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1.
Clin Infect Dis ; 2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1852997

ABSTRACT

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at sites of SARS-CoV-2 transmission in twelve patients enrolled in AGILE CST-2 (NCT04746183). Saliva, nasal and tear concentrations were 3, 21 and 22% that of plasma. Saliva and nasal NHC concentrations were significantly correlated with plasma (p<0.0001).

2.
Clin Pharmacol Ther ; 2022 May 14.
Article in English | MEDLINE | ID: covidwho-1843877

ABSTRACT

The coronavirus disease 2019 (COVID-19) antiviral nirmatrelvir/ritonavir (Paxlovid) has been granted authorization or approval in several countries for the treatment of patients with mild to moderate COVID-19 at high risk of progression to severe disease and with no requirement for supplemental oxygen. Nirmatrelvir/ritonavir will be primarily administered outside the hospital setting as a 5-day course oral treatment. The ritonavir component boosts plasma concentrations of nirmatrelvir through the potent and rapid inhibition of the key drug-metabolizing enzyme cytochrome P450 (CYP) 3A4. Thus nirmatrelvir/ritonavir, even given as a short treatment course, has a high potential to cause harm from drug-drug interactions (DDIs) with other drugs metabolized through this pathway. Options for mitigating risk from DDIs with nirmatrelvir/ritonavir are limited due to the clinical illness, the short window for intervention, and the related difficulty of implementing clinical monitoring or dosage adjustment of the comedication. Pragmatic options are largely confined to preemptive or symptom-driven pausing of the comedication or managing any additional risk through counseling. This review summarizes the effects of ritonavir on drug disposition (i.e., metabolizing enzymes and transporters) and discusses factors determining the likelihood of having a clinically significant DDI. Furthermore, it provides a comprehensive list of comedications likely to be used in COVID-19 patients which are categorized according to their potential DDI risk with nirmatrelvir/ritonavir. It also discusses recommendations for the management of DDIs which balance the risk of harm from DDIs with a short course of ritonavir, against unnecessary denial of nirmatrelvir/ritonavir treatment.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-311524

ABSTRACT

Background: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. Methods: /Design: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. Discussion: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tociluzimab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. Trial registrations: EudraCT Number: 2020-001860-27 14th March 2020 ClinicalTrials.gov Identifier: NCT04746183ISRCTN reference: 27106947

5.
Front Pharmacol ; 13: 814134, 2022.
Article in English | MEDLINE | ID: covidwho-1686524

ABSTRACT

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%-60%) and the plasma concentrations increased (170%-400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

6.
Lancet Glob Health ; 10(3): e331, 2022 03.
Article in English | MEDLINE | ID: covidwho-1683796
7.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296663

ABSTRACT

ABSTRACT Background Molnupiravir, an orally administered prodrug of the broadly active, direct-acting antiviral, ribonucleoside analogue ß-d-N4-hydroxycytidine (NHC) is a promising COVID-19 drug candidate. We characterised the pharmacokinetics of NHC in saliva, nasal secretions and tears of patients enrolled in the phase I AGILE trial ( NCT04746183 ) to understand its potential in preventing infection and transmission. Methods Patients with PCR-confirmed SARS-CoV-2 infection, within 5 days of symptom onset with mild-to-moderate disease were randomised to oral molnupiravir 300, 600 or 800 mg twice daily or placebo. Plasma and non-plasma (saliva, nasal secretions and tears) samples were collected at pre-dose, 0.5, 1, 2, and 4 hours post-dose on study days 1 and 5 and molnupiravir and NHC measured by LC/MS with a lower limit of quantification of 2.5 ng/mL in all matrices. Pharmacokinetic parameters were determined by noncompartmental methods and non-plasma:plasma ratios (R NP:P ;based on AUC 0-4 ) calculated. Results Twelve participants (n=4 per dosing arm;75% female) completed the study. NHC T max ranged between 1.00-4.00 hours for saliva (n=21) and nasal swabs (n=22) and 0.50-4.00 hours (n=17) for tears compared to 1.00-2.00 hours for plasma (n=19). Median (range) saliva R NP:P pooled across doses was 0.03 (0.01-0.11);n=16. R NP:P for nasal secretions and tears were 0.21 (0.05-0.73);n=17 and 0.22 (0.09-1.05);n=12, respectively. Non-plasma and plasma concentrations were significantly correlated ( p <0.0001). Conclusion These data provide encouraging information regarding the distribution of NHC at sites of viral transmission and have important implications for prophylactic coverage.

