J Neural Transm DOI 10.1007/s00702-015-1403-7

PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - ORIGINAL ARTICLE

Melperone but not bisoprolol or metoprolol is a clinically relevant inhibitor of CYP2D6: evidence from a therapeutic drug monitoring survey Gudrun Hefner1,2 • Stefan Unterecker3 • Mohamed E. E. Shams4,5 • Margarete Wolf6 • Tanja Falter2 • Ekkehard Haen6 • Christoph Hiemke1

Received: 6 January 2015 / Accepted: 29 April 2015  Springer-Verlag Wien 2015

Abstract Cytochrome P450 enzymes (CYP) can be inhibited or induced by drugs, resulting in clinically significant drug–drug interactions that can cause unanticipated adverse reactions or therapeutic failures. The objective of the study was to analyze the in vivo inhibitory potential of the beta-blockers bisoprolol and metoprolol as well as the low-potency antipsychotic melperone on CYP2D6. By utilizing a large therapeutic drug monitoring database of 2874 samples, data from patients who had been treated with venlafaxine (VEN) either without (control group) or with a concomitant medication with bisoprolol, metoprolol or melperone were evaluated retrospectively to study the CYP2D6-catalyzed O-demethylation to O-desmethylvenlafaxine (ODVEN). Dose-adjusted serum levels (C/D) of VEN and ODVEN as well as the metabolic ratios (ODVEN/VEN) were computed for the four groups and compared using Kruskal–Wallis test. In total, 381 patients

could be included for analysis. No significant difference was found in the median C/D (VEN), C/D (ODVEN) or C/ D of the active moiety (VEN ? ODVEN) in either the metoprolol (N = 103) or bisoprolol group (N = 101), compared to the control group (N = 108). In contrast, a significantly higher median C/D (VEN) (0.79 ng/ml/mg, range 0.13–5.73 ng/ml/mg) (P \ 0.01) was found in the melperone group (N = 69), compared to the control group (0.46 ng/ml/mg, range 0.02–7.39 ng/ml/mg). A significant decrease (P \ 0.01) was solely found in the median metabolic ratios of ODVEN/VEN between the melperone group (0.90, range 0.14–15.15), compared to the control group (2.39, range 0.06–15.31). The results of this study provided evidence that melperone but not bisoprolol or metoprolol has a clinically relevant inhibitory potential on CYP2D6. Keywords Therapeutic drug monitoring  Venlafaxine  CYP2D6  Metoprolol  Melperone  Bisoprolol

& Gudrun Hefner [email protected] 1

Department of Psychiatry and Psychotherapy, University Medical Centre Mainz, Mainz, Germany

2

Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany

3

Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Wu¨rzburg, Wu¨rzburg, Germany

4

Department of Pharmaceutics, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt

5

Department of Pharmacy Practice, Ministry of Health, College of Health Sciences, Muscat, Oman

6

Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

Introduction Multiple drug therapy is common in clinical practice and the resultant potential for drug–drug interactions (DDI) is increasing exponentially (Cadieux 1989) with increasing number of applied drugs. Predicting potential DDI is important for the safety and tolerability of pharmacotherapy in the clinical setting. Slaughter and Edwards (1995) reported that an improvement in the therapeutic risk/benefit ratio can only be reached if people know which enzymes are responsible for the metabolism of the drugs and if the ability of the drugs to inhibit or induce the activity of the cytochrome P450 (CYP) enzymes is known. Inhibition of CYP metabolism is

