key: cord-0999332-57w1nv3l authors: Schmith, Virginia D.; Zhou, Jie (Jessie); Lohmer, Lauren RL title: The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID‐19 date: 2020-05-07 journal: Clin Pharmacol Ther DOI: 10.1002/cpt.1889 sha: abdd02b8f977cbfea4b8222e901d94d1a65c7afc doc_id: 999332 cord_uid: 57w1nv3l Caly, Druce (1) reported that ivermectin inhibited SARS‐CoV‐2 in vitro for up to 48 h using ivermectin at 5μM. The concentration resulting in 50% inhibition (IC(50,) 2 µM) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted. Simulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration‐time profiles after a single and repeat fasted administration of the approved dose of ivermectin (200 μg/kg), 60 mg, and 120 mg. Plasma total Cmax was determined and then multiplied by the lung:plasma ratio reported in cattle to predict the lung Cmax after administration of each single dose. Plasma ivermectin concentrations of total (bound and unbound) and unbound concentrations do not reach the IC(50), even for a dose level 10x higher than the approved dose. Even with the high lung:plasma ratio, ivermectin is unlikely to reach the IC(50) in lungs after single oral administration of the approved dose (predicted lung: 0.0873 µM) or at doses 10x higher that the approved dose administered orally (predicted lung: 0.820 µM). In summary, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. Combination therapy should be evaluated in vitro. Re‐purposing drugs for use in COVID‐19 treatment is an ideal strategy but is only feasible when product safety has been established and experiments of re‐purposed drugs are conducted at clinically relevant concentrations. This article is protected by copyright. All rights reserved In order to understand how in vitro SARS-CoV-2 inhibition by ivermectin translates to humans, one must first evaluate these concentrations compared to predicted lung concentrations in humans after oral administration of ivermectin. Theoretically, only unbound drug in the plasma could access the lung and other tissues through passive diffusion. Ivermectin reaching the lung after oral dosing is also likely related to lipophilicity (which is high), the low ionization at physiologic pH, the binding of ivermectin to proteins in the lung (which is unknown), and any transporter(s) that may help maintain tissue distribution (which is unknown). While ivermectin concentrations in lung tissue cannot be measured in humans, ivermectin exposure in homogenates obtained from the left diaphragmatic lung was reported to be 2.7x higher than total plasma exposure in cattle after a single dose (4) . Even with these higher concentrations in lung, ivermectin is unlikely to reach the IC50 after oral administration of the approved dose in humans. Unlike the narrow therapeutic index for hydroxychloroquine and chloroquine, ivermectin has a wider safety margin (2) . The safety of higher doses of ivermectin has been evaluated in a Phase 3 study, where 200-400 g/kg doses were studied in patients with Dengue fever (5, 6) . Even higher doses (up to 10x higher than approved doses) were studied in a small Phase 1 trial (7). This trial showed that ivermectin administered orally in the fasted state was well tolerated both after a single 120 mg dose (10x higher than approved dose) and after 60 mg three times weekly (every 72 hours). The most common adverse events were headache, nausea, dizziness, and rash. The reported incidence and type of adverse events were relatively similar between ivermectin (24%) and placebo (35%) and did not increase with dose. All dosing regimens had a mydriatic effect (the primary safety endpoint based on results from toxicology studies) similar to placebo. It is important to note that while this This article is protected by copyright. All rights reserved study evaluated common adverse events, the presence and incidence of rare adverse events at these high doses are unknown, given the small number of subjects studied. The overall objective of this analysis was to evaluate what doses in humans would be predicted to result in lung concentrations reaching the IC50 in the lungs to help in designing a successful clinical trial with ivermectin in the treatment of COVID-19. A population pharmacokinetic model for ivermectin reported by Duthaler, Suenderhauf (8) This article is protected by copyright. All rights reserved A range of body weights in adults was sampled from the Center for Disease Control weight chart for 20 year old adults, with male:female ratio being 1:1 (9) . The median (3 rd and 97 th percentiles) weights were 70.6 (54.0-101) kg in males and 58.2 (45.0-89.0) kg in females, which represent most adults but does not include morbidly obese patients. Predicted concentrations required correction for the fact that the population pharmacokinetic model was built based on subjects who received ivermectin with a high-fat breakfast, yet ivermectin should be taken on an empty stomach (2) . Bioavailability of ivermectin is increased