The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) PK/PD Study Group has especially convened a group of clinical and PK/PD experts to provide guidance for all relevant drug therapies for infections caused by the SARS-COV-2 virus. The underlying presents guidance at a high level of detail on the key pharmacokinetic/pharmacodynamic characteristics of drugs at the current most commonly used antiviral regimens, clinically significant drug–drug interactions, and the effect of extracorporeal therapies (e.g. renal replacement therapy, extracorporeal membrane oxygenation) on dosing requirements. |
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1 Drugs Active Against SARS-CoV-2
2 Search Methodology
Substance generic name | Normal approved indication | Studied virus | Study phase for COVID-19 | Antiviral mode of action | Supplier/major countries where available | Currently used dose for approved indication (mg) | Adult dosing in COVID-19 (mg) | Child dosing in COVID-19 (mg) | Route of administrat-ion | Route of elimination |
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Remdesivir | Antiviral under investigation; FDA emergency use authorization to COVID-19 | COVID-19, MERS-CoV, SARS-CoV, HCoV-229E, HCoV-OC43 | Phase III/IV (NCT04292899; NCT04292730; NCT04280705; NCT04321616; NCT04315948) | Viral RNA polymerase inhibitor | Gilead® Europe USA | 200 mg on day 1, followed by 100 mg/day (total 10–14 days) | 200 mg on day 1 followed by 100 mg/day on days 2–10 | WT < 40 kg: 5 mg/kg load, then 2.5 mg/kg/24 h WT ≥ 40 kg: 200 mg load, then 100 mg/24 h [39] | IV | NA |
Chloroquine | Approved antimalarial; FDA emergency use authorization to COVID-19 | COVID-19, SARS-CoV, HCoV-OC43 | Cell cultures/co-cultures Phase III/IV (NCT04362332; NCT04331600; NCT04351191) | Inhibition of endosome-mediated viral entry, and pH-dependent steps in viral replication [40] | Sanofi-Aventis® Global | 100 mg/24 h | 600 mg/12 h on day 1, followed by 300 mg bid on days 2–5; alternative: 500 mg/12 h over 5 days [7] | NA | PO or IV | 50% renal clearance (excreted unchanged in the urine); metabolized by CYP2C8, CYP3A4 and, to lesser extent, CYP2D6 |
Lopinavir/ritonavir | Approved antiviral | COVID-19, MERS-CoV | Phase IV | HIV protease inhibitor/boost of other protease inhibitors | Abbott® Global | 400 mg/12 h + 100 mg/12 h | LPV/r 400/100 mg/12 h PO, 14 days [37] | (a) Age 14 days–12 months: 16 mg/4 mg (LPV/r)/kg/12 h (b) Age 12 months–18 years: (i) WT < 15 kg: 13 mg/3.25 mg (LPV/r)/kg/12 h; (ii) WT ≥ 15 to 40 kg: 11 mg/2.75 mg (LPV/r)/kg/12 h [41] | PO | LPV: metabolized by CYP3A Ritonavir: CYP3A4 and, to a lesser extent, CYP2D6 [42] |
Favipiravir | Approved antiviral | COVID-19 | Phase III (NCT04349241; NCT04356495; NCT04303299; NCT04373733; NCT04351295; NCT04361461; NCT04345419) | Viral RNA polymerase inhibitor | Fujifilm Toyama Chemical® China, Japan | 1600 mg/12 h on day 1 then 600 mg/12 h on days 2–5 | Under study | NA | PO; IV under development [43] | Genetic variant in digestive transport (Pgp; ABCB1) and metabolism (aldehyde oxydase) to an inactive M1, urinary excretion; both metabolized by and inhibited by aldehyde oxidase [43] |
Ribavirin | Approved antiviral | COVID-19 | Cell cultures/co-cultures; phase II (NCT04276688) | Unclear: multiple possible mechanisms | Generic Europe | 400–600 mg/12 h | 500 mg/12 h or 500 mg/8 h IV [44] | NA | Aerosol, PO or IV | Renal clearance (30%), some fecal excretion |
Arbidol/ Umifenovir | Approved antiviral | COVID-19 | Phase IV (NCT04350684; NCT04260594; NCT04286503) | Inhibits membrane fusion, stimulation of the immune system | Russian Research Chemical Pharmaceutical Institute Russia, China | 50–200 mg/6 h | 200 mg/8 h [44] | Safety unclear [45] | PO | Via the feces, metabolized in hepatic and intestinal microsomes (33 metabolites known), CYP3A4 [46] |
Hydroxychloroquine | Approved antimalarial; FDA emergency use authorization to COVID-19 | COVID-19 | Phase III/IV (NCT04261517; NCT04362332; NCT04334967; NCT04359615; NCT04316377) | Inhibition of endosome-mediated viral entry, and pH-dependent steps in viral replication [40] | Sanofi-Aventis® Europe | 100 mg/24 h | 400 mg/day for 5 days (NCT04261517) PO 400 mg/12 h on day 1 followed by 200 mg/12 h on days 2–5 [7] | NA | PO | 50% renal clearance (excreted unchanged in the urine); metabolized by CYP2C8, CYP3A4, and, to lesser extent, CYP2D6 |