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recognized as one of the most important mechanisms of clinical DDIs and may result in serious toxicological consequences, if dosage of the substrate is not adjusted (Hiemke et al. 2011). Most of orally administered drugs are metabolized via hepatic phase I metabolism by oxidative enzymes such as CYP which are predominantly present in the human liver (Gonzalez 1988). Seven isoforms are currently considered to be relevant for drug metabolism in humans and CYP3A4 and CYP2D6 are responsible for the metabolism of approximately 80 % of all marketed drugs (Guengerich 1996; Lewis et al. 1997; Shimada et al. 1994). Most of the psychotropic drugs are metabolized extensively via CYP enzymes and some of them are inhibitors or inducers of these enzymes. In particular, CYP2D6 catalyzes the metabolism of many psychotropic drugs (Eichelbaum et al. 1997; Michalets 1998). Because of a growing appreciation for CYP-mediated DDI, the understanding of pharmacokinetic DDI related to involvement of CYP isoenzymes has increased remarkably in the past decades, and many drugs have been identified as substrates, inhibitors or inducers of CYP. Therefore, several tables of drugs as substrates, inhibitors and inducers of drug-metabolizing CYP enzymes have been published (Hiemke et al. 2011; Polasek et al. 2011). In addition, a drug interaction website was established to document the Food and Drug Administration (FDA) current understanding of DDI related to involvement of CYP (Huang et al. 2008). Bisoprolol is a drug belonging to the group of betablockers, a class of medicines used primarily in cardiovascular diseases. It is a selective type b1 adrenergic receptor blocker. Data concerning a CYP2D6 inhibitory potential of bisoprolol are lacking, and it is not listed as inhibitor or inducer of drug-metabolizing CYP enzymes (Hiemke et al. 2011; Polasek et al. 2011). Metoprolol is also a widely prescribed selective type b1 adrenergic receptor blocker. The drug undergoes extensive hepatic firstpass metabolism (Borg et al. 1975) and is a selective substrate of CYP2D6 (Lennard et al. 1982). Polasek et al. (2011) listed metoprolol as a weak inhibitor of CYP2D6, defined as a C1.25-fold but less than twofold area under time–concentration curve (AUC) increase or C20 % but \50 % decrease in clearance probe substrate in vivo. The Arbeitsgemeinschaft fu¨r Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) listed metoprolol in their consensus guidelines as a clinically relevant CYP2D6 inhibitor. According to in vitro (Otton et al. 1983, 1984) and in vivo (Bax et al. 1981; Kallio et al. 1990; Ko¨hler et al. 1997; Perrild et al. 1989) studies, results concerning a CYP2D6 inhibitory effect of metoprolol are inconsistent and need further investigation. Melperone is an antipsychotic drug used for sleep induction (Christensson 1989; Kretzschmar et al. 1976)

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which is frequently prescribed in psychiatric setting. Ko¨hnke et al. (2006) reported an inhibitory effect of melperone on the metabolism of risperidone, a CYP2D6 and CYP3A4 substrate, in three cases. In a small study by Gro¨zinger et al. (2003), three patients who were treated concomitantly with venlafaxine (VEN) and melperone had significantly higher VEN (?52 %) and lower Odesmethylvenlafaxine (ODVEN, -29 %) serum concentrations compared to patients without melperone comedication. However, the FDA does not list melperone as a CYP2D6 inhibitor (U.S. Food and Drug Administration 2014), despite some studies (Gro¨zinger et al. 2003; Ko¨hnke et al. 2006) identified melperone as moderate CYP inhibitor, as defined by the FDA. VEN is a dual serotonin and noradrenaline reuptake inhibitor used as first-line treatment for depressive disorders. VEN is metabolized primarily by the highly polymorphic enzyme CYP2D6 to the active metabolite ODVEN, and to a lesser extent by CYP2C19 and CYP3A4, to yield N-desmethylvenlafaxine (NDVEN) (Fogelman et al. 1999; Hiemke et al. 2011). Regarding the variability of plasma concentrations at a given dose, phenotyping (Hiemke and Shams 2013) is most helpful to characterize the inhibitory or inducing potential of compounds with unknown activity. According to van der Weide et al. (2005) as well as Shams et al. (2006), phenotyping is appropriate to identify clinically relevant inhibitors of CYP2D6, as the metabolic ratio of ODVEN/ VEN represents a biomarker for VEN clearance. As data concerning a CYP2D6 inhibitory effect of bisoprolol were lacking and in case of metoprolol were inconsistent, as well as study samples concerning a CYP2D6 inhibitory effect of melperone were rather small, we analyzed the in vivo inhibitory potential of these drugs using the CYP2D6-catalyzed formation of ODVEN from the parent drug VEN as a marker reaction. We used data from a therapeutic drug monitoring (TDM) survey obtained of patients for whom blood level measurement of VEN and ODVEN had been requested to guide the antidepressant drug therapy.

