Baumann, Pierre

Berney, Patricia

Hiemke, Christoph

Kirchherr, Hartmut

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LETTER TO THE EDITORSFlupentixol: relevance of stereoselective therapeuticdrug monitoringPierre Baumann & Hartmut Kirchherr &Patricia Berney & Christoph HiemkeReceived: 12 January 2012 /Accepted: 17 March 2012 /Published online: 4 April 2012# Springer-Verlag 2012Positron emission tomography (PET) provides importantinformation in studies centered on the drug plasma concen-trations–clinical effectiveness relationship, as it directlyallows measuring of drug binding to pharmacologically rele-vant receptors in the brain. Such studies have been carried outfor many antipsychotics, the binding of which to centraldopamine D2 receptors can be observed with PET (Grunderet al. 2011). A study showed a 50–70 % D2-receptor occu-pancy by therapeutic doses (4–10 mg/day; 5.7±1.4 mg/day[mean ± SD]) of the antipsychotic drug flupentixol, whichreportedly lead to flupentixol plasma concentrations between0 and 6 ng/ml (1.47±0.97 ng/ml) after oral administration ofthis drug to 13 patients (Reimold et al. 2007). Flupentixol isavailable as a 1:1 mixture of the geometric isomers cis- andtrans-isomers (Z- and E-isomers, respectively) for oral admin-istration, while the depot preparation flupentixol decanoatecontains only cis-flupentixol. Only cis-flupentixol isconsidered to be pharmacologically active with regard to itsaffinity for dopamine (and serotonin) receptors, as also shownin clinical studies in which clinical efficacy of cis-flupentixol(α-flupentixol; Z-flupentixol) was found to be superior to thatof trans-flupentixol (β-flupentixol; E-flupentixol) (Johnstoneet al. 1978). An analysis of three-dimensional structures andmolecular electrostatic potentials confirms the higher receptoraffinities of cis-flupentixol in comparison to the trans-isomer(Sylte and Dahl 1991). In the already mentioned PET studywith flupentixol, the presented drug plasma concentrationsappear to be those of the sum of cis- and trans-flupentixol,as the standard analytical technique used by MDS PharmaServices (Fehraltorf, Switzerland) was not developed for theseparation of these isomers (Reimold et al. 2007; and PetraStruwe, Celerion, Fehraltdorf, personal communication).Recently, the AGNP-TDM group (Arbeitsgemeinschaftfür Neuropsychopharmakologie und Pharmakopsychiatrie)(Hiemke et al. 2011) recommended published updated con-sensus guidelines for therapeutic drug monitoring in psychi-atry: The therapeutic reference range (recommended plasmadrug concentration) for the antipsychotic drug flupentixol(flupenthixol) was given as 1–10 ng/ml. This range is relat-ed to the sum of the cis- and the trans-isomers concentra-tions, and the recommended range is mainly based on 2studies (Reimold et al. 2007; Balant-Gorgia et al. 1985). Thequestion arises whether after analysis of the literature, whichconsiders pharmacological and pharmacokinetic differencesbetween the cis- and trans-isomers of flupentixol, the recom-mended plasma concentration range of flupentixol may still beconsidered as valid.Only few studies considered the existence of two geo-metric isomers of flupentixol differing by their properties. In1985, a lower threshold of 2 ng/ml flupentixol was reportedfor 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 AGNP-TDM group (cf. Hiemke et al. 2011).P. Baumann (*)Département de Psychiatrie, DP-CHUV,Site de Cery,CH-1008 Prilly-Lausanne, Switzerlande-mail: pierre.baumann@chuv.chH. KirchherrMedizinisches Labor Bremen,Bremen, GermanyP. BerneyDépartement de Psychiatrie, Hôpitaux Universitaires de Genève,Chêne-Bourg, SwitzerlandC. HiemkeDepartment of Psychiatry and Psychotherapy,University Medical Center Mainz,Mainz, GermanyPsychopharmacology (2012) 221:719–720DOI 10.1007/s00213-012-2699-8but divided the measured flupentixol concentration by 2 inorder to consider only the concentration of cis-flupentixol,with the assumption, that cis- and trans-flupentixol plasmaconcentrations are equal in flupentixol treated patients. As aresult, patients treated orally with 6–12 mg/day flupentixolachieved maximally 10 ng/ml cis- + trans-flupentixol concen-trations. However, in 1987, the same group (Balant-Gorgiaet al. 1987) developed a stereospecific assay which revealedthat in a group of patients treated orally with flupentixol, 59 %of the patients had a trans-/cis-flupentixol ratio in plasmabetween 1.5 and 2.5 (range 0.77–6.0). In 93 % of the cases,the inactive trans-isomer concentration exceeded that of theactive cis-isomer. A graphic presentation suggests that inpatients treated orally with 4–15 mg/day flupentixol, cis-flupentixol concentrations vary between 0.5 and 5 ng/ml.This suggests that in the PET study (Reimold et al. 2007),significantly lower concentrations than 0.5–2 ng/ml cis-flupentixol