8.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295759

ABSTRACT

Synopsis Background The UK Medicines and Regulatory Healthcare Agency (MHRA) have recently licensed the anti-viral drug, molnupiravir, for use in patients with mild-moderate COVID-19 disease with one or more risk factors for serious illness. Treatment with anti-viral drugs is best initiated early to prevent progression to severe disease, although the therapeutic window for intervention has not yet been fully defined. Objectives This study aimed to determine the activity of the molnupiravir (NHC) to different SARS-CoV-2 Variants of Concern (VoCs), and to establish the therapeutic window in human lung cell model. Methods Dose response assays were performed in parallel to determine the IC50 (the concentration of drug required to inhibit virus titre by 50%) of NHC against different variants. Human ACE-2 A549 cells were treated with NHC at different time points either before, during or after infection with SARS- CoV-2. Results Here we demonstrate that ß-D-N4-hydroxycytidine (NHC), the active metabolite of molnupiravir, has equivalent activity against four variants of SARS-CoV-2 in a human lung cell line ranging 0.04-0.16µM IC50. Furthermore, we demonstrate that in-vitro activity of the drug is reduced in cells exposed to drug 48 hours after infection. Conclusions One of the main advantages of molnupiravir is that it can be administered orally, and thus given to patients in an out-patient setting. These results support giving the drug early on after diagnosis or even in prophylaxis for individuals with high risk of developing severe disease.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293082

ABSTRACT

Background: The UK Medicines and Regulatory Healthcare Agency (MHRA) have recently licensed the anti-viral drug, molnupiravir, for use in patients with mild-moderate COVID-19 disease with one or more risk factors for serious illness. Treatment with anti-viral drugs is best initiated early to prevent progression to severe disease, although the therapeutic window for intervention has not yet been fully defined. Objectives: This study aimed to determine the activity of the molnupiravir parent drug (NHC) to different SARS-CoV-2 Variants of Concern (VoCs), and to establish the therapeutic window in human lung cell model. Methods: Dose response assays were performed in parallel to determine the IC50 (the concentration of drug required to inhibit virus titre by 50%) of NHC against different variants. Human ACE-2 A549 cells were treated with NHC at different time points either before, during or after infection with SARS-CoV-2. Results: Here we demonstrate that β-D-N4-hydroxycytidine (NHC), the active metabolite of molnupiravir, has equivalent activity against four variants of SARS-CoV-2 in a human lung cell line ranging 0.04-0.16μM IC50. Furthermore, we demonstrate that activity of the drug begins to drop after 48 hours post-infection. Conclusions: One of the main advantages of molnupiravir is that it can be administered orally, and thus given to patients in an out-patient setting. These results support giving the drug early on after diagnosis or even in prophylaxis for individuals with high risk of developing severe disease.

10.
Clin Pharmacol Ther ; 111(3): 585-594, 2022 03.
Article in English | MEDLINE | ID: covidwho-1482119

ABSTRACT

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , Nitro Compounds/administration & dosage , Nitro Compounds/adverse effects , Nitro Compounds/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Drug Repositioning , Female , Healthy Volunteers , Humans , Male , Middle Aged , Young Adult
11.
J Pharm Biomed Anal ; 206: 114356, 2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1386097