Materials and methods The present study was conducted at the Departments of Psychiatry and Psychotherapy of the University of Regensburg and the University Medical Center Mainz in Germany. A large TDM database of TDM request forms of VEN in the two hospitals was analyzed in the period between October 2006 and April 2013. The database contained 2874 samples from in- and outpatients who had been treated with venlafaxine. Retrospective analysis of clinical data for this study was in accordance with regulations

Melperone but not bisoprolol or metoprolol…

¨ rztekammer given by the local ethics committee of the A Rheinland-Pfalz. Patients Patients were included when they had been treated with VEN without versus with comedication of bisoprolol, metoprolol or melperone under naturalistic conditions and for whom blood level measurements were requested. No restriction was made with respect to age, severity of illness at the time of clinical assessment, treatment time or dosage of VEN, bisoprolol, metoprolol and melperone before clinical assessment as well as to somatic comorbidities or the psychiatric diagnosis. Patients were excluded upon further comedication with any reported CYP2D6 inhibitor that was mentioned in the AGNP consensus guidelines (Hiemke et al. 2011). Samples with missing data regarding serum concentration of VEN or ODVEN were also not considered for evaluation. The recruited patients were divided into four groups. The first group represented patients who had been treated with VEN (control) without bisoprolol, metoprolol or melperone as comedication while other groups represented patients with coadministration of bisoprolol (second group), metoprolol (third group) or melperone (fourth group). Only the most recent TDM analysis per patient was considered to prevent the inclusion of multiple determinations of the same patient. Chromatographic determination of venlafaxine and its metabolites Racemic VEN and ODVEN serum concentrations were quantified using an isocratic reversed-phase high-performance liquid chromatography (HPLC) method with fluorescence detection in the TDM laboratory of the hospital in which the respective patient was treated. The method for the determination of VEN and ODVEN was developed and validated in the laboratories of the two hospitals in Mainz and Regensburg, Germany. Accuracy, precision, linearity and recovery fulfilled the criteria of the GTFCh guidelines (Schmitt et al. 2003). Both laboratories participated in the same external quality control program (Cardiff Bioanalytical Services, The Cardiff Medic Center, Cardiff, UK) with external control samples analyzed monthly. The quality control program was operated in both laboratories without rejects. The procedure of TDM is described in detail elsewhere (Hiemke et al. 2011). Statistical analysis Serum concentrations of VEN, ODVEN and of the active moiety (VEN ? ODVEN) were corrected by the applied

daily dose (C/D) and the ratios of ODVEN/VEN were calculated in accordance with the AGNP consensus guidelines (Hiemke et al. 2011). These variables were compared between the different groups using Kruskal– Wallis test. Furthermore, patients were phenotyped by the ratio ODVEN/VEN according to the classification of Shams et al. (2006). Statistical analysis was carried out using IBM SPSS Statistics version 20.0 (IBM GmbH, Ehningen, Germany). A P \ 0.05 was considered as statistically significant.

Results In total, 381 patients who met the inclusion criteria were retrospectively enrolled in the current research study. The demographic data of these patients are presented and summarized in Table 1. The bisoprolol group consisted of 101 patients, the metoprolol group of 103 patients, and the melperone group of 69 patients while the control group consisted of 108 patients. The median (range) serum concentrations (ng/ml) of VEN, ODVEN, the active moiety (VEN ? ODVEN), as well as the metabolic ratios (ODVEN/VEN) and the doseadjusted serum concentrations (ng/ml/mg) C/D (VEN), C/ D (ODVEN) and C/D (VEN ? ODVEN) of the four groups are displayed in Table 2. A marked inter-individual variability of the serum concentrations of VEN, ODVEN and the active moiety (VEN ? ODVEN) was detected in all groups (Table 2), also when adjusted by daily dosage. No significant difference was found in the median C/D (VEN), C/D (ODVEN) and C/D (VEN ? ODVEN) in case of the bisoprolol or metoprolol group when compared to the control group (Table 2). In contrast to the previous results, a significantly higher median C/D (VEN) was found in the melperone group (0.79 ng/ml/mg, range 0.13–5.73 ng/ml/mg) (P \ 0.01) compared to the control group (0.46 ng/ml/mg, range 0.02–7.39 ng/ml/mg). In all patients, coadministration of melperone significantly increased the median C/D (VEN) by 71.7 % (P \ 0.01) as shown in Table 3. However, no significant difference of the median C/D (ODVEN) or C/ D (VEN ? ODVEN) was observed between the melperone and the control group (Table 2). In addition, no significant difference was found in the median metabolic ratio ODVEN/VEN between the bisoprolol (2.42, range 0.13–11.29) or metoprolol group (2.18, range 0.06–18.36) and the control group (2.39, range 0.06–15.31), as shown in Fig. 1 and Table 2. However, the median ODVEN/VEN was significantly lower (P \ 0.01) in the melperone group (0.90, range 0.14–15.15) compared to the control group. Coadministration of melperone