PegIFN-α2β | Approved antiviral | COVID-19, MERS-CoV, HCoV | Phase IV (NCT04254874; NCT04291729) | Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms | – Europe | 1.5 μg/kg/week SC | 45–50 μg/12 h (NCT04254874;NCT04291729) | NA | Nebulized; SC | Renal clearance [47] |
IFN-α1β | Approved antiviral | COVID-19, MERS-CoV, HCoV | Early phase I (NCT04293887) | Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms | – China | – | 10 μg/12 h (NCT04293887) | NA | Nebulized | Renal clearance [47] |
IFN-α | Approved antiviral | COVID-19, MERS-CoV, HCoV | Not applicable (NCT04251871) [48] | Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms | – China | – | 5 million IU/12 h (NCT04251871) [48] | IFN-α 200,000– 400,000 IU/kg or 2–4 μg/kg in 2 mL sterile water, nebulization two times per day for 5–7 days [45] | Nebulized | Renal clearance [47] |
IFN-β1β | Approved antiviral | COVID-19, MERS-CoV, HCoV | Phase II (NCT04276688) | Adjuvant treatment: enhancement of phagocytic/cytotoxic mechanisms | – Europe, China | 25 μg SC injection alternate day | 25 μg SC injection alternate day for 3 days (NCT04276688) | SC | Renal clearance [47] | |
Camostat | Approved for chronic pancreatitis | COVID-19, MERS-CoV, SARS-CoV | Phase I/II/III (NCT04353284; NCT04321096; NCT04374019; NCT04355052) | Blocks interaction between the S1 protein and the SARS-CoV-2 target cell | Nichi Iko Japan | 200 mg/8 h | 200 mg/12 h or 8 h | NA | PO | Renal clearence [49] |
Nafamostat | Approved for pancreatitis | COVID-19, MERS-CoV, SARS-CoV | Phase II (NCT04352400) | Blocks the interaction between the S1 protein and the SARS-CoV-2 target cell | Nichi Iko Japan | 20–50 mg IV (prophylaxis of pancreatitis) [50] | NA | NA | IV | Renal clearence [51] |
Drug | PD metric (e.g. IC50) | Type of study used for COVID-19 experiments | EC50/EC90 for COVID-19 (μM) | EC50/EC90 for other indications | Blood concentrations |
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Remdesivir | EC50 | In vitro (vero E6 cells) | 0.77 [53] 23.15 [54] | 0.09 μM (MERS-CoV) in a mice model [55] | 10 μM in nonhuman primates was reached after a dose of 10 mg/kg IV [56] Note: treatment outcomes were no different from control patients hospitalized with COVID-19 [57] |
EC90 | In vitro (vero E6 cells) | 1.76 [53] | NA | ||
Chloroquine | EC50 | In vitro (vero E6 cells) | 1.13–7.36 | 0.05 μM (Plasmodium vivax) in vitro [58] 3.1 μM (HIV) in vitro [59] 3.0 μM (MERS-CoV) in vitro [60] 4.1 μM (SARS-CoV) in vitro [60] | A concentration of 6.9 μM is achievable in patients after a 500 mg dose [53, 61]; however, concentrations as low as 0.5–1.0 μM were also demonstrated after a 300 mg/12 h regimen (unpublished Data, Bruggemann on file). Note: higher adverse effects and lethality were found in patients with COVID-19 who received 600 mg/12 h for 10 days compared with 450 mg/12 h on day 1 and once daily between days 2 and 5 [10] and higher mortality in hospitalized patients [10, 11] |
EC90 | In vitro (vero E6 cells) | 6.9 [53] | 0.358 μM (P. vivax) in vitro at 30 h [58] | ||
Lopinavir/ritonavir | EC50 | In vitro (vero E6 cells) | LPV: 26.63 [54] | LPV: 17.1 μM (SARS-CoV) in vitro [60] Ritonavir: 24.9 μM (MERS-CoV) in a mice model [55] LPV/r: 8.5 μM (MERS-CoV) in a mice model [55] | LPV Cmax values average 12.72 μM (with p2.5 of 6.36 μM to p97.5 of 23.85 μM) and ritonavir Cmax values average 0.7 μM (with p2.5 of 0.2 μM to p97.5 of 2.22 μM) [62]. Note: treatment outcomes were no different from standard of care in hospitalized patients with COVID-19 [37]. LPV/r combined with ribarivin and interferon-β1β demonstrated better clinical and virological response than LPV/r alone in patients with mild to moderate disease [63] |