ABSTRACT

In light of the recent global pandemic, Molnupiravir (MPV) or EIDD-2801, developed for the treatment of patients with uncomplicated influenza, is now being trialled for the treatment of infections caused by highly pathogenic coronaviruses, including COVID-19. A sensitive LC-MS/MS method was developed and validated for the simultaneous quantification of MPV and its metabolite ß-d-N4-hydroxycytidine (NHC) in human plasma and saliva. The analytes were extracted from the matrices by protein precipitation using acetonitrile. This was followed by drying and subsequently injecting the reconstituted solutions onto the column. Chromatographic separation was achieved using a polar Atlantis C18 column with gradient elution of 1 mM Ammonium acetate in water (pH4.3) and 1 mM Ammonium acetate in acetonitrile. Analyte detection was conducted in negative ionisation mode using SRM. Analysis was performed using stable isotopically labelled (SIL) internal standards (IS). The m/z transitions were: MPV (328.1→126.0), NHC (258.0→125.9) and MPV-SIL (331.0→129.0), NHC-SIL (260.9→128.9). Validation was over a linear range of 2.5-5000 ng/ml for both plasma and saliva. Across four different concentrations, precision and accuracy (intra- and inter-day) were 15%; and recovery of both analytes from plasma and saliva was between 95% and 100% and 65-86% respectively. Clinical pharmacokinetic studies are underway utilising this method for determination of MPV and its metabolite in patients with COVID-19 infection.


Subject(s)
COVID-19 , Saliva , Chromatography, Liquid , Cytidine/analogs & derivatives , Humans , Hydroxylamines , Reproducibility of Results , SARS-CoV-2 , Tandem Mass Spectrometry
12.
Clin Pharmacol Ther ; 108(4): 775-790, 2020 10.
Article in English | MEDLINE | ID: covidwho-1384148

ABSTRACT

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.


Subject(s)
Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Delivery Systems/methods , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , Antiviral Agents/blood , COVID-19 , Coronavirus Infections/blood , Humans , Pandemics , Pneumonia, Viral/blood , SARS-CoV-2
13.
J Antimicrob Chemother ; 76(12): 3286-3295, 2021 11 12.
Article in English | MEDLINE | ID: covidwho-1376308

ABSTRACT

OBJECTIVES: AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. METHODS: We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. RESULTS: Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. CONCLUSIONS: Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Bayes Theorem , Humans , Research Design , Treatment Outcome
14.
Trials ; 21(1): 544, 2020 Jun 19.
Article in English | MEDLINE | ID: covidwho-1331953

ABSTRACT

OBJECTIVES: Phase I - To determine the optimal dose of each candidate (or combination of candidates) entered into the platform. Phase II - To determine the efficacy and safety of each candidate entered into the platform, compared to the current Standard of Care (SoC), and recommend whether it should be evaluated further in a later phase II & III platforms. TRIAL DESIGN: AGILE-ACCORD is a Bayesian multicentre, multi-arm, multi-dose, multi-stage open-label, adaptive, seamless phase I/II randomised platform trial to determine the optimal dose, activity and safety of multiple candidate agents for the treatment of COVID-19. Designed as a master protocol with each candidate being evaluated within its own sub-protocol (Candidate Specific Trial (CST) protocol), randomising between candidate and SoC with 2:1 allocation in favour of the candidate (N.B the first candidate has gone through regulatory approval and is expected to open to recruitment early summer 2020). Each dose will be assessed for safety sequentially in cohorts of 6 patients. Once a phase II dose has been identified we will assess efficacy by seamlessly expanding into a larger cohort. PARTICIPANTS: Patient populations can vary between CSTs, but the main eligibility criteria include adult patients (≥18 years) who have laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We will include both severe and mild-moderate patients defined as follows: Group A (severe disease) - patients with WHO Working Group on the Clinical Characteristics of COVID-19 infection 9-point ordinal scale of Grades 4 (hospitalised, oxygen by mask or nasal prongs), 5 (hospitalised, non-invasive ventilation or high flow oxygen), 6 (hospitalised, intubation and mechanical ventilation) or 7 (hospitalised, ventilation and additional organ support); Group B (mild-moderate disease) - ambulant or hospitalised patients with peripheral capillary oxygen saturation (SpO2) >94% RA. If any CSTs are included in the community setting, the CST protocol will clarify whether patients with suspected SARS-CoV-2 infection are also eligible. Participants will be recruited from England, North Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is the current standard of care (SoC), in some CSTs plus placebo. Candidates that prevent uncontrolled cytokine release, prevention of viral replication, and other anti-viral treatment strategies are at various stages of development for inclusion into AGILE-ACCORD. Other CSTs will be added over time. There is not a set limit on the number of CSTs we can include within the AGILE-ACCORD Master protocol and we will upload each CST into this publication as each opens to recruitment. MAIN OUTCOMES: Phase I: Dose limiting toxicities using Common Terminology Criteria for Adverse Events v5 Grade ≥3 adverse events. Phase II: Agreed on a CST basis depending on mechanism of action of the candidate and patient population. But may include; time to clinical improvement of at least 2 points on the WHO 9-point category ordinal scale [measured up to 29 days from randomisation], progression of disease (oxygen saturation (SaO2) <92%) or hospitalization or death, or change in time-weighted viral load [measured up to 29 days from randomisation]. RANDOMISATION: Varies with CST, but default is 2:1 allocation in favour of the candidate to maximise early safety data. BLINDING (MASKING): For the safety phase open-label although for some CSTs may include placebo or SoC for the efficacy phase. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Varies between CSTs. However simulations have shown that around 16 participants are necessary to determine futility or promise of a candidate at a given dose (in efficacy evaluation alone) and between 32 and 40 participants are required across the dose-finding and efficacy evaluation when capping the maximum number of participants contributing to the evaluation of a treatment at 40. TRIAL STATUS: Master protocol version number v5 07 May 2020, trial is in setup with full regulatory approval and utilises several digital technology solutions, including Medidata's Rave EDC [electronic data capture], RTSM for randomisation and patient eConsent on iPads via Rave Patient Cloud. The recruitment dates will vary between CSTs but at the time of writing no CSTs are yet open for recruitment. TRIAL REGISTRATION: EudraCT 2020-001860-27 14th March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Randomized Controlled Trials as Topic , Antiviral Agents/adverse effects , COVID-19 , Humans , Pandemics , SARS-CoV-2
15.
Trials ; 22(1): 487, 2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1327946

