Lopinavir/Ritonavir and COVID-19
Disclosure: The following article is for educational purposes only.
The following antiretroviral are used in combination or pairs to synergize their pharmacokinetic properties and delay their elimination from the body, providing more time for absorption. Although both have similar mechanisms of action in that, they are both protease inhibitors for HIV-1 and in the case of Ritonavir for Hepatitis C infection. There is limited information on their toxicity.
Lopinavir is an antiretroviral protease inhibitor used in combination with other anti-retrovirals in the treatment of HIV-1 infection. Lopinavir is marketed and administered exclusively in combination with ritonavir-this combination , first marketed under Abbott under the brand name Kaletra in 2000, is necessary due to lopinavir’s poor oral bioavailability and extensive biotransformation. (1) Although it has been tested in combination with other NNRTI, which conclusion is that drug monitoring is essential to account for drug optimization (18).
Ritonavir is a potent inhibitor of the enzymes responsible for lopinavir metabolism, and its co-administration “boost” lopinavir exposure and improves antiviral activity (2)
Ritonavir was approved in 1996 for the treatment of HIV. After saquinavir, it was the second approved protease inhibitor in the United States. Its importance is in its chief mechanism of action inhibition of P450-3A4. Therefore augmenting HIV treatments by increasing bioavailability of HIV medications (23).
Indication:
The combination product lopinavir/ritonavir, marketed under the brand name Kaletra, is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients ≥14 days old.(1)
Mechanism of Action:
Lopinavir is an inhibitor of the HIV-1 protease enzyme. Its design is based on the "peptidomimetic" principle, wherein the molecule contains a hydroxyethylene scaffold that mimics the normal peptide linkage (cleaved by HIV protease) but which itself cannot be cleaved. By preventing HIV-1 protease activity, and thus the proteolysis of the Gag polyprotein, lopinavir results in the production of immature, non-infectious viral particles. (3)
Absorption:
Lopinavir has very low bioavailability 25%, which is why it is exclusively administered with ritonavir, which dramatically improves bioavailability, hinders drug metabolism. (4,5) Maximal concentrations are achieved at 4.4 hours and Cmax and AUCtau are 9.8 ± 3.7 - 11.8 ± 3.7 µg/mL and 92.6 ± 36.7 - 154.1 ± 61.4 μg•h/mL, respectively (2)
Metabolism:
Lopinavir undergoes extensive oxidative metabolism, via hepatic CYP3A isozymes. (6)
Elimination:
Lopinavir is primarily eliminated in the feces. Following oral administration, approximately 10.4 ± 2.3% of the administered dose is excreted in the urine and 82.6 ± 2.5% is excreted in the feces.(2) Unchanged parent drug accounted for 2.2% and 19.8% of the administered dose in urine and feces, respectively. (6)
Overdose:
The risk related to overdose appears more pronounced in pediatric patients.
One case report detailed a fatal cardiogenic shock in a 2.1kg infant following an approximately 10-fold overdose of Kaletra oral solution, while other reported reactions to overdose in infants include complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure. (2)
Side Effects of the Class of Medications (Protease Inhibitors):
· Hyperglycemia
· Hyperlipidemia
· GI intolerance (Diarrhea)
· Lipodystrophy
Other curious side effect is that like hydroxychloroquine and azithromycin, its doses dependent mechanism also prolong QT.
COVID-19 and Lopinavir/Ritonavir:
Taking into consideration the literature reviews of Kaletra and COVID-19, the jury is still out. Lee and Park reported that they were not so sure that Kaletra was the responsible for a decrease in viral loads, following Kaletra or was due in part to the healing process of their patient (20). Patient zero in South Korea who emigrated from Wuhan, diagnosed at day 4, began administration of lopinavir 400 mg/Ritonavir 100 mg, only to see symptoms and laboratories began to normalize at day 10 of the disease. (21)
Similarly, Cao published that there was no significance in treatment of Kaletra with COVID-19 compared to standard treatment, only that there was an improvement of end of 1 day earlier of recovery. (22)
According to Clinical Trials.gov there are 7 new clinical trials, in recruitment phase for Kaletra.
References:
1. FDA Approved Drug Products: Kaletra (lopinavir/ritonavir) for oral use (Link)
2. De Clercq E: Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J. Antimicrob Agents. 2009 Apr;33(4): 307-20. Doi: 10.1016/j.ijantimicag.2008.10.010. Epub 2008 Dec 23. (PubMed: 19108994)
3. Canadian Drug Bank: Lopinavir
4. Niu WJ, Sun T, Liu L, Liu XQ, Zhang RF, Yin L, Wang JR, Jia XF, Lu HZ, Zhong MK, Jiao Z, Zhang LJ: Population pharmacokinetics and dosing regimen optimization of lopinavir in Chinese adults infected with HIV. Basci Clin Pharmacol Toxicol. 2019 Apr; 124(4): 456-465. (PubMed: 30346663)
5. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald R, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM, Plattner JJ, Norbeck DW: ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998 Dec;42(12): 3218-24 (PubMed: 9835517)
6. Health Canada Product Monograph: Kaletra (lopinavir/ritonavir) for oral use
7. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs. 2003;63(8):769–802. doi:10.2165/00003495-200363080-00004
8. Hurst M, Faulds D. Lopinavir. Drugs. 2000;60(6):1371–1381. doi:10.2165/00003495-200060060-00009
9. von Hentig N. Lopinavir/ritonavir: appraisal of its use in HIV therapy. Drugs Today (Barc). 2007;43(4):221–247. doi:10.1358/dot.2006.43.4.1050793
10. Gong Y, Haque S, Chowdhury P, et al. Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment. Expert Opin Drug Metab Toxicol. 2019;15(5):417–427. doi:10.1080/17425255.2019.1604685
11. Nisly SA, Stevens BN. Ritonavir- or cobicistat-boosted antiretroviral therapy and direct oral anticoagulants: A case for apixaban. Int J STD AIDS. 2019;30(7):718–722. doi:10.1177/0956462419832099
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18. Solas C, Poizot-Martin I, Drogoul MP, et al. Therapeutic drug monitoring of lopinavir/ritonavir given alone or with a non-nucleoside reverse transcriptase inhibitor. Br J Clin Pharmacol. 2004;57(4):436–440. doi:10.1046/j.1365-2125.2003.02020.x
19. Inciardi RM, Lupi L, Zaccone G, et al. Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19) [published online ahead of print, 2020 Mar 27]. JAMA Cardiol. 2020;10.1001/jamacardio.2020.1096. doi:10.1001/jamacardio.2020.1096
20. Lim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci. 2020;35(6):e79. Published 2020 Feb 17. doi:10.3346/jkms.2020.35.e79
21. Kim JY, Choe PG, Oh Y, et al. The First Case of 2019 Novel Coronavirus Pneumonia Imported into Korea from Wuhan, China: Implication for Infection Prevention and Control Measures. J Korean Med Sci. 2020;35(5):e61. Published 2020 Feb 10. doi:10.3346/jkms.2020.35.e61
22. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 [published online ahead of print, 2020 Mar 18]. N Engl J Med. 2020;10.1056/NEJMoa2001282. doi:10.1056/NEJMoa2001282
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