Favipiravir | IC50 | In vitro (vero E6 cells) | 61.88 [53] > 100 [54] | 67 μM for Ebola [64] | Concentrations of 1190 ± 478 μM were achieved 1 h after a favipiravir 400 mg loading dose in nonhuman primates [65]. Median total trough (predose) and average concentrations of 360 and 520 μM, respectively, following 1200 mg/12 h with a loading dose of 6000 mg in Ebola-infected patients [66], with a fall in average concentration on day 4. Non-linear PK Note: faster viral clearance and radiological improvement was reported in patients who received favipiravir when compared with LPV/r [67] |
Ribavirin | EC50 | In vitro (vero E6 cells) | 109.50 [53] > 100 [54] | 40.94 ± 12.17 μM (MERS-CoV) in vitro [17] | Concentration range between 25.0 and 10.65 μM achieved with a ribavirin dose regimen of 400–600 mg/12 h [68] |
Arbidol (Umifenovir) | EC50 | In vitro (vero E6 cells) | 4.11 uM (3.55–4.73) [69] | 24.72 μM (Avian infectious bronchitis virus as representative for Coronaviridae) [70] | Concentrations of 1.47, 2.60 and 4.53 μM achieved after 0.2, 0.4 and 0.8 g doses, respectively [71] Note: treatment outcomes were reported to be no different from standard of care (symptomatic and supportive treatment) in hospitalized patients with COVID-19 in a retrospective cohort [72] |
Hydroxychloroquine | EC50 | In vitro (vero E6 cells) | 0.72 μM [7] (outlying value) 4.51–12.96 [9] | Concentration > 1.49 μM (> 500 ng/ml) achievable following a 6 mg/kg/day dosing regimen [73] | |
Concentration shown to reduce viral titers | 80 μM (Zika virus) in vitro [74] | ||||
PegIFN-α2β | EC50 | NA | NA | 0.04 μg/L (HCV patients) [6] | Cmax of 0.53 μg/L in patients after 1.5 μg/kg SC [75] |
IFN-β1β | EC50 | NA | NA | Concentration of 240 UI/ml following 8 million IU SC [77] | |
IFN-β1β | EC90 | NA | NA | 38.8 U/ml (MERS-CoV) [76] | |
Camostat | EC50 | In vitro (Calu-3 cells) | 0.444 uM (MERS-CoV) [79] | Concentration of 589 uM was achieved 12 h after Camostat 40 mg IV administration in humans [49] | |
EC90 | In vitro (Calu-3 cells) | 5 [78] | 5 uM (SARS-CoV; MERS-CoV) [78] | ||
Nafamostat | EC50 | In vitro (Calu-3 cells) | 0.005 [79] | 0.0059 uM (MERS-CoV) [79] 0.0014 uM (SARS-CoV) [79] | Concentrations of 41, 116 and 174 uM after doses of 10, 20 and 40 IV, respectively [80] |
Proposed combination (with clinical trial reference if available) | Pharmacodynamic rationale | Drug–drug interactions with level of severity and therapeutic advice [81] | Level of evidence: 1. Clinical trial in coronavirus 2. Retrospective clinical data 3. In vivo animal or in vitro data |
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Ribavirin + LPV/r [82] | Inhibition of replication PLUS inhibition of RNA synthesis | Increased risk of liver toxicity Level of severity: major Therapeutic advice: monitor for increased liver toxicity | 1. Clinical trials: No data 2. Retrospective clinical data : (a) Retrospective matched cohort study for SARS-CoV infection: 41 cases treated with LPV/r + ribavirin vs. 111 historical controls treated with ribavirin alone; better clinical outcome (ARDS and death) at day 21 after onset of symptoms: 2.4% vs. 28.8%; p < 0.001. No difference in outcome reported for early vs. delayed treatment [15] (b) Multicenter retrospective matched cohort study for SARS-CoV infection: 75 cases treated with LPV/r + ribavirin vs. 977 controls treated with ribavirin. Reduction in death (2.3% vs. 15.6%; p < 0.05) and intubation (0% vs. 11%; p < 0.05) was evident only in the subgroup of initial treatment with LPV/r; no significant difference in the late treatment group [38] (c) MERS-CoV infection: post-exposure prophylaxis with ribavirin + LPV/r in 43 healthcare workers resulted in a 40% reduction in the risk of MERS-CoV infection, with no severe adverse events during treatment [83] 3. In vivo animal or in vitro data: |
LPV/r + Arbidol [82] | Inhibition of replication PLUS inhibition of RNA synthesis PLUS inhibition of viral entry | No clinical data available CYP3A4 is major pathway of metabolism for arbidol; strong inhibition of CYP3A4-mediated metabolism of arbidol by ritonavir is plausible Level of severity: Unknown Therapeutic advice: Monitor for increased toxicity of arbidol [70] | 1. Clinical trials: No data 2. Retrospective clinical data: Case series (n = 4) of mild or severe COVID-19 pneumonia successfully treated with LPV/r + arbidol + Shufeng Jiedo Capsule (traditional Chinese medicine) [85, 86] 3. In vivo animal or in vitro data: No data |
