Antimicrobial Agents and Chemotherapy

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe 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 an FDA approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modelling has indicated may provide antiviral concentrations across the dosing ...

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death from severe disease in non-hospitalized high-risk patients with mild-to-moderate COVID-19 following either intravenous (IV) or intramuscular (IM) administration. Population pharmacokinetic (popPK) and exposure-response (ER) analyses were performed to characterize sotrovimab PK and the relationship between exposure and response (probability of progression), as well as covar...

BackgroundAGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. CST-6 evaluated the safety and optimal dose of a novel intravenous (IV) formulation of favipiravir. MethodsCST-6 was a dose-escalating, open-label, randomised, controlled, Bayesian adaptive Phase Ib trial. Hospitalised adults with PCR-confirmed SARS-CoV-2 infection, within 14 days of symptomatic COVID-19 were randomised 2:1 in groups of 6 (n = 4 favipiravir, n = 2 standard of care (SoC)) to ascend...

We assessed the pharmacokinetics of favipiravir (FPV) in adults with symptomatic SARS-CoV-2 infection without pneumonia in Thailand. FPV dosing was 1800 mg twice-daily on day 1, then 800 mg twice-daily for 14 days. Eight subjects (7 female), median (range) age 39 (19-53) years and BMI 27.9 (18.0-33.6) were included. Inter-subject variability was high but all achieved minimum plasma concentrations (Cmin) above EC50 (9.7 mg/L). FPV was well tolerated; 1 subject stopped prematurely due to rash.

AimsNitazoxanide is a broad-spectrum antiviral with potential application in a number of viral infections. Its use is limited by gastrointestinal side effects associated with increasing dose. In this study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. MethodThis was a crossover drug-drug interaction study, 18 healthy participants received a single dose of 1000 mg of nitazoxanide alo...

Based on early reports of the efficacy of hydroxychloroquine sulfate (HCQS) to inhibit SARS-CoV-2 viral replication in vitro, and since severe pulmonary involvement is the major cause of COVID-19 mortality, we assessed the safety and efficacy of aerosolized HCQS (aHCQS) therapy in animals and humans. In a Phase 1 study of aHCQS in healthy volunteers, doses up to 50 mg were well tolerated and estimated epithelial lining fluid concentrations immediately after inhalation (>2,000 M) exceeded the in ...

Pretomanid is a key component of the bedaquiline, pretomanid, linezolid with or without moxifloxacin (BPaL/M)regimen recommended for treatment of rifampicin-resistant tuberculosis (RR-TB). To support dose optimization and efficacy interpretation, we developed a pretomanid population pharmacokinetic (PK) model and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received daily oral pretomanid at 200 mg, and plasma samples were collected at multiple time po...

BackgroundBroadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the only bnAb HIV prevention efficacy studies to date, the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. Greater efficacy is required before passively administered bnAbs become a viable optio...

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activ...

Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal with high mortality and morbidity, following current dosing guidelines. Given the lack of alternative therapies, there is a pressing need to optimize acyclovir dosing, especially since initial regimens were developed in the 1980s with incomplete pharmacokinetic data in the CNS. This study aimed to evaluate ...

BackgroundNicotinamide riboside (NR) is a promising compound for augmenting the intracellular NAD+ pool, potentially mitigating age-related decline and associated conditions. While oral NR supplementation has demonstrated safety and bioavailability in multiple animal and human studies, the effects of intravenous NR (NR IV) are far less understood. Until now, pharmaceutical grade NR was not available for injection research. ObjectivesGiven that intravenous administration may offer advantages in ...

Clofazimine is a key component of the BPaLC regimen (bedaquiline, pretomanid, linezolid, and clofazimine), an investigational treatment for rifampicin-resistant tuberculosis (RR-TB). However, clofazimines elimination half-life has never been formally characterized amongst tuberculosis patients and a pharmacokinetic (PK) - pharmacodynamic (PD) endpoint for probability of target attainment (PTA) evaluations is lacking. To support dose optimization and efficacy interpretation, we developed a clofaz...

BackgroundThe potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage. MethodsWe performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylis...

The potential of Dahuang to eliminate lung pathogens was often highlighted in Wenyi Lun. This investigation aimed to identify potential antiviral compounds of herbal component Dahuang (Rheum palmatum rhizomes and roots) of LianhuaQingwen capsule, with respect to their systemic exposure and lung reachability. Circulating Dahuang compounds were identified in human volunteers receiving LianhuaQingwen. The reachability of these compounds to SARS-CoV-2 3CLpro was assessed by in vitro transport, metab...

Linezolid is a key component of the BPaLM regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin), the recommended treatment for rifampicin-resistant tuberculosis (RR-TB). However, its optimal dosing and duration remain uncertain. To support dose optimization and efficacy interpretation, we developed a population pharmacokinetic (PK) model of linezolid and evaluated exposure and probability of target attainment (PTA). Ninety-four RR-TB patients received linezolid 600 mg daily for 16 weeks...

BackgroundTrans Sodium Crocetinate (TSC) is a bipolar synthetic carotenoid under development as a drug to enhance oxygenation to hypoxic tissue in addition to standard of care. TSC acts via a novel mechanism of action, improving the diffusivity of oxygen in blood plasma. Thus, it is based on physical-chemical principles, unlike most drugs which are based on biochemistry-based mechanisms. We explored the use of escalating doses and multiple daily dosing of TSC as a potential therapeutic for patie...

The safety, tolerability, pharmacokinetics, age-related effects of single (SD) and repeat (RD) doses of CMS121, a novel small molecule fisetin derivative, were evaluated in healthy adult volunteers. The effects of food were also evaluated in healthy young adult subjects. SD of up to 1800 mg or RD up to 900 mg/day for 7 days was generally well tolerated, with the majority of TEAEs mild in severity. Generally, the pharmacokinetics of CMS121 and its metabolites were well characterized and increased...

BackgroundCoronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP). MethodsLPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. L...

Pharmacometric assessment of antiviral efficacy in acute influenza informs treatment decisions and pandemic preparedness. We characterised natural viral clearance in acute influenza to guide phase II trial design using simulations based upon observed data. Standardized duplicate oropharyngeal swabs were collected daily over 14 days from 80 untreated low-risk Thai adults, with viral densities measured using qPCR. We evaluated three models to describe viral clearance: exponential, bi-exponential, ...

IntroductionCaly, Druce (1) reported that ivermectin inhibited SARS-CoV-2 in vitro for up to 48 h using ivermectin at 5M. The concentration resulting in 50% inhibition (IC50, 2 {micro}M) was >35x higher than the maximum plasma concentration (Cmax) after oral administration of the approved dose of ivermectin when given fasted. MethodSimulations were conducted using an available population pharmacokinetic model to predict total (bound and unbound) and unbound plasma concentration-time profiles af...