course of drug concentration in plasma during a 1-year period from electronically compiled dosing-time data used as input to individually parametrized pharmacokinetic models. J Clin Pharmacol 2005; 45: 461–7

    Article  PubMed  CAS  Google Scholar 

  30. Dailly E, Gagnieu MC, Allavena C, et al. No significant influence of saquinavir hard-gel capsule administration on pharmacokinetics of lopinavir in combination with ritonavir: a population approach. Ther Drug Monit 2005; 27: 782–4

    Article  PubMed  CAS  Google Scholar 

  31. Dailly E, Allavena C, Raffi F, et al. Pharmacokinetic evidence of the induction of lopinavir metabolism by efavirenz. Br J Clin Pharmacol 2005; 60: 32–4

    Article  PubMed  CAS  Google Scholar 

  32. Crommentuyn KML, Kappelhoff BS, Mulder JW, et al. Population pharmacokinetics of lopinavir in combination with ritonavir in HIV-1-infected patients. Br J Clin Pharmacol 2005; 60: 378–89

    Article  PubMed  CAS  Google Scholar 

  33. Boffito M, Hoggard PG, Lindup WE, et al. Lopinavir protein binding in vivo through the 12-hour dosing interval. Ther Drug Monit 2004; 26: 35–9

    Article  PubMed  CAS  Google Scholar 

  34. Boffito M, Sciole K, Raitieri R, et al. α-1 acid glycoprotein levels in human immunodeficiency virus-infected subjects on antiretroviral regimens. Drug Metab Dispos 2002; 30: 859–60

    Article  PubMed  CAS  Google Scholar 

  35. Oie S, Jacobson MA, Abrams DI. Alpha-1-acid glycoprotein levels in AIDS patients before and after short-term treatment with zidovudine (ZDV). J Acquir Immune Defic Syndr 1993; 5: 531–3

    Google Scholar 

  36. Jones K, Hoggard PG, Khoo S, et al. Effect of alphal-acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro. Br J Clin Pharmacol 2001; 51: 99–102

    Article  PubMed  CAS  Google Scholar 

  37. Holladay JW, Dewey MJ, Michniak BB, et al. Elevated alpha-1-acid glycoprotein reduces the volume of distribution and systemic clearance of saquinavir. Drug Metab Dispos 2001; 29: 299–303

    PubMed  CAS  Google Scholar 

  38. Colombo S, Buclin T, Décosterd LA, et al. Orosomucoid (alphal-acid glycoprotein) plasma concentrations and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation. Clin Pharmacol Ther 2006; 80: 307–18

    Article  PubMed  CAS  Google Scholar 

  39. Hoggard PG, Owen A. The mechanisms that control intracellular penetration of the HIV protease inhibitors. J Antimicrob Chemother 2003; 51: 493–6

    Article  PubMed  CAS  Google Scholar 

  40. Kumar GN, Jayanti VK, Johnson MK, et al. Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans. Pharm Res 2004; 21: 1622–30

    Article  PubMed  CAS  Google Scholar 

  41. Eron J, Feinberg J, Kessler HA, et al. Once-daily versus twice-daily lopinavir/ritonavir in antiretroviral-naive HIV-positive patients: a 48-week randomized clinical trial. J Infect Dis 2004; 189: 265–72

    Article  PubMed  CAS  Google Scholar 

  42. van Heeswijk RPG, Bourbeau M, Seguin I, et al. Absence of circadian variation in the pharmacokinetics of lopinavir/ritonavir given as a once daily dosing regimen in HIV-1 infected patients. Br J Clin Pharmacol 2005; 59: 398–404

    Article  PubMed  Google Scholar 

  43. Barrett JS, Labbe L, Pfister M. Application and impact of population pharmacokinetics in the assessment of antiretroviral pharmacotherapy. Clin Pharmacokinet 2005; 44: 591–625

    Article  PubMed  CAS  Google Scholar 

  44. Klein CE, Chiu YL, Awni W, et al. The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. J Acquir Immune Defic Syndr 2007; 44: 401–10

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank staff at the clinical sites that collaborated in this study, the patients who participated and, in particular, Sebastià Videla for carefully reviewing the manuscript. Mary Ellen Kerans assisted with English language expression in the final version of the manuscript.

José Moltó was supported by FIS through grant no. CM030135 from the Fundació per a la Recerca Biomédica Germans Trias i Pujol, Badalona, in collaboration with the Spanish Health Department. Marta Valle is supported by FIS through grant no. CP04/00121 from the Spanish Health Department in collaboration with Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, and is a member of ISCIII-RETIC RD06/0011 (REM-TAP Network). The study was supported by FIPSE, Caixa de Sabadell and ISCIII-RETIC RD06/006.

The authors have no conflicts of interest that are directly relevant to the content of this study.

Author information

Authors and Affiliations

  1. “Lluita contra la SIDA” Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

    José Moltó, Cristina Miranda, José Ramón Santos & Eugenia Negredo

  2. Universidad Autonóma de Barcelona, Barcelona, Spain

    José Moltó, Manuel José Barbanoj, Bonaventura Clotet & Marta Valle

  3. Centre d’Investigació del Medicament, Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Manuel José Barbanoj & Marta Valle

  4. “IrsiCaixa” Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

    Asunción Blanco & Bonaventura Clotet

  5. Department of Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

    Joan Costa

  6. Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

    Pere Domingo

Authors
  1. José Moltó
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manuel José Barbanoj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cristina Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asunción Blanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José Ramón Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eugenia Negredo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joan Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pere Domingo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bonaventura Clotet
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marta Valle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Moltó.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moltó, J., Barbanoj, M.J., Miranda, C. et al. Simultaneous Population Pharmacokinetic Model for Lopinavir and Ritonavir in HIV-Infected Adults. Clin Pharmacokinet 47, 681–692 (2008). https://doi.org/10.2165/00003088-200847100-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200847100-00005

Keywords

Search

Navigation