by 2.57-fold increase in fed state with no change in Tmax and parallel concentration-time curves (7) (suggesting a change in extent of absorption, but not rate of absorption). Therefore, all plasma concentration-time data were divided by the geometric least squares mean ratio of AUCinf fed:fasted (2.57) to predict concentrations when ivermectin is administered in the fasted state. Unbound plasma concentration-time data were predicted by multiplying the total concentration by the unbound fraction in plasma (0.068). The Cmax values for total plasma concentration were determined and multiplied by the lung homogenate:plasma ratio (2.67:1) in cattle reported by Lifschitz, Virkel (4) at each single dose to derive the Cmax values for total lung concentrations. The lung:plasma ratio after repeat dosing could not be determined without further modeling of the data from cattle. Some accumulation is expected in lung (but not plasma) with weekly or 3x weekly administration, but needs further investigation with more experimental data. A ball-park accumulation ratio (AR) in lung was calculated using Equation 1: = − − * This article is protected by copyright. All rights reserved The in vitro studies showing that ivermectin inhibited SARS-CoV-2 (1) were conducted at concentrations that were substantially higher than predicted plasma and lung concentrations in humans receiving the approved dose of ivermectin. Therefore, the likelihood of a successful clinical trial using the approved dose of ivermectin is low. If a clinical trial is conducted, a well-controlled dose-response study should be considered and the feasibility of ivermectin as an inhaled treatment should be evaluated. A first step would be to conduct the in vitro study reported by Caly, Druce (1) This article is protected by copyright. All rights reserved correlate with concentrations at the site of action or those expected based on ivermectin's large volume of distribution, concentrations of drug do not need to reach the IC50 for clinical benefit (i.e., the IC50 is not relevant), distribution into or retention in the lung tissue of humans is greater than in cattle, or that accumulation in lung tissue is much greater (>20fold) than expected after repeat dosing. Given that lung tissue:plasma concentration ratio in goats (3x at 2 and 7 days after oral administration) was similar to cattle and lung tissue:plasma concentration ratio in mice (1.4x 24 hours after oral administration) was slightly lower, excessive accumulation of ivermectin in human lungs is unlikely (11, 12) . If a clinical study is conducted with ivermectin, it would be important to conduct a well- have only been studied in small studies for serious infections where an unapproved subcutaneous formulation was used (13) . Therefore, if higher doses are studied weekly, if the approved dose is studied daily, or a parenteral formulation is used, subjects will need to be monitored closely. Ivermectin is extensively metabolized by CYP3A4 to numerous metabolites and is a substrate for P-glycoprotein. Less than 1% of the ivermectin dose is eliminated unchanged in the urine. Thus, any study would need to control for factors affecting variability in the exposure to ivermectin, including administering the dose in the fasted state and excluding P- This article is protected by copyright. All rights reserved glycoprotein and CYP3A4 inhibitors (2) , which could increase ivermectin exposure. The pharmacokinetics of ivermectin in elderly patients have not been reported. Theoretically, metabolism may decrease with age resulting in a higher exposure to ivermectin in elderly patients as well. Lastly, a potential longer-term solution would be to consider whether inhaled treatment with ivermectin is feasible. Inhaled treatment would allow for higher concentrations at the site of action while limiting the systemic exposure but may require further study of the safety and tolerability in animals prior to human exposure. Only one nonclinical study has been published on inhaled ivermectin in Sprague Dawley rats, in which the no-observed-adverseeffect level (NOAEL) after 28 days of inhaled ivermectin was identified to be 380 mg/m 3 (14) , and no studies using the inhaled route of administration have been identified in humans. Of key importance is determining whether ivermectin has general properties that would allow inhalation, with no local tolerability issues. Experts must, therefore, evaluate whether ivermectin possesses the ideal properties for inhalation, and whether inhalation of ivermectin poses any theoretical risks that might limit this route of administration. Overall, the results identified in the paper by Caly, Druce (1) create an opportunity for interdisciplinary collaboration in helping to understand the highest probability of success for ivermectin treatment, prior to exploration in clinical studies (or worse yet, off-label use by the general public) with a less-than-ideal dose. 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