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Evaluation of the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine in patients living with HIV in Lagos University Teaching Hospital, South-Western Nigeria

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

Abstract

Purpose

Atazanavir-ritonavir (ATVr)-based antiretroviral therapy and artemether-lumefantrine (AL) are commonly used drugs for the treatment of human immune deficiency virus (HIV) infection and malaria respectively. However, interaction of both drugs, with Cytochrome P 3A4 (CYP 3A4) isoenzyme, may spawn clinically significant pharmacokinetic interactions. This study evaluated the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine.

Method

In a case-control study, twenty participants having Plasmodium falciparum malaria were recruited and divided into two groups (ATVr-arm, n=10; and control-arm, n= 10). All the participants were administered six oral doses of AL 80-480 mg (Coartem). Thereafter, their blood samples were collected at different time intervals over seven days. The concentration of lumefantrine in each sample was quantified with high-performance liquid chromatography (HPLC) and used to determine its pharmacokinetic parameters which were compared between the test and control groups.

Results

ATVr increased the mean day 7 concentration of lumefantrine (ATVr 3847.09 ± 893.35 ng/mL, control 1374.53 ± 265.55 ng/mL, p = 0.016) and the area under its plasma concentration-time curve (ATVr 670529.57 ± 157172.93 ng.h/mL, control 447976.28 ± 80886.99 ng.h/mL, p = 0.224) by 179.88 % and 49.68 %, respectively, but decreased its mean maximum plasma drug concentration (Cmax) (ATVr 13725.70 ± 2658.44 ng/mL, control 15380.48 ± 2332.62 ng/mL, p = 0.645) by 10.76 %.

Conclusion

ATVr increased drug exposure and day 7 plasma concentration of lumefantrine. AL is therefore considered effective for the treatment of malaria in patients taking ATVr-based regimen. However, the safety associated with the interaction requires further elucidation.

Trial registration

Clin ClinicalTrials.gov Identifier: NCT04531072, August 27, 2020. “Retrospectively registered”

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Data Availability

Data and materials are available.

Code availability

Not applicable.

References

  1. UNAIDS.Global HIV Statistics 2019. https://www.unaids.org/sites/default/files/media_asset/UNAIDSFact Sheeten.pdf. Accessed 17 June 2020

  2. Akanmu AS, Usman SO, Oreagba IA, Agbaje EO, Oshikoya K, Abideen AG, Opanuga OO (2015) Antiretrovirals and co-prescribed drugs for people living with HIV/AIDS (PLWHA) in a University Teaching Hospital, Southwest Nigeria. West Afr J Pharmacy 26(2):103–115

    Google Scholar 

  3. Oreagba IA, Usman SO, Oshikoya KA, Agbaje EO, Akinyede AA, Opanuga OO, Akanmu AS (2019) Clinically significant drug-drug interaction in a large antiretroviral treatment Centre in Lagos, Nigeria. J Popul Ther Clin Pharmacol 26(1):1–23

    Article  Google Scholar 

  4. Kwenti TE (2018) Malaria and HIV co-infection in sub-Saharan Africa: prevalence, impact and treatment strategies. Res Rep Trop Med 9:123–136

    PubMed  PubMed Central  Google Scholar 

  5. Federal Republic of Nigeria (2005) National Antimalarial Treatment Policy, FMOH, National malaria and Vector Control Division, Abuja, Nigeria, 2005

  6. Federal Ministry of Health (2008) National Malaria Control Programme, Abuja, Nigeria. Strategic Plan 2009-2013 Federal Ministry of Health, National Malaria Control Programme

  7. White NJ, Van Vugt M, Ezzet F (1999) Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet 37(2):105–125

    Article  CAS  Google Scholar 

  8. Walubo A (2007) The role of cytochrome P450 in antiretroviral drug interactions. Expert Opin Drug Metab Toxicol 3(4):583–598

    Article  CAS  Google Scholar 

  9. Bouchaud O, Imbert P, Touze JT, Dodoo AN, Danis M, Legros F (2009) Fatal cardiotoxicity related to halofantrine: a review based on a worldwide safety data base. Mal J 8:289

    Article  Google Scholar 

  10. Byakika-Kibwika P, Lamorde M, Mayito J, Nabukeera L, Namakula R, Mayanja-Kizza H (2012) Significant pharmacokinetic interactions between artemether-lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother 67(9):2213–2221

    Article  CAS  Google Scholar 

  11. Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, Mayanja-Kizza H (2012) Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether-lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother 67(5):1217–1223

    Article  CAS  Google Scholar 

  12. German P, Parikh S, Lawrence J (2009) Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr 51(4):424–429

    Article  CAS  Google Scholar 

  13. Hoglund RM, Byakika-Kibwika P, Lamorde M, Merry C, Ashton M, Hanpithakpong W (2016) Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications of antiretroviral therapy in HIV-1 infected patients. BMC Infect Dis 16:30–36

    Google Scholar 

  14. Kredo T, Mauff K, Workman L, Van der Walt JS, Wiesner L, Smith PJ (2015) The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral regimen. Br J Clin Pharmacol 79(4):636–649

    Article  Google Scholar 

  15. Maganda BA, Ngaimisi E, Kamuhabwa AR, Aklillu E, Minzi OMR (2015) The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment. Mal J 14:179–184

    Article  Google Scholar 

  16. Usman SO, Oreagba IA, Akinyede AA, Agbaje EO, Akinleye MO, Onwujuobi AG, Ken-Owotor C, Adeuja O, Ogunfowokan T, Kogbe S, Owolabi ET, Adeniji H, Busari A, Hassan OO, Abideen G, Akanmu AS (2020) Effect of nevirapine, efavirenz and lopinavir-ritonavir on the therapeutic concentration and toxicity of lumefantrine in patients living with HIV in Lagos University Teaching Hospital. J Pharmacol Sci 144(3):95–101