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G. Hefner et al. Table 1 Patients’ characteristics Group

Number of patients

Number of patients aged C65 years (%)

Age (years) Median (range)

Gender % Females

% Males

Bisoprolol

101

36 (35.6)

56 (26–86)

59.4

40.6

Metoprolol

103

42 (40.8)

58 (20–89)

65.0

35.0

225.0 (37.5–450.0)

Melperone

69

14 (20.3)

50 (21–86)

65.2

34.8

168.75 (75.0–375.0)

108

43 (39.8)

54 (21–87)

66.7

33.3

150.0 (37.5–450.0)

Control

significantly decreased (P \ 0.01) the median ODVEN/ VEN by 62.3 % compared to the control group (Table 3). According to the CYP2D6 phenotype classification by Shams et al. (2006), a higher rate of CYP2D6 poor metabolizer phenotypes and a lower rate of ultra-rapid metabolizer phenotypes were detected in the melperone group, compared to the other groups. In the melperone group, 11 patients (15.9 %) were poor metabolizers and five patients (7.2 %) were ultra-rapid metabolizers. In contrast, in the control group, only nine patients (8.3 %) were poor metabolizers and 20 patients (18.5 %) were ultra-rapid metabolizers. In the bisoprolol group, only two patients (2.0 %) were poor metabolizers and 15 patients (14.9 %) were ultra-rapid metabolizers and in the metoprolol group, only five patients (4.9 %) were poor metabolizers, while 16 patients (15.5 %) were ultra-rapid metabolizers.

Discussion To the best of our knowledge, this is the largest study that analyzed the inhibitory effect of metoprolol, bisoprolol and melperone on CYP2D6 in a naturalistic setting. In addition, the present study is the first that employed the CYP2D6catalyzed formation of ODVEN from VEN as marker reaction to analyze CYP2D6 inhibitory effects of metoprolol and bisoprolol. In this TDM study, a marked inter-individual variability of the serum concentrations of VEN, ODVEN and the active moiety (VEN ? ODVEN) was detected in all groups, also when adjusted by dosage. The high variability of dose-adjusted serum concentrations could be explained by the dependence of venlafaxine serum levels on, e.g., gender, age, smoking status, and comedication. Unterecker et al. (2012) demonstrated an additive effect of gender (females ?30 %), age (elderly ?46 %) and smoking status (smokers -21 %), resulting in a high variability of venlafaxine serum levels. Furthermore, because of multiple drug intake (Vestal 1997), age-related pharmacokinetic changes (Turnheim 2003) and a higher prevalence rate of comorbidities (Salive 2013), as renal disease (Nagler et al. 2012), elderly patients C65 years might have a much higher variability in dose-adjusted venlafaxine serum

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Venlafaxine dose (mg/day) Median (range) 225.0 (22.5–375.0)

