Flupentixol: relevance of stereoselective therapeutic drug monitoring

Abstract

Positron emission tomography (PET) provides important information in studies centered on the drug plasma concentrations–clinical effectiveness relationship, as it directly allows measuring of drug binding to pharmacologically relevant receptors in the brain. Such studies have been carried out for many antipsychotics, the binding of which to central dopamine D2 receptors can be observed with PET (Grunder et al. 2011). A study showed a 50–70 % D2-receptor occupancy by therapeutic doses (4–10 mg/day; 5.7±1.4 mg/day [mean ± SD]) of the antipsychotic drug flupentixol, which reportedly lead to flupentixol plasma concentrations between 0 and 6 ng/ml (1.47±0.97 ng/ml) after oral administration of this drug to 13 patients (Reimold et al. 2007). Flupentixol is available as a 1:1 mixture of the geometric isomers cisand trans-isomers (Zand E-isomers, respectively) for oral administration, while the depot preparation flupentixol decanoate contains only cis-flupentixol. Only cis-flupentixol is considered to be pharmacologically active with regard to its affinity for dopamine (and serotonin) receptors, as also shown in clinical studies in which clinical efficacy of cis-flupentixol (α-flupentixol; Z-flupentixol) was found to be superior to that of trans-flupentixol (β-flupentixol; E-flupentixol) (Johnstone et al. 1978). An analysis of three-dimensional structures and molecular electrostatic potentials confirms the higher receptor affinities of cis-flupentixol in comparison to the trans-isomer (Sylte and Dahl 1991). In the already mentioned PET study with flupentixol, the presented drug plasma concentrations appear to be those of the sum of cisand trans-flupentixol, as the standard analytical technique used by MDS Pharma Services (Fehraltorf, Switzerland) was not developed for the separation of these isomers (Reimold et al. 2007; and Petra Struwe, Celerion, Fehraltdorf, personal communication). Recently, the AGNP-TDM group (Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie) (Hiemke et al. 2011) recommended published updated consensus guidelines for therapeutic drug monitoring in psychiatry: The therapeutic reference range (recommended plasma drug concentration) for the antipsychotic drug flupentixol (flupenthixol) was given as 1–10 ng/ml. This range is related to the sum of the cisand the trans-isomers concentrations, and the recommended range is mainly based on 2 studies (Reimold et al. 2007; Balant-Gorgia et al. 1985). The question arises whether after analysis of the literature, which considers pharmacological and pharmacokinetic differences between the cisand trans-isomers of flupentixol, the recommended plasma concentration range of flupentixol may still be considered as valid. Only few studies considered the existence of two geometric isomers of flupentixol differing by their properties. In 1985, a lower threshold of 2 ng/ml flupentixol was reported for satisfactory antipsychotic effect (Balant-Gorgia et al. 1985). The authors did not use a stereoselective method, P. Baumann, H. Kirchherr and C. Hiemke are members of the AGNPTDM group (cf. Hiemke et al. 2011).