    Article  CAS  Google Scholar 

  17. FDA (1997) Guideline on validation of analytical procedures: methodology. (62 FR 27463)

  18. Zeng M, Lu Z, Yang S, Zhang M, Liao J, Liu S, Teng X (1996) Determination of benflumetol in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr 681:299–306

    Article  CAS  Google Scholar 

  19. Boffito M, Else L, Back D, Taylor J, Khoo S, Sousa M (2008) Pharmacokinetics of atazanavir/ritonavir once daily and lopinavir/ritonavir twice and once daily over 72 h following drug cessation. Antiviral Therapy 13:901–907

    CAS  PubMed  Google Scholar 

  20. Ezzet F, van-Vugt M, Nosten F, Looareesuwan S, White NJ (2000) Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria. Antimicrob Agents Chemother 44(3):697–704

    Article  CAS  Google Scholar 

  21. Granfors MT, Wang JS, Kajosaari L et al (2006) Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol 98:79–85

    Article  CAS  Google Scholar 

  22. Brenchley JM, Douek DC (2008) HIV infection and the gastrointestinal immune system. Mucosal Immunol 1(1):23–30

    Article  CAS  Google Scholar 

  23. Mukonzo JK, Nanzigu S, Rekic D, Waako P, Roshammar D, Ashton M, Ogwal-Okeng J, Gustafsson LL, Aklillu E (2011) HIV/AIDS patients display lower relative bioavailability of efavirenz than healthy subjects. Clin Pharmacokinet 50(8):531–540

    Article  Google Scholar 

  24. Endrenyi L, Fritsch S, Yan W (1991) Cmax/AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence. Int J Clin Pharmacol Ther Toxicol 29(10):394–399

    CAS  PubMed  Google Scholar 

  25. Price RN, Uhlemann AC, van Vugt M, Brockman A, Hutagalung R, Nair S et al (2006) Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria. Clin Infect Dis 42:1570–1577

    Article  CAS  Google Scholar 

  26. Mutagonda RF, Kamuhabwa AAR, Minzi OMS, Massawe SN, Maganda BA, Aklillu E (2006) Malaria Prevalence, severity and treatment outcome in relation to day 7 lumefantrine plasma concentration in pregnant women. Mal J 15:278

    Article  Google Scholar 

Download references

Acknowledgments

This study was financed with a mentored-research grant (Award no: D43TW010134) from BRAINS (Building Research and Innovation in Nigeria Science), a research developmental project sponsored by the National Institute of Health (NIH).

Funding

Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number D43TW010134. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology, Therapeutics and Toxicology, College of Medicine of the University of Lagos, Idi-Araba, Lagos State, Nigeria

    Sikiru Olatunji Usman, Ibrahim Adekunle Oreagba, Michael Rotimi Kadri, Ololade Oluwatosin Adewumi, Akinwumi Akinyede, Esther Oluwatoyin Agbaje, Ganiyu Abideen & AbdulWasiu Adeniyi Busari

  2. Lagos University Teaching Hospital, Lagos, Nigeria

    Olayinka Olaiwola Hassan

  3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy of the University of Lagos, Idi-Araba, Lagos State, Nigeria

    Moshood Olusola Akinleye

  4. Department of Haematology and Blood Transfusion, Faculty of Clinical Science, College of Medicine of the University of Lagos, Idi-Araba, Lagos State, Nigeria

    Alani Sulaimon Akanmu

  5. Apin Clinic, Lagos University Teaching Hospital, Idi-Araba, Lagos State, Nigeria

    Alani Sulaimon Akanmu

Authors
  1. Sikiru Olatunji Usman
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  2. Ibrahim Adekunle Oreagba
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  5. Akinwumi Akinyede
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  11. Alani Sulaimon Akanmu
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Contributions

Sikiru Olatunji Usman: designed study, performed research, analyzed data, and wrote the manuscript. Ibrahim Adekunle Oreagba: designed the study and reviewed the manuscript. Michael Rotimi Kadri: recruited participants, performed research, and collected and analyzed data. Ololade Oluwatosin Adewumi: recruited participants, performed research, collected, and analyzed data. Akinwumi Akinyede: reviewed manuscript and monitored participants medically. Esther Oluwatoyin Agbaje: designed study and reviewed manuscript. Ganiyu Abideen: participated in conception of the study, design of study, and review of manuscript. AbdulWasiu Adeniyi Busari: reviewed the manuscript and monitored participants medically. Olayinka Olaiwola Hassan: reviewed manuscript and monitored participants medically. Moshood Olusola Akinleye: performed research, analyzed data, and reviewed manuscript. Sulaimon Alani Akanmu: reviewed manuscript at conception and final stage.

Corresponding author

Correspondence to Sikiru Olatunji Usman.

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Ethics approval

Ethical approval was obtained from the Health Research Ethics Committee of the College of Medicine of the University of Lagos (CMUL/HREC/06/18/354: Sept 2018-Sept 2019).

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All authors gave their consent to participate in the study.

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All authors gave consent to publish the article in the European Journal of Clinical Pharmacology.

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Usman, S.O., Oreagba, I.A., Kadri, M.R. et al. Evaluation of the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine in patients living with HIV in Lagos University Teaching Hospital, South-Western Nigeria. Eur J Clin Pharmacol 77, 1341–1348 (2021). https://doi.org/10.1007/s00228-021-03116-x

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