Medical research into COVID-19 is mainly focused on two general areas. Development of a vaccine and evaluation of drugs to treat the major symptoms of the disease. Much of the latter work has involved the repurposing of existing drugs. For these licensed drugs the challenge is determining the therapeutic dose necessary to treat COVID-19. Understanding the pharmacokinetics (PK) of these drugs in patients with COVID 19 is a crucial step in designing effective dosing regimens for the treatment of this disease. Unsurprisingly, there is a growing literature on this topic. It includes the anti-virals; favipiravir, remdesivir and lopinavir and, the anti-parasitic drug, ivermectin. The PK of favipiravir, approved for use in influenza, have been summarised in the context of COVID-19 with a view to aiding the design of studies with this agent in this patient group1.
Ivermectin
In vitro work found that ivermectin at a concentration of 5μM reduced the viral RNA load of SARS-CoV-2 by 99.98% at 48 h2. Nonetheless, the efficacious concentrations demonstrated in vitro cannot be achieved clinically with the currently available formulations for human use. Even at the highest reported dose 1700 µg/kg (> 8.5-fold more than the recommended FDA dose) free ivermectin was 250 times lower than that required to reduce SARS-CoV-2 in vitro. Further work is required to improve the amount of ivermectin that can be delivered systemically, in addition to understanding tolerability at anti-viral concentrations of the drug.
Remdesivir
Remdesivir has shown a broad-spectrum potent antiviral activity in vitro against multiple genetically unrelated RNA viruses similar to SARS-CoV-2, such as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Remdesevir (RDV) PK was examined in healthy volunteers following single and multiple doses3. The active moiety RDV triphosphate was measured in peripheral blood mononuclear cells as a surrogate for efficacy. High concentrations were found that were around 220-fold to 370-fold higher than the in vitro half-maximal effective concentration against SARS-CoV-2.
Lopinavir
Researchers found that lopinavir plasma concentrations in COVID-19 patients were extremely high (around 3-fold) compared with those usually observed in HIV-infected patients4. Lopinavir is metabolised by cytochrome P450 (CYP) 3A4 and it is well known that infection and inflammation are associated with down-regulation of CYPs. It was also noted that going forward it would be important to evaluate the influence of tablet versus oral solution administration on lopinavir PK in COVID-19 ICU patients.
The brief overview presented here indicates that when repurposing drugs for the treatment of Covid-19, an understanding of their PK is a critical step in determining an effective dosing regimen.
- Du YX, Chen XP. Favipiravir: Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection. Clin Pharmacol Ther. 2020 Aug;108(2):242-247.
- Peña-Silva R, Duffull SB, Steer AC, Jaramillo-Rincon SX, Gwee A, Zhu X. Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19. Br J Clin Pharmacol. 2020 Jul 17
- Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, Ling J, Vu A, German P. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin Transl Sci. 2020 Jun
- Gregoire M, Le Turnier P, Gaborit BJ, Veyrac G, Lecomte R, Boutoille D, Canet E, Imbert BM, Bellouard R, Raffi F. Lopinavir pharmacokinetics in COVID-19 patients. J Antimicrob Chemother. 2020 Sep 1;75(9):2702-2704.