Chloroquine + LPV/r | Inhibition of replication PLUS inhibition of viral entry | Increased risk of QTc prolongation (potentially dangerous interaction) Inhibition of CYP3A-mediated metabolism of chloroquine by ritonavir Level of severity: Major Therapeutic advice: Monitor ECG and monitor for increased toxicity of chloroquine if used in combination. Dose reduction of chloroquine might be necessary in case of severe toxicity | 1. Clinical trials: No data, but ongoing open-label study currently being undertaken in China (ChiCTR2000029741) [87] 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data |
Emtricitabine + tenofovir (Truvada) | Inhibition of RNA synthesis (dual therapy) | No data | 1. Clinical trials: No data 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data |
Favipiravir + interferon | Inhibition RNA synthesis PLUS immune modulation | No data | 1. Clinical trials: Open-label, nonrandomized, comparative controlled study in 80 patients with SARS-CoV-2 infection. Thirty-five patients were treated with FPV plus inhaled IFN-α. Forty-five historic controls received LPV/r plus inhaled IFN-α. Treatment with FPV/IFN led to shorter viral clearance time and improvement in chest imaging at D14. Fewer adverse events were found in the FPV/IFN arm [67] 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data |
Emtricitabine + tenofovir (Truvada) + LPV/r [88] | Inhibition of replication PLUS inhibition of RNA synthesis | Increased tenofovir absorption (i.e. 32% AUC increase; 51% Cmin increase) through P-glycoprotein inhibition Level of severity: Moderate Therapeutic advice: Monitor for tenofovir-associated toxicity | 1. Clinical trials: No data 2. Retrospective clinical data: No data 3. In vivo animal or in vitro data: No data |
Interferon + ribavirin | Immune modulation PLUS inhibition of RNA synthesis | No data | 1. Clinical trials: Ongoing open-label, single-center, prospective, randomized controlled clinical trial in China comparing LPV/r plus IFN-α vs. ribavirin plus IFN-α, vs. LPV/r plus IFN-α plus ribavirin [89] 2. Retrospective clinical data: (a) Multicenter observational study in critically ill patients with MERS-CoV infection. Of 349 MERS-CoV-infected patients, 144 received RBV/rIFN (rIFN-α2a, rIFN-α2b or rIFN-ß1a). Treatment was not associated with a reduction in 90-day mortality or faster MERS-CoV RNA clearance [90] b. Retrospective cohort study of patients with MERS-CoV requiring ventilation support who received supportive care (n = 24) vs. oral ribavirin + pegylated IFN-α2a (n = 20). Treatment with ribavirin + IFN-α2a was associated with significantly improved survival at 14 days, but not at 28 days [91] |
LPV/r + interferon + ribavirin | Immune modulation PLUS inhibition of RNA synthesis PLUS inhibition of replication | Level of severity: Major Therapeutic advice: Monitor for increased risk for hepatotoxicity (for combination protease inhibitor + ribavirin and protease inhibitor + interferon) | 1. Clinical trials: One open-label, randomized, multicenter, phase II trial in Hong Kong in 127 patients with confirmed SARS-CoV2 infection. Eighty-six patients received LPV/r + interferon-β1b + ribavirin combination treatment, and 41 received LPV/r alone. The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab, and shorter duration of hospitalization than the control group [63] Ongoing open-label, single-center, prospective, randomized controlled clinical trial in China comparing LPV/r plus IFN-α vs. ribavirin plus IFN-α, vs. LPV/r plus IFN-α plus ribavirin [89] 2. Retrospective clinical data: Two case reports, one patient recovered, one patient died during hospital stay due to septic shock [94, 95] 3. In vivo animal or in vitro data: No data |
