Crushing Lopinavir/ritonavir Tablets Does Not Result in Lower Exposure to Lopinavir/ritonavir in Adult Patients with COVID-19

Overview

Journal Eur J Hosp Pharm

Publisher BMJ Publishing Group

Specialty Pharmacy

Date 2021 May 15

PMID 33990390

Authors

Shaghayegh Mohsenian Naghani

Mark Mpm Jansen

Tessa Jaspers

Diane Bastiaans

David Burger

Affiliations

Soon will be listed here.

Abstract

Objective: Lopinavir/ritonavir (LPV/RTV) exposure is decreased in children after crushing the tablets. Whether exposure is also decreased in adult patients is not known. This study evaluated the exposure of LPV/RTV in adult patients after administration of crushed LPV/RTV tablets.

Methods: Blood samples were drawn from patients with COVID-19 who were receiving crushed LPV/RTV 400/100 mg tablets twice daily.

Results: Plasma concentrations for 11 patients with COVID-19 (eight men, mean age 62.6 years) were included. The measured plasma concentrations of LPV were substantially higher than reported for patients with HIV.

Conclusions: There is adequate exposure from crushed LPV/RTV tablets, but because of limited experience, therapeutic drug monitoring is still advised.

References

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

Schmitt C, Kuhn B, Zhang X, Kivitz A, Grange S . Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther. 2011; 89(5):735-40. DOI: 10.1038/clpt.2011.35. View

Sunman J, Hawke R, LeCluyse E, Kashuba A . Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos. 2004; 32(3):359-63. DOI: 10.1124/dmd.32.3.359. View

Chan J, Yao Y, Yeung M, Deng W, Bao L, Jia L . Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015; 212(12):1904-13. PMC: 7107395. DOI: 10.1093/infdis/jiv392. View

Loyer P, Fautrel A, GAUTIER J, Corcos L, Turlin B, Beaune P . Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol. 1993; 44(4):707-15. View

Bastiaans D, Cressey T, Vromans H, Burger D . The role of formulation on the pharmacokinetics of antiretroviral drugs. Expert Opin Drug Metab Toxicol. 2014; 10(7):1019-37. DOI: 10.1517/17425255.2014.925879. View

Muntane-Relat J, Ourlin J, Domergue J, Maurel P . Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. Hepatology. 1995; 22(4 Pt 1):1143-53. View

Best B, Capparelli E, Diep H, Rossi S, Farrell M, Williams E . Pharmacokinetics of lopinavir/ritonavir crushed versus whole tablets in children. J Acquir Immune Defic Syndr. 2011; 58(4):385-91. PMC: 3205189. DOI: 10.1097/QAI.0b013e318232b057. View

Ding X, Staudinger J . Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. Biochem Pharmacol. 2005; 69(5):867-73. DOI: 10.1016/j.bcp.2004.11.025. View

10.

Klein C, Chiu Y, Awni W, Zhu T, Heuser R, Doan T . 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(4):401-10. DOI: 10.1097/QAI.0b013e31803133c5. View

11.

Marra F, Smolders E, El-Sherif O, Boyle A, Davidson K, Sommerville A . Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment. Drugs R D. 2020; 21(1):9-27. PMC: 7745756. DOI: 10.1007/s40268-020-00333-0. View

12.

Lee C, Gottesman M, Cardarelli C, Ramachandra M, Jeang K, Ambudkar S . HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry. 1998; 37(11):3594-601. DOI: 10.1021/bi972709x. View

13.

Kacevska M, Robertson G, Clarke S, Liddle C . Inflammation and CYP3A4-mediated drug metabolism in advanced cancer: impact and implications for chemotherapeutic drug dosing. Expert Opin Drug Metab Toxicol. 2008; 4(2):137-49. DOI: 10.1517/17425255.4.2.137. View

14.

Chu C, Cheng V, Hung I, Wong M, Chan K, Chan K . Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004; 59(3):252-6. PMC: 1746980. DOI: 10.1136/thorax.2003.012658. View

15.

Batchelor H, Kendall R, Desset-Brethes S, Alex R, Ernest T . Application of in vitro biopharmaceutical methods in development of immediate release oral dosage forms intended for paediatric patients. Eur J Pharm Biopharm. 2013; 85(3 Pt B):833-42. DOI: 10.1016/j.ejpb.2013.04.015. View

16.

Rijpma S, van den Heuvel J, van der Velden M, Sauerwein R, Russel F, Koenderink J . Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity. Malar J. 2014; 13:359. PMC: 4172838. DOI: 10.1186/1475-2875-13-359. View

17.

Lindenberg M, Kopp S, Dressman J . Classification of orally administered drugs on the World Health Organization Model list of Essential Medicines according to the biopharmaceutics classification system. Eur J Pharm Biopharm. 2004; 58(2):265-78. DOI: 10.1016/j.ejpb.2004.03.001. View

18.

Chen F, Chan K, Jiang Y, Kao R, Lu H, Fan K . In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004; 31(1):69-75. PMC: 7128415. DOI: 10.1016/j.jcv.2004.03.003. View