Pharmacokinetics of Orally Administered GS-441524 in Dogs.
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ABSTRACT:
SUBMITTER: Yan VC
PROVIDER: S-EPMC8183013 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNucleoside analog GS-441524 is effective in treating cats with feline infectious peritonitis (FIP). Investigation into the use of parent nucleotide analog remdesivir (GS-5734) is needed.ObjectivesTo assess efficacy and tolerability of remdesivir with or without transition to GS-441524 in cats with FIP and document clinical and clinicopathologic progression over 6 months.AnimalsTwenty-eight client-owned cats with FIP.MethodsCats were prospectively recruited between May 2021 and May 2022. An induction dosage of remdesivir 10 to 15 mg/kg intravenously or subcutaneously q24h was utilized for 4 doses, with a maintenance dosage of remdesivir (6-15 mg/kg SC) or GS-441524 (10-15 mg/kg per os) every 24 hours continued for at least 84 days. Laboratory testing, veterinary, and owner assessments were recorded.ResultsTwenty-four cats survived to 6 months (86%). Three cats died within 48 hours. Excluding these, survival from 48 hours to 6 months was 96% (24/25). Remission was achieved by day 84 in 56% (14/25). Three cats required secondary treatment for re-emergent FIP. Remission was achieved in all 3 after higher dosing (15-20 mg/kg). Adverse reactions were occasional site discomfort and skin irritation with remdesivir injection. Markers of treatment success included resolution of pyrexia, effusions, and presenting signs of FIP in the first half of treatment and normalization of globulin concentration, and continued body weight gains in the latter half of the treatment period.Conclusions and clinical importanceParenteral administration of remdesivir and oral administration of GS-441524 are effective and well-tolerated treatments for FIP. Early emphasis on clinical, and later emphasis on clinicopathologic response, appears prudent when monitoring treatment efficacy.
| S-EPMC10473006 | biostudies-literature
Project description:The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.
| S-EPMC8354861 | biostudies-literature
Project description:BACKGROUND:Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. OBJECTIVES:To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. METHODS:Remdesivir was administered at 200?mg loading dose on the first day followed by 12?days of 100?mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24?h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. RESULTS:We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. CONCLUSIONS:We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.
| S-EPMC7337789 | biostudies-literature
Project description:AIMS:In light of the growing recognition of renal disease in thalassemia, it is important to understand the impact of renal impairment on the pharmacokinetics of iron chelators. This study evaluated the pharmacokinetics and safety of the iron chelator deferiprone (DFP) in subjects with renal impairment in comparison with healthy volunteers (HVs). METHODS:Thirty-two subjects were categorized into four groups based on degree of renal impairment: none, mild, moderate or severe, as determined by estimated glomerular filtration rate (eGFR). All subjects received a single oral dose of 33 mg kg(-1) DFP, provided serum and urine samples for pharmacokinetic assessment over 24 h and were monitored for safety. RESULTS:Renal clearance of DFP decreased as renal impairment increased. However, based on Cmax , AUC(0,t) and AUC(0,?), there were no significant group differences in systemic exposure, because less than 4% of the drug was excreted unchanged in the urine. DFP is extensively metabolized to a renally excreted, pharmacologically inactive metabolite, deferiprone 3-O-glucuronide (DFP-G), which exhibited higher Cmax , AUC(0,t), AUC(0,?) and longer tmax and t1/2 in the renally impaired groups compared with HVs. The Cmax and AUCs of DFP-G increased as eGFR decreased. Overall, 75%-95% of the dose was retrieved in urine, either as DFP or DFP-G, regardless of severity of renal impairment. With respect to safety, DFP was well tolerated. CONCLUSIONS:These data suggest that no adjustment of the DFP dosage regimen in patients with renal impairment is necessary, as there were no significant changes in the systemic exposure to the drug.
| S-EPMC5137824 | biostudies-literature
Project description:BackgroundItraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost.ObjectiveTo determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs.AnimalsNine healthy, adult research Beagle dogs.MethodsA randomized, 3-way, 3-period, crossover design with an 8-day washout period. After a 12-hour fast, each dog received 100 mg (average: 10.5 mg/kg) of either innovator itraconazole, an approved human generic capsule, or compounded itraconazole (compounded using a commercially available compounding vehicle) with a small meal. Plasma was collected at predetermined intervals for high pressure liquid chromatography analysis. Concentration data were analyzed using noncompartmental pharmacokinetics to determine area under the curve (AUC), peak concentration (C(MAX)), and terminal half-life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation.ResultsAverage ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for C(MAX) were 4.14% and 86.34%, respectively. A test of bioequivalence using 2 one-sided tests and 90% confidence intervals did not meet bioequivalence criteria for either formulation.Conclusion and clinical importanceNeither generic nor compounded itraconazole is bioequivalent to the reference formulation in dogs. However, pharmacokinetic data for generic formulation were similar enough that therapeutic concentrations could be achieved. Compounded itraconazole produced such low plasma concentrations, it is unlikely to be effective; therefore, compounded itraconazole should not be used in dogs.