Hydroxychloroquine + azithromycin | Immune modulation PLUS inhibition of viral entry | Increased risk of QTc prolongation (potentially dangerous interaction) Level of severity: Major Therapeutic advice: Monitor ECG | 1. Clinical trials: One open-label, non-randomized clinical study in 36 patients with confirmed SARS-CoV2 infection (interim analysis of ongoing trial) [96]. Of 36 patients, 14 received hydroxychloroquine treatment, 6 received hydroxychloroquine/azithromycin combination treatment and 16 were controls. The proportion of patients with negative PCR in nasopharyngeal samples was significantly higher in hydroxychloroquine-treated patients at days 3–6 post-inclusion vs. control patients. If hydroxychloroquine was used in combination with azithromycin, the proportion of patients with negative PCR in nasopharyngeal samples was significantly higher on days 3–6 when compared with patients treated with hydroxychloroquine monotherapy. One open-label, non-randomized clinical study in 80 patients with confirmed SARS-CoV2 infection [97]. Of 80 patients, all expect 2 improved clinically. A rapid fall in nasopharyngeal viral load was observed, with 83% negative at day 7, and 93% at day 8 2. Retrospective clinical data: One retrospective cohort study of 1438 patients hospitalized for COVID-19 in 25 hospitals in metropolitan New York. 735 patients received hydroxychloroquine + azithromycin, 211 received azithromycin alone, 271 received hydroxychloroquine alone, and 221 received neither drug [98] There we no differences in hospital mortality between different treatments One retrospective study of 1061 confirmed SARS-CoV2 patients treated with hydroxychloroquine + azithromycin for at least 3 days in Marseille, France. Good clinical and virological cure was obtained in 973 (91.7%) patients within 10 days [99] Retrospective electronic case record review of 96,032 hospitalized patients. Multivariable Cox proportional hazard model with matched case–control analysis found hydroxychloroquine plus a macrolide resulted in 23.8% mortality vs. 9.3% in controls. Significantly higher mortality was seen with hydroxychloroquine, or chloroquine alone and chloroquine plus macrolide vs. control [11] 3. In vivo animal or in vitro data: No effect of hydroxychloroquine, with or without azithromycin, on viral load in either treatment or prophylaxis in a non-human primate model [100] |
Name of antiviral | Effects on pharmacokinetic parameters | Protein binding (%) | ||
---|---|---|---|---|
RRT | ECMO | Extracorporeal systemic inflammatory responsea | ||
Remdesivir | NA | NA | NA | NA |
Chloroquine | – | Likelyb | Alterations in cytochrome metabolism | |
Lopinavir | – | Likelyb | Alterations in cytochrome metabolism | 98–99 [101] |
Ritonavir | – | Likelyb | Alterations in cytochrome metabolism | 99 [102] |
Favipiravir | – | Increases Vd | Alterations in cytochrome metabolism | 54 [32] |
Ribavirin | – | Increases Vd | – | 0 [26] |
Arbidol (Umifenovir) | – | – | Alterations in cytochrome metabolism | NA |
Hydroxychloroquine | – | Likelyb | Alterations in cytochrome metabolism | |
PegIFN-α2β | – | – | – | NA |
IFN-α1β | – | – | – | NA |
IFN-α | – | – | – | NA |
3 List of experimental antiviral agents explored for treatment of Covid 19
3.1 Antiviral Agents for the Treatment of COVID-19
3.2 Pharmacokinetics/Pharmacodynamics (PK/PD) of Antiviral Agents for the Treatment of COVID-19
3.3 Combination SARS-CoV-2 Antiviral Agents and Associated Drug–Drug Interactions
3.4 Most Commonly Used Supportive Agents (Intensive Care Unit, Pain, Fever, Anticoagulation)
3.5 Interaction Between Antivirals and Supportive Drugs
3.6 The Effect of Extracorporeal Treatments on the PK of COVID-19 Therapies
3.7 The Impact of Extracorporeal Membrane Oxygenation
3.8 The Impact of Renal Replacement Therapy
3.9 PK Data of Drugs Active Against SARS-CoV-2
4 Discussion
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When is the optimal time point to start antiviral therapy, what is the required duration, and when is it too late to initiate treatment?
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In line with the open questions regarding dexamethasone, when is it time to start anti-inflammatory drugs and which biomarkers can we use to tailor this therapy?
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What role can the individualization of therapy based on dose adaption and therapeutic drug monitoring (TDM) play in the treatment of COVID-19?