Top

Open Access 19-12-2023 | Ritonavir | Original Article

Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin

Authors: Evelyn Krohmer, Brit Silja Rohr, Felicitas Stoll, Katja S. Gümüs, Mariano Bergamino, Gerd Mikus, Max Sauter, Jürgen Burhenne, Johanna Weiss, Andreas D. Meid, David Czock, Antje Blank, Walter E. Haefeli

Published in: Cardiovascular Drugs and Therapy

Abstract

Purpose

Early antiviral treatment with nirmatrelvir/ritonavir is recommended for SARS-CoV-2-infected patients at high risk for severe courses. Such patients are usually chronically ill and susceptible to adverse drug interactions caused by ritonavir. We investigated the interactions of short-term low-dose ritonavir therapy with atorvastatin and rosuvastatin, two statins commonly used in this population.

Method

We assessed exposure changes (area under the concentration–time curve (AUC_∞) and maximum concentration (C_max)) of a single dose of 10 mg atorvastatin and 10 mg rosuvastatin before and on the fifth day of ritonavir treatment (2 × 100 mg/day) in healthy volunteers and developed a semi-mechanistic pharmacokinetic model to estimate dose adjustment of atorvastatin during ritonavir treatment.

Results

By the fifth day of ritonavir treatment, the AUC_∞ of atorvastatin increased 4.76-fold and C_max 3.78-fold, and concurrently, the concentration of atorvastatin metabolites decreased to values below the lower limit of quantification. Pharmacokinetic modelling indicated that a stepwise reduction in atorvastatin dose during ritonavir treatment with a stepwise increase up to 4 days after ritonavir discontinuation can keep atorvastatin exposure within safe and effective margins. Rosuvastatin pharmacokinetics were only mildly modified; ritonavir significantly increased the C_max 1.94-fold, while AUC_∞ was unchanged.

Conclusion

Atorvastatin doses should likely be adjusted during nirmatrelvir/ritonavir treatment. For patients on a 20-mg dose, we recommend half of the original dose. In patients taking 40 mg or more, a quarter of the dose should be taken until 2 days after discontinuation of nirmatrelvir/ritonavir. Patients receiving rosuvastatin do not need to change their treatment regimen.

Trial Registration

EudraCT number: 2021–006634-39.

DRKS00027838.

Available only for authorised users

Xiao X, Mehta HB, Curran J, et al. Potential drug-drug interactions among U.S. adults treated with nirmatrelvir/ritonavir: a cross-sectional study of the National Covid Cohort Collaborative (N3C). Pharmacotherapy. 2023. https://doi.org/10.1002/phar.2860.CrossRefPubMed

Najjar-Debbiny R, Gronich N, Weber G, et al. Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clin Infect Dis. 2023;76(3):e342–9. https://doi.org/10.1093/cid/ciac443.CrossRefPubMed

Marzolini C, Kuritzkes DR, Marra F, et al. Recommendations for the management of drug-drug interactions between the COVID-19 antiviral nirmatrelvir/ritonavir (Paxlovid) and comedications. Clin Pharmacol Ther. 2022;112(6):1191–200. https://doi.org/10.1002/cpt.2646.CrossRefPubMed

Hsu A, Granneman GR, Witt G, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. 1997;41(5):898–905. https://doi.org/10.1128/aac.41.5.898.CrossRefPubMedPubMedCentral

Eichbaum C, Cortese M, Blank A, Burhenne J, Mikus G. Concentration effect relationship of CYP3A inhibition by ritonavir in humans. Eur J Clin Pharmacol. 2013;69(10):1795–800. https://doi.org/10.1007/s00228-013-1530-8.CrossRefPubMed

Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet. 1998;35:275–91. https://doi.org/10.2165/00003088-199835040-00002.CrossRefPubMed

Kis O, Robillard K, Chan GN, Bendayan R. The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci. 2010;31(1):22–35. https://doi.org/10.1016/j.tips.2009.10.001.CrossRefPubMed

Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother. 2008;42(7):1048–59. https://doi.org/10.1345/aph.1K615.CrossRefPubMed

Hafner V, Jager M, Matthee AK, et al. Effect of simultaneous induction and inhibition of CYP3A by St John’s Wort and ritonavir on CYP3A activity. Clin Pharmacol Ther. 2010;87(2):191–6. https://doi.org/10.1038/clpt.2009.206.CrossRefPubMed

10.

