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Objectives: The aims of this study were to determine the side effect frequency and serum and urine drug concentrations of amoxicillin-clavulanic acid in cats with and without azotemic chronic kidney disease (azCKD)., Methods: Owners whose cats had been prescribed amoxicillin-clavulanic acid completed a survey regarding the occurrence and type of side effects, and whether treatment was altered as a result. Cats were defined as azCKD (serum creatinine concentration >2.0 mg/dl, urine specific gravity [USG] <1.035 with a clinical diagnosis of chronic kidney disease) and without azCKD (serum creatinine concentration <2.0 mg/dl). Data were assessed with Fisher's exact test. Serum and urine samples were obtained from client-owned cats with azCKD (n = 6) and without azCKD (n = 6, serum creatinine concentration <1.8 mg/dl, USG >1.035) that were receiving amoxicillin-clavulanic acid. Amoxicillin and clavulanic acid were measured with liquid chromatography coupled to tandem mass spectrometry and compared between groups with a Mann-Whitney test. Correlation between serum creatinine and drug concentrations in urine and serum was determined using Spearman's rank test., Results: Sixty-one surveys were returned (11 azCKD cats and 50 without azCKD cats). No significant difference in the presence of side effects or type of side effects was seen between groups; however, significantly more azCKD cats had more than one side effect ( P  = 0.02). More owners of azCKD cats reported that an alteration in treatment plan was necessitated by side effects (55% vs 12%; P  = 0.008). Urine amoxicillin was significantly lower in cats with azCKD ( P  = 0.01) and serum amoxicillin trended toward significance ( P  = 0.07). Serum amoxicillin concentration was positively correlated with serum creatinine ( P  = 0.02; r  = 0.62) and urine amoxicillin concentration was negatively correlated with serum creatinine ( P  = 0.01; r  = -0.65)., Conclusions and Relevance: The data suggest that cats with azCKD have altered pharmacokinetics of amoxicillin, which may contribute to an increased incidence of multiple side effects.

Objectives: The aim of this study was to assess the appetite stimulation properties of compounded transdermal mirtazapine (CTM) in cats with chronic kidney disease (CKD)., Methods: Two sequential double-blind placebo-controlled crossover prospective studies were performed in client-owned cats with stable stage 2 or 3 CKD and a history of decreased appetite. In the first study nine CKD cats were randomized to receive 3.75 mg/0.1 ml CTM gel or placebo on the inner pinna every other day for 3 weeks, then, after a 4 day washout period, the cats were crossed over to the alternate 3 week treatment. In a second study, 10 CKD cats were randomized to receive 1.88 mg/0.1 ml CTM or placebo on the same schedule. Physical examination and serum biochemistry were performed before and after each treatment period, and owners kept daily logs of appetite, activity and eating behaviors. Mirtazapine concentrations in CTM gels and steady-state mirtazapine serum concentrations were measured using liquid chromatography/tandem mass spectrometry., Results: Administration of both 3.75 mg and 1.88 mg CTM resulted in a statistically significant increase in weight ( P = 0.002 for both), increase in appetite ( P = 0.01 and P = 0.005, respectively), and increase in rate of food consumption ( P = 0.03 and P = 0.008, respectively). No significant difference in activity or vocalization was seen at either dose; however, individual cats experienced excessive meowing. Median weight increase for the 3.75 mg arm was 0.22 kg (range 0.04-0.44 kg), while median weight increase for the 1.88 mg arm was 0.26 kg (range -0.25 to 0.5 kg). Improvement in body condition score was seen in 5/9 cats in the 3.75 mg arm (P = 0.04) and 6/10 cats in the 1.88 mg arm (P = 0.004)., Conclusions and Relevance: CTM increased appetite and resulted in weight gain in CKD cats despite significant inconsistencies in compounding, and may benefit cats in countries where an approved product is not available.

