What plasma concentrations of mirtazapine would be expected in therapeutic use?

Fråga: What plasma concentrations of mirtazapine would be expected in therapeutic use?

Sammanfattning: In a group of twenty patients, treatment with mirtazapine 60 mg/d resulted in a mean steady-state plasma level of 252 nmol/L and in another 51 patients, a mean dose of 76.2 mg/d gave a mean steady-state level of 261 nmol/L. These dose/concentration relationships suggest that the recommended dose range of 15-45 mg/d would result in plasma concentrations of approximately 55-165 nmol/L (point estimates of range limits).

Therapeutic intervals of 75-283 and 184-350 nmol/L have been suggested, but the underlying documentation does not seem very convincing. In two intoxication cases, the mirtazapine levels exceeded 500 nmol/L. The picture is further complicated by the fact that mirtazapine´s N-demethylated metabolite is pharmacologically active.

Svar: Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) with a molecular weight of 265.4 g/mol. Its N-desmethyl metabolite is supposedly pharmacologically active (1).

In 51 depressed patients treated with mirtazapine doses titrated to achieve blood levels between 50-100 ng/mL (188-377 nmol/L), a mean dose of 76.2 mg/d (range 40-100 mg/d) resulted in a mean blood concentration of 69.3 ng/mL (range 48.8-92.8 ng/mL). This would be equivalent to 261 nmol/L (184-350 nmol/L). The therapeutic interval of 50-100 ng/mL used in this study was rather arbitrarily selected to include the mean steady-state concentration of 67 ng/mL (252 nmol/L) from a pilot study where twenty patients had been given mirtazapine 60 mg/d, (2). Notably, this dose exceeds the standard dose range mentioned in the Swedish catalogye of approved medical products FASS, 15-45 mg/d (3).

In a male patient showing somnolence and memory disturbances following ingestion of 150 mg mirtazapine, the plasma concentration of the mother compound was 325 ng/mL (1225 nmol/L) and that of the demethylated metabolite 160 ng/mL (4).

In another case of intoxication, without further clinical information, the concentrations of mirtazapine and demethylmirtazapine were 140 ng/mL (528 nmol/L) and 60 ng/mL, respectively. In this publication, comparisons are made to an alleged therapeutic range of 20-75 ng/mL (75-283 nmol/L) (4). However, the reference quoted does not mention any therapeutic range whatsoever and it is consequently impossible to evaluate the clinical relevance of the proposed therapeutic interval (5).