Kharasch ED, Mitchell D, Coles R, Blanco R. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother. 2008;52(5):1663–9. https://doi.org/10.1128/AAC.01600-07.CrossRefPubMedPubMedCentral

11.

Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet (London, England). 2003;361(9364):1149–58. https://doi.org/10.1016/S0140-6736(03)12948-0.CrossRefPubMed

12.

Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141–60. https://doi.org/10.2165/00003088-200342130-00005.CrossRefPubMed

13.

Kanukula R, Salam A, Rodgers A, Kamel B. Pharmacokinetics of rosuvastatin: a systematic review of randomised controlled trials in healthy adults. Clin Pharmacokinet. 2021;60(2):165–75. https://doi.org/10.1007/s40262-020-00978-9.CrossRefPubMed

14.

Group SC, Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008;359(8):789–99. https://doi.org/10.1056/NEJMoa0801936.CrossRef

15.

Hua WJ, Hua WX, Fang HJ. The role of OATP1B1 and BCRP in pharmacokinetics and DDI of novel statins. Cardiovasc Ther. 2012;30(5):e234–41. https://doi.org/10.1111/j.1755-5922.2011.00290.x.CrossRefPubMed

16.

Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292(21):2585–90. https://doi.org/10.1001/jama.292.21.2585.CrossRefPubMed

17.

Holbrook A, Wright M, Sung M, Ribic C, Baker S. Statin-associated rhabdomyolysis: is there a dose-response relationship? Can J Cardiol. 2011;27(2):146–51. https://doi.org/10.1016/j.cjca.2010.12.024.CrossRefPubMed

18.

Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004;109(23 Suppl 1):Iii50-7. https://doi.org/10.1161/01.CIR.0000131519.15067.1f.CrossRefPubMed

19.

Ravnan SL, Locke C, Yee WP, Haase K. Cerivastatin-induced rhabdomyolysis: 11 case reports. Pharmacotherapy. 2002;22(4):533–7. https://doi.org/10.1592/phco.22.7.533.33674.CrossRefPubMed

20.

Cheng CH, Miller C, Lowe C, Pearson VE. Rhabdomyolysis due to probable interaction between simvastatin and ritonavir. Am J Health Syst Pharm. 2002;59(8):728–30. https://doi.org/10.1093/ajhp/59.8.728.CrossRefPubMed

21.

U.S. Food and Drug Administration. Drug development and drug interactions, table of substrates, inhibitors and inducers. 2022. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Accessed 13 Dec 2023.

22.

Katzenmaier S, Markert C, Mikus G. Proposal of a new limited sampling strategy to predict CYP3A activity using a partial AUC of midazolam. Eur J Clin Pharmacol. 2010;66(11):1137–41. https://doi.org/10.1007/s00228-010-0878-2.CrossRefPubMed

23.

Katzenmaier S, Markert C, Riedel KD, et al. Determining the time course of CYP3A inhibition by potent reversible and irreversible CYP3A inhibitors using a limited sampling strategy. Clin Pharmacol Ther. 2011;90(5):666–73. https://doi.org/10.1038/clpt.2011.164.CrossRefPubMed

24.

Burhenne J, Halama B, Maurer M, et al. Quantification of femtomolar concentrations of the CYP3A substrate midazolam and its main metabolite 1’-hydroxymidazolam in human plasma using ultra performance liquid chromatography coupled to tandem mass spectrometry. Anal Bioanal Chem. 2012;402(7):2439–50. https://doi.org/10.1007/s00216-011-5675-y.CrossRefPubMed

25.

International Council for Harmonization (ICH). Bioanalytical method validation and sample analysis M10. Final Version of May 24, 2022. https://database.ich.org/sites/default/files/M10_Guideline_Step4_2022_0524.pdf. Accessed 13 Dec 2023.

26.

Aklillu E, Mugusi S, Ngaimisi E, et al. Frequency of the SLCO1B1 388A>G and the 521T>C polymorphism in Tanzania genotyped by a new LightCycler(R)-based method. Eur J Clin Pharmacol. 2011;67(11):1139–45. https://doi.org/10.1007/s00228-011-1065-9.CrossRefPubMed

27.