concentration, compared to patients \65 years. Some previous studies (Sigurdsson et al. 2014; Unterecker et al. 2012) established that elderly patients show higher venlafaxine serum levels. The variables gender, age and smoking status could not be considered in our study and might therefore confound our results. It was the primary aim of this data mining study to compare the potential of three comedications to inhibit CYP2D6. Venlafaxine was used as a ‘‘probe drug’’. The CYP2D6-catalyzed formation of O-desmethylvenlafaxine was a measure of CYP2D6 in vivo activity. Other interfering factors were neglected. The number of patients above age 65 was lower in the melperone group (20 %) compared to the other three groups (35–40 %). Age does not have an impact on the ratio of concentrations ODVEN/VEN as we have shown previously (Sigurdsson et al. 2014; Unterecker et al. 2012). Observed differences between the melperone and the control group were therefore not due to age differences. Lastly, genetic polymorphisms of the isoenzyme CYP2D6, which has been demonstrated to cause relevant variance of the inter-individual serum levels (McAlpine et al. 2011), have not been determined in our study. Under consideration of the limitations of this study, we found that melperone but neither metoprolol nor bisoprolol is a clinically relevant inhibitor of CYP2D6. Previous in vitro and in vivo studies (Bax et al. 1981; Kallio et al. 1990; Ko¨hler et al. 1997; Otton et al. 1984; Polasek et al. 2011) that analyzed the CYP2D6 inhibitory potential of metoprolol were restricted by small sample sizes or methodical issues, thus, no good quantitative data were readily available. It has to be considered that data from in vitro studies are not always applicable to the effects shown in clinical practice. In addition, different CYP2D6 substrates (debrisoquine, sparteine, antipyrine and dextromethorphan) were used to analyze CYP2D6-inhibitory effects of metoprolol and confounding factors such as age, gender, smoking status, genotype and comedication were differentially considered in these studies. Hence, data have been inconsistent and a comparison of results between these studies and the present one needs to be done with caution. An in vivo study by Kallio et al. (1990) analyzed a weak CYP2D6 inhibitory effect of metoprolol (100 mg/day) given to six healthy volunteers with a mean age of 24 years

** Significant difference (P \ 0.01) compared to the control group receiving solely venlafaxine (Kruskal–Wallis test)

* Significant difference (P \ 0.05) compared to the control group receiving solely venlafaxine (Kruskal–Wallis test)

VEN venlafaxine, ODVEN O-desmethylvenlafaxine, C/D dose-adjusted serum concentration

Data presented as median (range)

1.73 (0.39–7.00)

1.66 (0.10–7.87) 1.00 (0.01–4.20) 0.46 (0.02–7.39) 2.39 (0.06–15.31) 319.6 (23.6–1180.9) 81.5 (6.4–1108.3) Control

185.8 (2.0–743.0)

1.76 (0.34–12.05) 1.04 (0.07–9.19)

0.79 (0.08–3.35) 0.79 (0.13–5.73)**

0.64 (0.03–3.75) 2.18 (0.06–18.36)

0.90 (0.14–15.15)** 307.0 (78.0–1117.0)

324.0 (50.8–1133.0)

158.0 (14.0–860.0)* Melperone

136.0 (16.9–1005.0)

116.0 (3.8–714.0) Metoprolol

224.0 (5.0–733.0)

1.73 (0.28–6.91) 1.03 (0.17–4.33) 342.0 (29.0–1370.0) 208.0 (14.0–750.0) 89.0 (10.0–1212.0) Bisoprolol

VEN

ODVEN

VEN ? ODVEN

2.42 (0.13–11.29)

0.51 (0.08–3.23)

VEN

C/D (ng/ml/mg) Metabolic ratio (ODVEN/VEN) Serum concentration (ng/ml) Group

Table 2 Serum concentrations, dose-adjusted serum concentrations and metabolic ratios of venlafaxine in the different study groups

