Extreme Values of the Concentration/Dose Ratio as a Risk Factor of Obtaining Suboptimal Nortriptyline Serum Concentrations

Abstract

Using nortriptyline as an example of a typical tricyclic antidepressant, I studied the relation between the steady-state concentration/dose ratio (C/D) and the performance of therapeutic drug monitoring (TDM), with a focus on the frequency of serum concentrations located in the therapeutic interval. A TDM database comprising 1,214 patients, of whom 619 patients had more than one sample taken, was used. The median C/D value for the patients was 4.05 [nM]/mg with 5th and 95th percentiles of 1.80 and 9.60, respectively. A total of 18.6% of the patients with C/D values below the 5th percentile had serum concentrations in the therapeutic interval at the first occasion, increasing to 49% for the average of the succeeding samples. These values were lower than those for the total group, 60.4 and 68.9%, respectively. For those with C/D values exceeding the 95th percentile, 36.2% had initial serum concentrations in the therapeutic interval, increasing to 66.3% for the average of succeeding samples. Only 11 patients (0.9%) had very high initial serum concentrations (> 1,200 nM). Thus patients with low C/D values are at risk of being underdosed, even after successive samples, whereas adequate dose correction is more likely to be implemented for those with average or high C/D values. Saturation kinetics for those with low C/D values was not a problem of clinical significance. Neither was lack of steady-state at the first occasion a problem for those with high C/D values (suspected poor metabolizers).