ABSTRACT

BACKGROUND: There is an urgent unmet clinical need for the identification of novel therapeutics for the treatment of COVID-19. A number of COVID-19 late phase trial platforms have been developed to investigate (often repurposed) drugs both in the UK and globally (e.g. RECOVERY led by the University of Oxford and SOLIDARITY led by WHO). There is a pressing need to investigate novel candidates within early phase trial platforms, from which promising candidates can feed into established later phase platforms. AGILE grew from a UK-wide collaboration to undertake early stage clinical evaluation of candidates for SARS-CoV-2 infection to accelerate national and global healthcare interventions. METHODS/DESIGN: AGILE is a seamless phase I/IIa platform study to establish the optimum dose, determine the activity and safety of each candidate and recommend whether it should be evaluated further. Each candidate is evaluated in its own trial, either as an open label single arm healthy volunteer study or in patients, randomising between candidate and control usually in a 2:1 allocation in favour of the candidate. Each dose is assessed sequentially for safety usually in cohorts of 6 patients. Once a phase II dose has been identified, efficacy is assessed by seamlessly expanding into a larger cohort. AGILE is completely flexible in that the core design in the master protocol can be adapted for each candidate based on prior knowledge of the candidate (i.e. population, primary endpoint and sample size can be amended). This information is detailed in each candidate specific trial protocol of the master protocol. DISCUSSION: Few approved treatments for COVID-19 are available such as dexamethasone, remdesivir and tocilizumab in hospitalised patients. The AGILE platform aims to rapidly identify new efficacious and safe treatments to help end the current global COVID-19 pandemic. We currently have three candidate specific trials within this platform study that are open to recruitment. TRIAL REGISTRATION: EudraCT Number: 2020-001860-27 14 March 2020 ClinicalTrials.gov Identifier: NCT04746183  19 February 2021 ISRCTN reference: 27106947.


Subject(s)
COVID-19 , Pandemics , Cohort Studies , Humans , SARS-CoV-2 , Treatment Outcome
16.
J Antimicrob Chemother ; 76(9): 2230-2233, 2021 08 12.
Article in English | MEDLINE | ID: covidwho-1276183

ABSTRACT

This article provides a brief overview of drug resistance to antiviral therapy as well as known and emergent variability in key SARS-CoV-2 viral sequences. The purpose is to stimulate deliberation about the need to consider drug resistance prior to widespread roll-out of antivirals for SARS-CoV-2. Many existing candidate agents have mechanisms of action involving drug targets likely to be critical for future drug development. Resistance emerged quickly with monotherapies deployed for other pulmonary viruses such as influenza virus, and in HIV mutations in key drug targets compromised efficacy of multiple drugs within a class. The potential for drug resistance in SARS-CoV-2 has not yet been rigorously debated or assessed, and we call for more academic and industry research on this potentially important future threat prior to widespread roll-out of monotherapies for COVID-19 treatment and prevention.


