Could mirtazapine be administered to a patient with renal insufficiency and if so, in what doses?/n

Fråga: Could mirtazapine be administered to a patient with renal insufficiency and if so, in what doses?

The question concerns a patient with polycystic kidney disease. The patient´s iohexol clearance was 44 mL/min a year ago. A general practitioner instituted mirtazapine approximately a year ago with an initially dose of 30 mg once daily and has now increased it to 45 mg daily.

Sammanfattning: Mirtazapine has been used in patients with renal failure. Dose reduction may be necessary due to increased elimination half-life in patients with severe renal failure, but probably not a GFR 44 mL/min.

Svar: A similar question has been answered previously (1). In that document it is stated that mirtazapine clearance is reduced by 50% in patients with severe renal impairment and that the volume of distribution is very large; approximately 15.7 L/kg.

Mirtazapine is an antidepressant with noradrenergic and specific serotonergic antidepressant efect. Mirtazapine is a racemat extensively metabolised by CYP3A4, CYP2D6 and probably by CYP1A2 (2,3,4). Less than 4% of the parent compound is excreted unchanged in the urine. Demethylmirtazapine is the only active metabolite with a 5-10-fold lower pharmacodynamic activity than mirtazapine (4).

The effect of renal impairment on the pharmacokinetics of mirtazapine has been studied (2). Patients with severe renal failure (< 10 mL/min) had a significantly lower oral clearance (0.30 L/h/kg +/- 0.11) and increased elimination half-life (42.1 h +/- 10.7) compared with the healthy controls (0.60 L/h/kg +/- 0.21 and 32.8 +/- 6.7, resepctively). This is surprising considering that mirtazapine is eliminated by metabolism. However, it is in concordance with other data showing that nonrenal clearance of several drugs is reduced in patients with chronic renal failure, probably due to enzyme inhibition (5,6).

The metabolic clearance of sparteine was decreased in extensive metabolises with chronic renal failure, suggesting a decrease in CYP2D6 activity (7). In a study of nimodipine, a calcium-channel blocker, mean terminal half-life and the mean area under the plasma level time curve (AUC) was increased in patients with renal failure compared with healthy subjects, suggesting a decrease in CYP3A4 activity (8). Hence, the decrease in oral clearance and the increased elimination half-life of mirtazapine in renal failure patients is probably caused by inhibition of cytochrome CYP3A4 and CYP2D6. However, the degree of inhibition is unpredictable and therapeutic drug monitoring of mirtazpaine and its metabolite is therefore advisable. It is also advisable to start the treatment with the lowest recommended dose and follow the clinical outcome. Mirtazapine concentration is analysed at the Department of Clinical Pharmacology in Lund.