In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease

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.