Background: Intestinal dysbiosis has been documented in humans with chronic kidney disease (CKD) and is thought to contribute to production of the uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (pCS). Characteristics of the fecal microbiome in cats with CKD and correlation to serum concentrations of uremic toxins are unknown., Objectives: To characterize the fecal microbiome and measure serum IS and pCS concentrations of cats with CKD in comparison to healthy older cats., Animals: Thirty client-owned cats with CKD (International Renal Interest Society stages 2-4) and 11 older (≥8 years) healthy control cats., Methods: Prospective, cross-sectional study. Fecal samples were analyzed by sequencing of 16S rRNA genes and Escherichia coli quantitative PCR (qPCR). Serum concentrations of IS and pCS measured using liquid chromatography tandem mass spectrometry., Results: Cats with CKD had significantly decreased fecal bacterial diversity and richness. Escherichia coli qPCR showed no significant difference in bacteria count between control and CKD cats. Cats with stage 2 (P = .01) and stages 3 and 4 (P = .0006) CKD had significantly higher serum IS concentrations compared to control cats. No significant difference found between stage 2 and stages 3 and 4 CKD. The pCS concentrations were not significantly different between CKD cats and control cats., Conclusions and Clinical Importance: Decreased fecal microbiome diversity and richness is associated with CKD in cats. Indoxyl sulfate concentration is significantly increased with CKD, and cats with stage 2 CKD may suffer from a similar uremic toxin burden as do cats with later stage disease., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Liver disease (LD) prolongs mirtazapine half-life in humans, but it is unknown if this occurs in cats with LD and healthy cats., Hypothesis/objectives: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats., Animals: Eleven LD and 11 age-matched control cats., Methods: Case-control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half-life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD., Results: There was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1-4] hours versus 1 [1-4] hours; P = .03). The calculated half-life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9-61.4] hours versus 7.4 [6.7-9.1] hours; P < .002). Mirtazapine half-life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (-0.0022 min -1 , CI: -0.0050 to 0.00054 min -1 ) and cats without LD (0.01849 min -1 , CI: -0.025 to -0.012 min -1 ; P = .002)., Conclusions and Clinical Importance: Cats with LD might require less frequent administration of mirtazapine than normal cats., (© 2018 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Ondansetron, a 5-HT3 receptor antagonist, is an effective anti-emetic in cats. The purpose of this study was to compare pharmacokinetics of subcutaneous (SQ) ondansetron in healthy geriatric cats to cats with chronic kidney disease (CKD) or liver disease using a limited sampling strategy. 60 cats participated; 20 per group. Blood was drawn 30 and 120 min following one 2 mg (mean 0.49 mg/kg, range 0.27-1.05 mg/kg) SQ dose of ondansetron. Ondansetron concentrations were measured by liquid chromatography coupled to tandem mass spectrometry. Drug exposure represented as area under the curve (AUC) was predicted using a limited sampling approach based on multiple linear regression analysis from previous full sampling studies, and clearance (CL/F) estimated using noncompartmental methods. Kruskal-Wallis anova was used to compare parameters between groups. Mean AUC (ng/mL·h) of subcutaneous ondansetron was 301.4 (geriatric), 415.2 (CKD), and 587.0 (liver). CL/F (L/h/kg) of SQ ondansetron was 1.157 (geriatric), 0.967 (CKD), and 0.795 (liver). AUC was significantly higher in liver and CKD cats when compared to geriatric cats (P < 0.05). CL/F in liver cats was significantly decreased (P < 0.05) compared to geriatric cats. In age-matched subset analysis, AUC and CL/F in liver cats remained significantly different from geriatric cats., (© 2015 John Wiley & Sons Ltd.)

Background: Cats with chronic kidney disease (CKD) often experience inappetence, and may benefit from administration of mirtazapine, an appetite stimulant. The pharmacokinetics of mirtazapine in CKD cats is unknown., Hypothesis: CKD delays the clearance/bioavailability (CL/F) of mirtazapine., Animals: Six CKD cats and 6 age-matched controls (AMC) were enrolled. Two CKD cats each from International Renal Interest Society (IRIS) stage II, III and IV were included., Methods: Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 8, 24, and 48 hours after a single PO dose of 1.88 mg of mirtazapine. Mirtazapine concentrations were measured by liquid chromatography coupled to tandem mass spectrometry. Non-compartmental pharmacokinetic modeling was performed., Results: Mean age was 11 years (CKD cats) and 10.8 years (AMC cats). Mean serum creatinine concentration ± standard deviation (SD) was 3.8 ± 1.6 mg/dL (CKD) and 1.3 ± 0.4 mg/dL (AMC). Mean half-life ± SD was 15.2 ± 4.2 hours (CKD) and 12.1 ± 1.1 hours (AMC). Mean area under the curve (AUC) ± SD was 770.6 ± 225.5 ng/mL•hr (CKD) and 555.5 ± 175.4 ng/mL•hr (AMC). Mean CL/F ± SD was 0.6 ± 0.1 L/hr/kg (CKD) and 0.8 ± 0.16 L/hr/kg (AMC). A Mann-Whitney test indicated statistically significant differences in AUC (P = 0.01) and CL/F (P = 0.04) between groups. Calculated accumulation factor for 48-hour dosing in CKD cats was 1.15., Conclusion: CKD may delay the CL/F of mirtazapine. A single low dose of mirtazapine resulted in a half-life compatible with a 48-hour dosing interval in CKD cats., (Copyright © 2011 by the American College of Veterinary Internal Medicine.)

Critically ill animals are by nature a diverse group with multiple presenting complaints and differing levels of organ function. Pharmacokinetics and pharmacodynamics of administered compounds are affected both by the disease processes and by the interventions of the treating veterinarian. Polypharmacy is not an exception but a rule within this caseload. Basic principles of pharmacology allow for safe and effective administration of pharmaceuticals, especially in the critically ill. Future research evaluating the pharmacokinetics and pharmacodynamics of drugs important in the management of critically ill animals is imperative, and will allow evidence-based dose modification., (Copyright © 2011 Elsevier Inc. All rights reserved.)