ODVEN

VEN ? ODVEN

Melperone but not bisoprolol or metoprolol…

(mixed gender). All subjects were classified as extensive metabolizers before the beginning of the treatment. An increase in debrisoquine metabolic ratio for approximately 25 percent was observed after 1 week of treatment, not reaching statistical significance. In an in vivo study by Bax et al. (1981), five non-smoking, healthy males (aged 24–37 years) received 200 mg/day of metoprolol, without further co-administered drugs. Metoprolol significantly decreased the antipyrine clearance by 18.0 ± 4.7 %, keeping in mind that antipyrine is not an evidence-based selective CYP2D6 substrate. Because of the inconsistent genotype and the small sample size, the results of this study have to be dealt with caution. In another study by Ko¨hler et al. (1997), one patient treated with metoprolol who had been genotyped as CYP2D6 intermediate metabolizer (reduced expression of CYP2D6 due to a genetic deficit) and using dextromethorphan as a probe drug displayed a poor metabolizer phenotype. Other factors could have influenced the phenotyping as a poor metabolizer in the predisposed patient which have not been taken into account, as presented for venlafaxine in a case report of Geber et al. (2013). Considering the small sample size of these studies, the results could be partially confirmed by the metoprolol sample in the present study, as a non-significant 39.1 % increase in C/D (VEN) and an 8.8 % decrease in metabolic ratio ODVEN/VEN could be observed. Nevertheless, these non-significant changes are probably explained by the high variability of C/D (VEN) because of different confounding factors (Unterecker et al. 2012), as mentioned above, and not because of a CYP2D6-inhibitory potential of metoprolol. This assumption is confirmed by the results of the bisoprolol group. Regarding published tables of drugs as inhibitors or inducers of drug-metabolizing CYP enzymes, bisoprolol has no CYP2D6-inhibitory potential (Hiemke et al. 2011; Polasek et al. 2011; U.S. Food and Drug Administration 2014). In the present study, C/D (VEN) increased non-significantly by 10.9 % and the metabolic ratio ODVEN/VEN increased by 1.3 % in the bisoprolol group. Comparing the metabolic ratio (ODVEN/VEN) of a patient as a surrogate for CYP2D6 activity (van der Weide et al. 2005) is more reliable for an inhibitory effect of a drug than comparing the C/D between the study groups because of a low within-patient variability of the metabolic ratio ODVEN/VEN (Reis et al. 2002). Therefore, the most plausible explanation for our findings would be that metoprolol and bisoprolol are no CYP2D6 inhibitors, as defined by the FDA (U.S. Food and Drug Administration 2014). Furthermore, the study by Perrild et al. (1989) confirms our results that metoprolol has no relevant CYP2D6 inhibitory potential.

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G. Hefner et al. Table 3 The percentage of change in the metabolic ratio (ODVEN/ VEN) and dose-adjusted serum concentrations of venlafaxine (VEN), O-desmethylvenlafaxine (ODVEN), and the active moiety Group

Metabolic ratio (ODVEN/VEN) (%)

(VEN ? ODVEN) in the study groups compared to the control group receiving solely venlafaxine C/D (ng/ml/mg) VEN (%)

ODVEN (%)

VEN ? ODVEN (%)

Bisoprolol

1.3:

10.9:

3.0:

4.2:

Metoprolol

8.8;

39.1:

4.0:

6.0:

Melperone

62.3**;

21.0;

4.2:

71.7**:

C/D dose-adjusted serum concentration * Significant difference (P \ 0.05) compared to the control group receiving solely venlafaxine (Kruskal–Wallis test) ** Significant difference (P \ 0.01) compared to the control group receiving solely venlafaxine (Kruskal–Wallis test) : increase, ; decrease

Fig. 1 Metabolic ratios of ODVEN/VEN in patients receiving venlafaxine either alone (control) or in combination with bisoprolol, metoprolol or melperone. **Significant difference (P \ 0.01) compared to the control group receiving solely venlafaxine (Kruskal–Wallis test)

In the melperone group, the median C/D (VEN) was 72 % higher (P \ 0.01) and the metabolic ratio ODVEN/ VEN was 62 % lower (P \ 0.01) compared to patients in the control group. This result roughly confirms another study by Gro¨zinger et al. (2003) who also measured the CYP2D6 inhibitory potential of melperone on the formation of VEN and ODVEN in three patients before, during, and after melperone coadministration. According to the CYP2D6 phenotype classification by Shams et al. (2006), most of the patients with concomitant melperone intake were not phenotyped as CYP2D6 poor metabolizers. This can be explained by the finding that

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melperone exhibited only properties of a moderate inhibitor of CYP2D6. Thus, many patients had a decreased CYP2D6 metabolism and might succumb to a metabolic shift from ultra-rapid to extensive metabolizers or from extensive to intermediate or poor metabolizer phenotype, even if the majority could not be classified as CYP2D6 poor metabolizer. Melperone did not affect the active moiety concentration of venlafaxine (VEN) plus O-desmethylvenlafaxine (ODVEN), but markedly decreased the ratio of concentrations ODVEN/VEN due to inhibition of CYP2D6 by mean from 2.4 to 0.9. This indicated that melperone is a significant inhibitor of CYP2D6. Inhibition of CYP2D6 has