Cooper-DeHoff RM, Niemi M, Ramsey LB, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and statin-associated musculoskeletal symptoms. Clin Pharmacol Ther. 2022;111(5):1007–21. https://doi.org/10.1002/cpt.2557.CrossRefPubMed

28.

Halama B, Hohmann N, Burhenne J, et al. A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions. Clin Pharmacol Ther. 2013;93(6):564–71. https://doi.org/10.1038/clpt.2013.27.CrossRefPubMed

29.

Ratiopharm GmbH Germany. Summary of product charcteristics Atorvastatin-ratiopharm®10 mg, 20 mg, 40 mg, 80 mg film-coated tablets. March 2023. https://www.ratiopharm.de/assets/products/de/label/Atorvastatin-ratiopharm%2010%20mg20%20mg40%20mg80%20mg%20Filmtabletten%20-%2011.pdf. Accessed 13 Dec 2023.

30.

Ratiopharm GmBH Germany. Summary of product characteristics Rosuvastatin-ratiopharm® 10 mg film-coated tablets. May 2023. https://www.ratiopharm.de/assets/products/de/label/Rosuvastatin-ratiopharm%20Filmtabletten%20-%2015.pdf. Accessed 13 Dec 2023.

31.

Yadav J, Korzekwa K, Nagar S. Improved predictions of drug-drug interactions mediated by time-dependent inhibition of CYP3A. Mol Pharm. 2018;15(5):1979–95. https://doi.org/10.1021/acs.molpharmaceut.8b00129.CrossRefPubMedPubMedCentral

32.

Fidler M, Hooijmaijers R, Schoemaker R, et al. R and nlmixr as a gateway between statistics and pharmacometrics. CPT Pharmacometrics Syst Pharmacol. 2021;10(4):283–5. https://doi.org/10.1002/psp4.12618.CrossRefPubMedPubMedCentral

33.

Schoemaker R, Fidler M, Laveille C, et al. Performance of the SAEM and FOCEI algorithms in the open-source, nonlinear mixed effect modeling tool nlmixr. CPT Pharmacometrics Syst Pharmacol. 2019;8(12):923–30. https://doi.org/10.1002/psp4.12471.CrossRefPubMedPubMedCentral

34.

Wang W, Hallow KM, James DA. A tutorial on RxODE: Simulating differential equation pharmacometric models in R. CPT Pharmacometrics Syst Pharmacol. 2016;5(1):3–10. https://doi.org/10.1002/psp4.12052.CrossRefPubMed

35.

European Medicines Agency. Guideline on the investigation of bioequivalence. 2010. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf. Accessed 13 Dec 2023.

36.

PharMaAnalyst WIdO. Verordnungsdaten. 2021. https://arzneimittel.wido.de/PharMaAnalyst/?0. Accessed 13 Dec 2023.

37.

Cox DS, Rehman M, Khan T, et al. Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants. Br J Clin Pharmacol. 2023. https://doi.org/10.1111/bcp.15835.CrossRefPubMed

38.

Ambrus C, Bakos E, Sarkadi B, Ozvegy-Laczka C, Telbisz A. Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics. Sci Rep. 2021;11(1):17810. https://doi.org/10.1038/s41598-021-97160-3.CrossRefPubMedPubMedCentral

39.

Vildhede A, Karlgren M, Svedberg EK, et al. Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos: Biol Fate Chem. 2014;42(7):1210–8. https://doi.org/10.1124/dmd.113.056309.CrossRefPubMed

40.

Ziesenitz VC, Weiss J, Haefeli WE, Mikus G. Cytochrome P450–3A phenotyping using midazolam is not altered by OATP1B1 polymorphisms. Clin Pharmacol Ther. 2013;93(5):388. https://doi.org/10.1038/clpt.2013.46.CrossRefPubMed

41.

Maeda K, Ikeda Y, Fujita T, et al. Identification of the rate-determining process in the hepatic clearance of atorvastatin in a clinical cassette microdosing study. Clin Pharmacol Ther. 2011;90(4):575–81. https://doi.org/10.1038/clpt.2011.142.CrossRefPubMed

42.

Netsomboon K, Laffleur F, Suchaoin W, Bernkop-Schnurch A. Novel in vitro transport method for screening the reversibility of P-glycoprotein inhibitors. Eur J Pharm Biopharm. 2016;100:9–14. https://doi.org/10.1016/j.ejpb.2015.11.019.CrossRefPubMed

43.