Subject(s)
COVID-19 , Coronavirus Infections , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Drug Resistance, Viral , Humans , SARS-CoV-2
17.
J Antimicrob Chemother ; 76(8): 2121-2128, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1254771

ABSTRACT

OBJECTIVES: Favipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5'-triphosphate (FAVI-RTP)]. METHODS: Published in vitro data for intracellular production and elimination of FAVI-RTP in Madin-Darby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions. RESULTS: Parameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of ∼1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of ∼2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. CONCLUSIONS: Population mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9 days with a 1200 mg twice-daily regimen (following a 1600 mg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.


Subject(s)
COVID-19 , SARS-CoV-2 , Amides , Animals , Antiviral Agents/therapeutic use , Dogs , Humans , Polyphosphates , Pyrazines
18.
Drugs R D ; 21(1): 9-27, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-986820

ABSTRACT

INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Drug Repositioning/methods , Kidney Diseases/drug therapy , Liver Diseases/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Alanine/administration & dosage , Alanine/analogs & derivatives , COVID-19/diagnosis , COVID-19/epidemiology , Clinical Trials as Topic/methods , Dexamethasone/administration & dosage , Dose-Response Relationship, Drug , Humans , Hydroxychloroquine/administration & dosage , Kidney Diseases/diagnosis , Kidney Diseases/epidemiology , Liver Diseases/diagnosis , Liver Diseases/epidemiology
19.
Trials ; 21(1): 935, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-934299