| S-EPMC4895533 | biostudies-literature
Project description:Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects; we sought to determine whether branaplam may affect postnatal cerebellar development and brain neurogenesis. Here, we describe a novel approach for developmental neurotoxicity testing (DNT) of a central nervous system (CNS) active drug. The effects of orally administered branaplam were evaluated in the SMA neonatal mouse model (SMN▵7), and in juvenile Wistar Hanover rats and Beagle dogs. Histopathological examination and complementary immunohistochemical studies focused on areas of neurogenesis in the cerebellum (mice, rats, and dogs), and the subventricular zone of the striatum and dentate gyrus (rats and dogs) using antibodies directed against Ki67, phosphorylated histone H3, cleaved caspase-3, and glial fibrillary acidic protein. Additionally, image analysis based quantification of calbindin-D28k and Ki67 was performed in rats and dogs. The patterns of cell proliferation and apoptosis, and neural migration and innervation in the cerebellum and other brain regions of active adult neurogenesis did not differ between branaplam- and control-treated animals. Quantitative image analysis did not reveal any changes in calbindin-D28k and Ki67 expression in rats and dogs. The data show that orally administered branaplam has no impact on neurogenesis in juvenile animals. Application of selected immunohistochemical stainings in combination with quantitative image analysis on a few critical areas of postnatal CNS development offer a reliable approach to assess DNT of CNS-active drug candidates in juvenile animal toxicity studies.
| S-EPMC8565466 | biostudies-literature
Project description:The objective of this experimental study was to assess the insecticidal efficacy of afoxolaner (NexGard®) against bedbugs (Cimex lectularius) on dogs. For each challenge, 20 bedbugs were placed in two chambers positioned in contact to the dog's skin for 15 min, after which live fed parasites were counted and incubated for survival evaluations. On Day 0, 7 dogs assigned to the treated group were administered afoxolaner orally at the registered dose. All 14 dogs were challenged on Days 1, 7, 14, 21 and 28, and the collected live fed C. lectularius incubated for 72 h (Day 1), and 72 h and 96 h (Days 7, 14, 21 and 28) for survival evaluation. The percent feeding in the control group ranged from 95% to 98.6% and the percent of live fed bedbugs at 96 h ranged from 99.3% to 100% in the control group, demonstrating the viability of the strain and their capacity to feed on dogs. Significantly fewer live fed bedbugs were counted in the treated group, compared to the control group, at all time-points. The reduction of live fed C. lectularius in the afoxolaner group was 41.4% at 72 h after the Day 1 challenge, and 77.2%, 82.7%, 85.0% and 63.5% at 96 h after the Days 7, 14, 21 and 28 challenges, respectively. It is hypothesized that monthly treatment of dogs with afoxolaner could help in preventing a bed bug population from installing in a household if bedbugs bite dogs in the presence of humans.
| S-EPMC7852378 | biostudies-literature
Project description:The intravenous administration of remdesivir for COVID-19 confines its utility to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524) against viruses that cause diseases of human public health concern, including SARS-CoV-2. ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had near-equivalent activity to remdesivir in primary-like human small airway epithelial cells. Our results warrant investigation of ODBG-P-RVn efficacy in vivo.
| S-EPMC8366795 | biostudies-literature
Project description:Recent international epidemics of coronavirus-associated illnesses underscore the urgent medical and public health need for vaccine development and regulatory body approved therapies. In particular, the current coronavirus disease 2019 (COVID-19) pandemic has quickly intensified interest in developing treatment options to mitigate impact on human life. Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being tested as a potential treatment for COVID-19 in international, multi-site clinical trials. Currently available evidence about the antiviral effects of remdesivir against coronaviruses is primarily based on in vitro and in vivo studies (including some on a chemically related compound, GS-441524™), which have demonstrated largely favorable findings. As the pandemic progresses, information from human compassionate use cases will continue to accumulate before the clinical trials are concluded. It is imperative for public health practitioners and the One Health community to stay up to date on the most promising potential therapeutic options that are under investigation. Thus, the purpose of this review is to synthesize the knowledge to date about remdesivir as a therapeutic option for coronaviruses, with a special focus on information relevant to the One Health community.
| S-EPMC7125341 | biostudies-literature
Project description:Recent international epidemics of coronavirus-associated illnesses underscore the urgent medical and public health need for vaccine development and regulatory body approved therapies. In particular, the current coronavirus disease 2019 (COVID-19) pandemic has quickly intensified interest in developing treatment options to mitigate impact on human life. Remdesivir (GS-5734™) is a broad-spectrum antiviral drug that is now being tested as a potential treatment for COVID-19 in international, multi-site clinical trials. Currently available evidence about the antiviral effects of remdesivir against coronaviruses is primarily based on in vitro and in vivo studies (including some on a chemically related compound, GS-441524™), which have demonstrated largely favorable findings. As the pandemic progresses, information from human compassionate use cases will continue to accumulate before the clinical trials are concluded. It is imperative for public health practitioners and the One Health community to stay up to date on the most promising potential therapeutic options that are under investigation. Thus, the purpose of this review is to synthesize the knowledge to date about remdesivir as a therapeutic option for coronaviruses, with a special focus on information relevant to the One Health community.
| S-EPMC7118644 | biostudies-literature