Shitara Y, Takeuchi K, Horie T. Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake. J Pharm Sci. 2013;102(9):3427–35. https://doi.org/10.1002/jps.23477.CrossRefPubMed

44.

Pham PA, la Porte CJ, Lee LS, et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother. 2009;53(10):4385–92. https://doi.org/10.1128/AAC.00449-09.CrossRefPubMedPubMedCentral

45.

Samineni D, Desai PB, Sallans L, Fichtenbaum CJ. Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin. J Clin Pharmacol. 2012;52(6):922–31. https://doi.org/10.1177/0091270011407494.CrossRefPubMed

46.

Elsby R, Coghlan H, Edgerton J, et al. Mechanistic in vitro studies indicate that the clinical drug-drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3. Pharmacol Res Perspect. 2023;11(2):e01060. https://doi.org/10.1002/prp2.1060.CrossRefPubMedPubMedCentral

47.

Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82(6):726–33. https://doi.org/10.1038/sj.clpt.6100220.CrossRefPubMed

48.

Hirota T, Fujita Y, Ieiri I. An updated review of pharmacokinetic drug interactions and pharmacogenetics of statins. Expert Opin Drug Metab Toxicol. 2020;16(9):809–22. https://doi.org/10.1080/17425255.2020.1801634.CrossRefPubMed

49.

Zhu V, Burhenne J, Weiss J, et al. Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers. Front Pharmacol. 2023;14:1128547. https://doi.org/10.3389/fphar.2023.1128547.CrossRefPubMedPubMedCentral

50.

Kindla J, Muller F, Mieth M, Fromm MF, Konig J. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab Dispos: Biol Fate Chem. 2011;39(6):1047–53. https://doi.org/10.1124/dmd.110.037622.CrossRefPubMed

51.

Gomez Sandoval YH, Braganza MV, Daskalopoulou SS. Statin discontinuation in high-risk patients: a systematic review of the evidence. Curr Pharm Des. 2011;17(33):3669–89. https://doi.org/10.2174/138161211798220891.CrossRefPubMed

52.

Vitturi BK, Gagliardi RJ. The influence of statin withdrawal and adherence on stroke outcomes. Neurol Sci. 2021;42(6):2317–23. https://doi.org/10.1007/s10072-020-04790-y.CrossRefPubMed

53.

Jeong HY, Lee SY, Kim SH, Kim J. Long-term benefit and withdrawal effect of statins after percutaneous coronary intervention: a nationwide population-based cohort study. Patient Prefer Adherence. 2020;14:717–24. https://doi.org/10.2147/PPA.S245324.CrossRefPubMedPubMedCentral

54.

Kuno T, So M, Iwagami M, Takahashi M, Egorova NN. The association of statins use with survival of patients with COVID-19. J Cardiol. 2022;79(4):494–500. https://doi.org/10.1016/j.jjcc.2021.12.012.CrossRefPubMed

55.

Cilla DD Jr, Whitfield LR, Gibson DM, Sedman AJ, Posvar EL. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects. Clin Pharmacol Ther. 1996;60(6):687–95. https://doi.org/10.1016/s0009-9236(96)90218-0.CrossRefPubMed

Title: Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin
Authors: Evelyn Krohmer
Brit Silja Rohr
Felicitas Stoll
Katja S. Gümüs
Mariano Bergamino
Gerd Mikus
Max Sauter
Jürgen Burhenne
Johanna Weiss
Andreas D. Meid
David Czock
Antje Blank
Walter E. Haefeli
Publication date: 19-12-2023
Publisher: Springer US
Keywords: Ritonavir
Atorvastatin
Rosuvastatin
Pharmacokinetics
SARS-CoV-2
Midazolam
Statins
Published in: Cardiovascular Drugs and Therapy
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI: https://doi.org/10.1007/s10557-023-07538-w

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Influence of a Short Course of Ritonavir Used as Booster in Antiviral Therapies Against SARS-CoV-2 on the Exposure of Atorvastatin and Rosuvastatin

Abstract

Purpose

Method

Results

Conclusion

Trial Registration

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Method

Results

Conclusion

Trial Registration

Please log in to get access to this content

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page