lead to 50–70 % D2-receptor occupancy.Other authors developed stereoeselective methods of flu-pentixol in the blood of patients treated with flupentixol.Ulrich (1995) described disappearance of cis-flupentixolexposed to daylight and its trans-isomerization to trans-flupentixol until a 1:1 mixture of both isomers is reached.In the clinical part of his study, none of the few patientstreated with 20 mg/day flupentixol p.os had cis-flupixollevels >10 ng/ml. After a treatment of dozens of patientswith 2.5–40 mg/day oral flupentixol, cis-flupentixol levelswere found to be <10 ng/ml in all but one patient. Theseauthors carefully avoided exposition of the probes to day-light during drug analysis (Walter et al. 1998). In cocainedependent patients treated with low doses (2.5 or 5 mg/day)of oral flupentixol, cis-flupentixol plasma trough levels asmeasured with a stereoselective method only reached 0.53±0.2 ng/ml (means ± SEM) (Evans et al. 2001).Several authors did not mention the existence of cis–trans isomerism of flupentixol in their publications, wherethey proposed non-stereoselective assays for therapeuticdrug monitoring (Gutteck and Rentsch 2003; Kumazawaet al. 2000).In conclusion, considering the pharmacological and phar-macokinetic differences between cis- and trans-flupentixol,therapeutic monitoring studies with oral flupentixol in psy-chiatric patients should include stereoselective assays inconditions protected from daylight. Moreover, more dataare needed to clearly define an optimal therapeutic rangefor cis-flupentixol plasma levels, as almost all studies wereperformed in a limited number of patients treated withrelatively low doses (2.5–20 mg/day) of flupentixol.Tentatively, a therapeutic reference range/recommendedcis-flupentixol concentration range of 0.5–5 ng/ml isproposed.Conflict of interest The authors have no competing interestsReferencesBalant-Gorgia AE, Eisele R, Aeschlimann JM, Balant LP, Garrone G(1985) Plasma flupentixol concentrations and clinical response inacute schizophrenia. Ther Drug Monit 7:411–414Balant-Gorgia AE, Balant LP, Gex-Fabry M, Genet C (1987) Stereo-selective dispotion of flupentixol: influence on steady-state plas-ma concentrations. Eur J Drug Metab Pharmacokinet 12:123–128Evans SM, Walsh SL, Levin FR, Foltin RW, Fischman MW, BigelowGE (2001) Effect of flupenthixol on subjective and cardiovascularresponses to intravenous cocaine in humans. Drug AlcoholDepend 64:271–283Grunder G, Hiemke C, Paulzen M, Veselinovic T, Vernaleken I (2011)Therapeutic plasma concentrations of antidepressants and anti-psychotics: lessons from PET imaging. Pharmacopsychiatry44:236–248Gutteck U, Rentsch KM (2003) Therapeutic drug monitoring of 13antidepressant and five neuroleptic drugs in serum with liquidchromatography-electrospray ionization mass spectrometry. ClinChem Lab Med 41:1571–1579Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, EgbertsK, Fric M, Gerlach M, Greiner C, Gründer G, Haen E,Havemann-Reinecke U, Jaquenoud Sirot E, Kirchherr H, LauxG, Lutz UC, Messer T, Müller MJ, Pfuhlmann B, Rambeck B,Riederer P, Schoppek B, Stingl J, Uhr M, Ulrich S, Waschgler R,Zernig G, The TDM group of the AGNP (2011) AGNP consensusguidelines for therapeutic drug monitoring in psychiatry: update2011. Pharmacopsychiatry 44:195–235Johnstone EC, Crow TJ, Frith CD, Carney MW, Price JS (1978)Mechanism of the antipsychotic effect in the treatment of acuteschizophrenia. Lancet 1:848–851Kumazawa T, Seno H, Watanabe-Suzuki K, Hattori H, Ishii A, Sato K,Suzuki O (2000) Determination of phenothiazines in human bodyfluids by solid-phase microextraction and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 35:1091–1099Reimold M, Solbach C, Noda S, Schaefer JE, Bartels M, Beneke M,Machulla HJ, Bares R, Glaser T, Wormstall H (2007) Occupancyof dopamine D(1), D(2) and serotonin (2A) receptors in schizo-phrenic patients treated with flupentixol in comparison with ris-peridone and haloperidol. Psychopharmacology (Berl) 190:241–249Sylte I, Dahl SG (1991) Molecular structure and dynamics of cis(Z)- andtrans(E)-Flupenthixol and Clopenthixol. Pharm Res 8:462–470Ulrich S (1995) Sensitive gas-liquid chromatographic method for theassay of the neuroleptic drug cis(Z)-flupentixol in human serum orplasma. J Chromatogr B Biomed Appl 668:31–40Walter S, Bauer S, Roots I, Brockmoller J (1998) Quantification of theantipsychotics flupentixol and haloperidol in human serum byhigh-performance liquid chromatography with ultraviolet detec-tion. J Chromatogr B: Biomed Sci Appl 720:231–237720 Psychopharmacology (2012) 221:719–720

Flupentixol: relevance of stereoselective therapeutic drug monitoring

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Flupentixol: relevance of stereoselective therapeutic drug monitoring

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