Effects of Comedication on the Serum Levels of Aripiprazole: Evidence from a Routine Therapeutic Drug Monitoring Service

• Abstract
• Introduction
• Material and Methods
• Results
• Discussion
• References

Abstract

Introduction: The objective of the study was to compare the serum concentrations of the atypical antipsychotic aripiprazole in monotherapy with the concentrations found during concomitant therapy with other drugs.

Methods: Samples analyzed for aripiprazole by a liquid chromatography-mass spectrometry method in a routine therapeutic drug monitoring setting were collected consecutively.

Results: Samples from 81 patients were included in the study. Comedication with the CYP3A4 inducer carbamazepine lowered the dose-adjusted aripiprazole concentration by 88%. Comedication with CYP2D6 inhibitors gave a mean concentration 44% higher than in the monotherapy group. Subjects comedicated with valproate had lower aripiprazole concentrations, while subjects comedicated with lamotrigine, citalopram/escitalopram and lithium had higher concentrations than the subjects in the monotherapy group.

Conclusion: Although the study is small and the results should be interpreted very cautiously, it indicates that comedication with drugs inhibiting or inducing CYP2D6 or CYP3A4 affects the serum concentrations of aripiprazole. The other findings should be considered as preliminary and have to be replicated in a larger setting before firm conclusions can be drawn.

Introduction

The currently available antipsychotic agents all share varying degrees of dopamine D₂ receptor blockade as an important mechanism of action. The atypical antipsychotic aripiprazole exerts a partial agonist activity at dopamine D₂ and serotonin 5-HT_1A receptors in addition to being a 5-HT_2A antagonist [8] [14].

Aripiprazole is extensively metabolized in the liver by the cytochrome P-450 enzymes CYP2D6 and CYP3A4 via N-dealkylation, hydroxylation and dehydrogenation pathways [13]. In CYP2D6 extensive metabolizers, the ratio of hepatic clearance by CYP2D6 and CYP3A4 is approximately 1:1. The active metabolite dehydroaripiprazole represents about 39% of the aripiprazole AUC in plasma [3], and CYP3A4 is the most important enzyme involved in the metabolism of this metabolite [13]. The elimination half-life of aripiprazole has been found to be 48-68 hours in healthy volunteers and the pharmacokinetics appears to be dose proportional in the dose range of 5 to 30 mg/d [14].

In a study in healthy volunteers, concomitant treatment with the CYP3A4 inhibitor itraconazole was shown to increase the area under the time-concentration curve (AUC) for aripiprazole by 48%[13]. We have not identified any published studies on the influence of CYP3A4 inducers on the pharmacokinetics of aripiprazole, but the manufacturer states that concomitant treatment with carbamazepine reduces the AUC by 73%[10]. In an open study in 12 and 10 patients, respectively, concomitant treatment with lithium increased the aripiprazole AUC by 15%, whereas coadministration with valproate reduced the AUC by 24%[3]. The CYP2D6 genotype has been found to affect the plasma concentrations of aripiprazole [13], but we have not found any studies on the effects of CYP2D6 inhibitors on the pharmacokinetics of aripiprazole.

Aripiprazole was first approved in the treatment of schizophrenia, and its effects in patients with schizophrenia and schizophrenia-like psychoses have recently been evaluated by the Cochrane Collaboration [6] [7]. There is also growing evidence for a possible augmentation role for aripiprazole in the treatment of a range of other psychiatric illnesses [1] [12] [17] [4] [11] [16]. As the number of indications for aripiprazole thus seems to increase, it could be expected that concomitant treatment with other psychotropic drugs, including antipsychotics, antidepressants, benzodiazepines and mood stabilizers, will be increasingly common in the future.

The rationale for using therapeutic drug monitoring (TDM) for new antipsychotics, including aripiprazole, is a matter of debate [10]. Well funded data on therapeutic drug concentrations of aripiprazole are so far lacking. Based on data from pharmacokinetic studies in healthy volunteers and patients with schizophrenia, the reference range in our laboratory is 250-1200 nmol/L, corresponding to 110-540 ng/mL. (The conversion factor from nmol/L to ng/mL for aripiprazole is 0.45).