Melperone but not bisoprolol or metoprolol…

consequences for drugs that are preferred substrates of CYP2D6 and degraded to inactive metabolites, e.g., nortriptyline (Hefner et al. 2014). With regard to drugs such as venlafaxine the situation is more complex. Since the active moiety concentration was not changed by addition of melperone, it may be concluded that venlafaxine effects may not change under combination with melperone. On the other hand, Lobello et al. (2010) found in depressed patients who had been phenotyped by measuring the ratio of concentration ODVEN/VEN that therapeutic efficacy was enhanced in patients with extensive metabolizer phenotypes compared to poor metabolizer phenotypes. Referring to this study, Preskorn (2010) concluded that venlafaxine is a good example that the metabolic ratio of a drug is a useful tool to detect alterations in drug metabolism and that such alterations have an impact on drug efficacy. The results indicate that melperone is a moderate CYP2D6 inhibitor, in relation to the FDA definition ([twofold but \fivefold increase in the AUC or 50–80 % decrease in clearance) (U.S. Food and Drug Administration 2014). Although melperone is not approved in the United States (US), the FDA should consider melperone as moderate CYP2D6 inhibitor in future tables, as melperone is widely used in Europe. Melperone is mostly administered for sleep induction and hypnosis. The applied doses are usually as low as 25 or 50 mg. Therefore, it would have been of interest to know doses of melperone that have contributed to the reported effect. Doses of melperone, however, were not available for our patients, since melperone was used as comedication. Case reports, however, detected inhibitory effects on the CYP2D6-mediated degradation of risperidone (Ko¨hnke et al. 2006) and nortriptyline (Hefner et al. 2014) by concomitant ingestion of 50 mg melperone. Approximately 50 % higher serum levels of these CYP2D6 substrates could be detected (Hefner et al. 2014; Ko¨hnke et al. 2006). Moreover, Gro¨zinger et al. (2003)and co-workers phenotyped seven patients who had received single doses of 50 (n = 5) or 75 mg (n = 2) melperone with the CYP2D6 probe drug dextromethorphan. These patients had a by mean 50 % reduction of the formation of dextrorphan. According to these findings at single doses of 50 mg, melperone can be categorized as an at least moderate CYP2D6 inhibitor (U.S. Food and Drug Administration 2014) which was now confirmed by this data mining study.

Limitations The sample of the present study comprised a large population of naturalistic nature and relies on retrospective data which has the limitation that patient information may

be assumed less reliable than in case of a prospective study, e.g., because of incomplete TDM request forms. Data about trough value or steady-state conditions, comorbidities or duration of prior venlafaxine, bisoprolol, metoprolol and melperone exposure were lacking and could therefore not be considered in the study. Due to the clinical setting, there is also a large individual variation in sampling time which may have partially contributed to the inter-individual variation in serum concentrations and metabolic ratios. By including only one analysis per patient in case of multiple serum concentration determinations, a patient bias was avoided. Furthermore, differences in sample characteristics and sample size in the four patient groups occurred which is limiting the comparability of the study groups with the control group and therefore our results. Information regarding comedication was assessed. Consequently, patients with co-administered CYP2D6 inhibitors were excluded from the study. Therefore, confounding factors of pharmacokinetic nature on serum concentration due to DDI are prevented. Nevertheless, CYP2C19 inhibitors and inducers were not excluded from this analysis, and could therefore have influenced the serum levels of venlafaxine (Fukuda et al. 2000; Grasmader et al. 2004).

Conclusions Therapeutic drug monitoring of venlafaxine seems to be a useful tool to detect a possible CYP2D6 inhibitory effect of drugs by comparing the metabolic ratio of ODVEN/VEN and C/D (VEN) of patients with and without drug comedication. To the best of our knowledge, this is the largest study that has analyzed the inhibitory effect of metoprolol, bisoprolol and melperone on CYP2D6 in a naturalistic setting. Under consideration of the limitations of this study, the results provide further evidence that metoprolol and bisoprolol have no relevant inhibitory potential on CYP2D6. In agreement with previous studies, the results further indicate that melperone is a moderate CYP2D6 inhibitor according to the FDA definition. The FDA should consider melperone as a moderate CYP2D6 inhibitor in future tables, as melperone is widely used in Europe. Acknowledgments Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Astra Zeneca, Janssen-Cilag, Pfizer, Lilly and Servier. He is managing director of the psiac GmbH which provides an internet based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Gudrun Hefner has received speaker’s fee from Servier. She reports no conflict of interest with this publication. All other authors declare no conflicts of interest as well. The research study did not receive funds or support from any source.

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