ABSTRACT

OBJECTIVES: The GETAFIX trial will test the hypothesis that favipiravir is a more effective treatment for COVID-19 infection in patients who have early stage disease, compared to current standard of care. This study will also provide an important opportunity to investigate the safety and tolerability of favipiravir, the pharmacokinetic and pharmacodynamic profile of this drug and mechanisms of resistance in the context of COVID-19 infection, as well as the effect of favipiravir on hospitalisation duration and the post COVID-19 health and psycho-social wellbeing of patients recruited to the study. TRIAL DESIGN: GETAFIX is an open label, parallel group, two arm phase II/III randomised trial with 1:1 treatment allocation ratio. Patients will be randomised to one of two arms and the primary endpoint will assess the superiority of favipiravir plus standard treatment compared to standard treatment alone. PARTICIPANTS: This trial will recruit adult patients with confirmed positive valid COVID-19 test, who are not pregnant or breastfeeding and have no prior major co-morbidities. This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. Patients must meet all of the following criteria: 1. Age 16 or over at time of consent 2. Exhibiting symptoms associated with COVID-19 3. Positive for SARS-CoV-2 on valid COVID-19 test 4. Point 1, 2, 3, or 4 on the WHO COVID-19 ordinal severity scale at time of randomisation. (Asymptomatic with positive valid COVID-19 test, Symptomatic Independent, Symptomatic assistance needed, Hospitalized, with no oxygen therapy) 5. Have >=10% risk of death should they be admitted to hospital as defined by the ISARIC4C risk index: https://isaric4c.net/risk 6. Able to provide written informed consent 7. Negative pregnancy test (women of childbearing potential*) 8. Able to swallow oral medication Patients will be excluded from the trial if they meet any of the following criteria: 1. Renal impairment requiring, or likely to require, dialysis or haemofiltration 2. Pregnant or breastfeeding 3. Of child bearing potential (women), or with female partners of child bearing potential (men) who do not agree to use adequate contraceptive measures for the duration of the study and for 3 months after the completion of study treatment 4. History of hereditary xanthinuria 5. Other patients judged unsuitable by the Principal Investigator or sub-Investigator 6. Known hypersensitivity to favipiravir, its metabolites or any excipients 7. Severe co-morbidities including: patients with severe hepatic impairment, defined as: • greater than Child-Pugh grade A • AST or ALT > 5 x ULN • AST or ALT >3 x ULN and Total Bilirubin > 2xULN 8. More than 96 hours since first positive COVID-19 test sample was taken 9. Unable to discontinue contra-indicated concomitant medications This is a multi-centre trial, patients will be recruited from in-patients and outpatients from three Glasgow hospitals: Royal Alexandra Hospital; Queen Elizabeth University Hospital; and the Glasgow Royal Infirmary. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm of GETAFIX will receive standard treatment for COVID-19 at the discretion of the treating clinician plus favipiravir. These patients will receive a loading dose of favipiravir on day 1 of 3600mg (1800mg 12 hours apart). On days 2-10, patients in the experimental arm will receive a maintenance dose of favipiravir of 800mg 12 hours apart (total of 18 doses). Patients randomised to the control arm of the GETAFIX trial will receive standard treatment for COVID-19 at the discretion of the treating clinician. MAIN OUTCOMES: The primary outcome being assessed in the GETAFIX trial is the efficacy of favipiravir in addition to standard treatment in patients with COVID-19 in reducing the severity of disease compared to standard treatment alone. Disease severity will be assessed using WHO COVID 10 point ordinal severity scale at day 15 +/- 48 hours. All randomised participants will be followed up until death or 60 days post-randomisation (whichever is sooner). RANDOMISATION: Patients will be randomised 1:1 to the experimental versus control arm using computer generated random sequence allocation. A minimisation algorithm incorporating a random component will be used to allocate patients. The factors used in the minimisation will be: site, age (16-50/51-70/71+), history of hypertension or currently obsess (BMI>30 or obesity clinically evident; yes/no), 7 days duration of symptoms (yes/no/unknown), sex (male/female), WHO COVID-19 ordinal severity score at baseline (1/2or 3/4). BLINDING (MASKING): No blinding will be used in the GETAFIX trial. Both participants and those assessing outcomes will be aware of treatment allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In total, 302 patients will be randomised to the GETAFIX trial: 151 to the control arm and 151 to the experimental arm. There will be an optional consent form for patients who may want to contribute to more frequent PK and PD sampling. The maximum number of patients who will undergo this testing will be sixteen, eight males and eight females. This option will be offered to all patients who are being treated in hospital at the time of taking informed consent, however only patients in the experimental arm of the trial will be able to undergo this testing. TRIAL STATUS: The current GETAFIX protocol is version 4.0 12th September 2020. GETAFIX opened to recruitment on 26th October 2020 and will recruit patients over a period of approximately six months. TRIAL REGISTRATION: GETAFIX was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT) Database on 15th April 2020; Reference number 2020-001904-41 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001904-41/GB ). GETAFIX was registered on ISRCTN on 7th September 2020; Reference number ISRCTN31062548 ( https://www.isrctn.com/ISRCTN31062548 ). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (see Additional file 2).


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Pyrazines/therapeutic use , Adult , Amides/administration & dosage , Amides/pharmacokinetics , Amides/pharmacology , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , COVID-19 , Case-Control Studies , Coronavirus Infections/classification , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Female , Hospitalization , Humans , Male , Pandemics/classification , Pneumonia, Viral/classification , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Pyrazines/administration & dosage , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , SARS-CoV-2 , Safety , Scotland/epidemiology , Severity of Illness Index , Treatment Outcome
20.
Br J Clin Pharmacol ; 87(4): 2078-2088, 2021 04.
Article in English | MEDLINE | ID: covidwho-883246

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug, has been shown to exhibit in vitro activity against SARS-CoV-2. The present study used physiologically based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS-CoV-2 EC90 . METHODS: A whole-body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500 and 4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. RESULTS: The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID and 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12 hours post dose was estimated. CONCLUSION: The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS-CoV-2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , COVID-19/prevention & control , Drug Repositioning , Models, Biological , Nitro Compounds/administration & dosage , Thiazoles/administration & dosage , Adult , Antiviral Agents/blood , Antiviral Agents/pharmacokinetics , COVID-19/blood , Computer Simulation , Drug Dosage Calculations , Female , Humans , Lung/metabolism , Male , Middle Aged , Nitro Compounds/blood , Nitro Compounds/pharmacokinetics , Reproducibility of Results , Thiazoles/blood , Thiazoles/pharmacokinetics , Tissue Distribution , Young Adult
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