First analytical confirmation of drug-induced crystal nephropathy in felines caused by GS-441524, the active metabolite of Remdesivir.

GS-441524 is an adenosine nucleoside antiviral demonstrating significant efficacy in the treatment of feline infectious peritonitis (FIP), an otherwise fatal illness, resulting from infection with feline coronavirus. However, following the emergence of COVID-19, veterinary development was halted, and Gilead pursued clinical development of a GS-441524 pro-drug, resulting in the approval of Remdesivir under an FDA emergency use authorization. Despite lack of regulatory approval, GS-441524 is available without a prescription through various unlicensed online distributors and is commonly purchased by pet owners for the treatment of FIP. Herein, we report data obtained from the analytical characterization of two feline renal calculi, demonstrating the propensity for GS-441524 to cause renal toxicity through drug-induced crystal nephropathy in vivo. As definitive diagnosis of drug-induced crystal nephropathy requires confirmation of the lithogenic material to accurately attribute a mechanism of toxicity, renal stone composition and crystalline matrix were characterized using ultra-performance liquid chromatography photodiode array detection (UPLC-PDA), ultra-performance liquid chromatography mass spectrometry (LCMS), nuclear magnetic resonance (NMR) spectroscopy, X-ray powder diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). This work serves to provide the first analytical confirmation of GS-441524-induced crystal nephropathy in an effort to support toxicologic identification of adverse renal effects caused by administration of GS-441524 or any pro-drug thereof.

Uroliths composed of antiviral compound GS-441524 in 2 cats undergoing treatment for feline infectious peritonitis.

Feline infectious peritonitis (FIP) historically has been a fatal disease in cats. Recent unlicensed use of antiviral medication has been shown to markedly improve survival of this infection. An 8-month-old female spayed domestic short-haired cat undergoing treatment for presumptive FIP with the antiviral nucleoside analog GS-441524 developed acute progressive azotemia. Abdominal ultrasound examination identified multifocal urolithiasis including renal, ureteral, and cystic calculi. Unilateral ureteral obstruction progressed to suspected bilateral ureteral obstruction and subcutaneous ureteral bypass (SUB) was performed along with urolith removal and submission for analysis. A 2-year-old male neutered domestic medium-haired cat undergoing treatment for confirmed FIP with GS-441524 developed dysuria (weak urine stream, urinary incontinence, and difficulty expressing the urinary bladder). This cat also was diagnosed sonographically with multifocal urolithiasis requiring temporary tube cystostomy after cystotomy and urolith removal. In both cases, initial urolith analysis showed unidentified material. Additional testing confirmed the calculi in both cats to be 98% consistent with GS-441524. Additional clinical studies are required to determine best screening practices for cats presented for urolithiasis during treatment with GS-441524.

Comparison of point-of-care NOVA CCX blood gas analyzer to laboratory analyzer in a population of healthy adult cats.

OBJECTIVE: To compare the level of agreement of measurement of analytes (sodium, chloride, potassium, urea nitrogen [UN], creatinine, glucose) in a population of healthy adult cats between the point-of-care (POC) analyzer and laboratory analyzer. To establish reference intervals for the POC analyzer in healthy adult cats. DESIGN: Prospective observational study. SETTING: University teaching hospital. ANIMALS: Fifty-five cats were screened. Seven cats were excluded due to aggression that prohibited phlebotomy, and 1 cat was excluded due to prolonged restraint; 47 cats were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In this patient population, reference intervals for the POC analyzer were calculated: sodium 145-157 mmol/L; chloride 116-124 mmol/L; potassium 3.4-5.5 mmol/L; UN 5.71-13.9 mmol/L (16-39 mg/dl); creatinine 74.3-189.2 mmol/L (0.84-2.14 mg/dl); and glucose 4-11.8 mmol/L (72-213 mg/dl). Comparison between the POC analyzer and laboratory analyzer using the Bland-Altman method was performed. The bias for each analyte is as follows: sodium 1.55 mmol/L; chloride 0.99 mmol/L; potassium 0.21 mmol/L; UN -0.25 mmol/L (-0.7 mg/dl); creatinine 9.73 mmol/L (0.11 mg/dl); and glucose 0.5 mmol/L (9.79 mg/dl). CONCLUSIONS: Reference intervals for each analyte were similar to other chemistry analyzers. There was no significant difference between the POC and laboratory analyzers in analysis of UN, with a statistically significant difference observed with sodium, potassium, chloride, creatinine, and glucose. However, the values are likely not sufficiently different to alter initial clinical decisions regarding patient care.

Pharmacokinetics of minocycline in domestic cats.

OBJECTIVES: Recently, the increased cost and decreased availability of doxycycline has sparked an interest in using minocycline as an alternative. The purpose of this study was to determine the pharmacokinetics of minocycline in domestic cats in order to facilitate dosage decisions. METHODS: Purpose-bred, young adult cats were administered a single dose of either intravenous (IV; n = 4; 5 mg/kg) or oral (n = 6; 50 mg/cat) minocycline. Blood was collected from each at intervals up to 24 h afterwards. Minocycline was measured using high performance liquid chromatography with ultraviolet detection. A one-compartment pharmacokinetic model was fit to the oral data and a two-compartment model to the IV data via a computer program. Plasma protein binding was measured by fortifying blank plasma from untreated healthy cats with minocycline at two concentrations and applying an ultracentrifugation method. RESULTS: Two cats became transiently lethargic and tachypneic during IV drug infusion. One cat vomited 6.0 h after infusion, and two cats vomited either 1.5 h or ~5.0 h after oral drug administration. The mean oral dose administered was 13.9 ± 0.47 mg/kg. Oral bioavailability was approximately 62%. Plasma protein binding was 60% at 5 µg/ml and 46% at 1 µg/ml. After IV administration, elimination half-life (t(½)), apparent volume of distribution at steady-state, and systemic clearance were 6.7 h (coefficient of variation [CV] 14.4%), 1.5 l/kg (CV 34.5%) and 2.9 ml/kg/min (CV 40.8%), respectively. After oral administration the terminal t(½) and peak concentration (Cmax) were 6.3 h (CV 9%) and 4.77 µg/ml (CV 36%), respectively. CONCLUSIONS AND RELEVANCE: Because most bacteria will have a minimum inhibitory concentration of ⩽0.5 µg/ml, an oral dose of 8.8 mg/kg q24h would be adequate to meet pharmacokinetic-pharmacodynamic targets after adjusting for protein binding. Although some gastrointestinal upset may occur, one 50 mg capsule orally q24h would provide appropriate dosing for most cats.