As there is very limited documentation available on the effects of comedication on the pharmacokinetics of aripiprazole in a naturalistic setting, the objective of this study was to investigate this issue by using data from a routine TDM database.

Material and Methods

Samples sent to our laboratory for routine TDM of aripiprazole were collected consecutively. Information regarding age, gender, dose, time interval from last dose to sampling, and comedication with other drugs was registered. No reliable data were available on the dosage of the drugs used concomitantly. One hundred samples with complete information from 81 patients were chosen for further analysis. The indication to request serum level monitoring of aripiprazole was in most cases not stated. To include each patient only once, a mean value of dose and serum concentration was calculated for those patients who were represented by two or more samples, if their comedication was unchanged. If their comedication varied, only the first sample from the patient was included in the material. Thus, a total of 81 observations were included.

All samples were analyzed with a liquid chromatography-mass spectrometry (LC-MS) method. In brief, aripiprazole was extracted from 1 mL serum with 4 mL hexane:butanol: acetonitrile (93:5:2) after addition of an internal standard solution (25 μL of 10 μmol/L flurazepam in methanol) and alkalinization with 0.2 mL of 1 mol/L sodium carbonate. After mixing and centrifugation the organic extract was evaporated to dryness with air, the residue was reconstituted in 50 μL of 96% ethanol, transferred to vials and injected on an Agilent MSD 1100 LC-MS system (Agilent, Palo Alto, CA). Separation was performed on a Zorbax LC-CN (150×4.6 mm) column with a mobile phase consisting of methanol:ammonium acetate (75:25). Aripiprazole was monitored after positive chemical ionization (APCI) at m/z=448.2, the internal standard flurazepam at m/z=388.1. The method was linear up to at least 2000 nmol/L. Inter-day coefficient of variability was better than 9.9% at 50 nmol/L and better than 7.8% at 500 nmol/L. The limit of quantification was 10 nmol/L, corresponding to 4.5 ng/mL.

Due to the exploratory nature of the study and the low numbers of samples in the subgroups with various comedications, formal statistical testing with this regard was considered not meaningful. Comparisons of doses, concentrations and concentration/dose (C/D) ratios between males and females, and of doses in subjects using other antipsychotics or not, were carried out by the Mann-Whitney U test. P values <0.05 were considered statistically significant.

Results

Of the 81 patients included, there were 46 males and 35 females. Total and gender-specific values for age, aripiprazole doses, serum concentrations and C/D ratios are given in [Table 1]. There were no statistically significant differences between genders regarding these variables. There was no trend towards increasing C/D ratios with age.

Other drugs were used concomitantly by 58 of the 81 patients. The mean number of comedications was 1.7 (range 0-6). The effects of comedication on the serum levels of aripiprazole are shown in [Fig. 1]. The patient comedicated with the CYP3A4 inducer carbamazepine had a C/D ratio 88% lower than the mean value in the monotherapy group. No patients used CYP3A4 inhibitors concomitantly. In five patients comedicated with CYP2D6 inhibitors the mean C/D ratio was 44% higher than in the monotherapy group. In subjects comedicated with valproate, the mean C/D ratio was 24% lower than in the monotherapy group. Subjects comedicated with lamotrigine, citalopram/escitalopram and lithium had mean C/D ratios 51%, 39% and 34% higher than the monotherapy group, respectively.

One or two antipsychotics were used in addition to aripiprazole by 38% of the patients. The mean aripiprazole dose given to these patients was 23.1 mg/d, which is significantly higher than the dose in the group not treated with any other antipsychotic drug(s) (17.8 mg/d) (p=0.004).

Discussion

This study presents an overview of the doses and serum concentrations of aripiprazole achieved in a naturalistic setting, including the pharmacokinetic interaction potential of drugs often used concomitantly.

The findings that comedication with the CYP3A4 inducer carbamazepine seems to considerably decrease the serum levels of aripiprazole, whereas treatment with CYP2D6 inhibitors seems to increase the serum levels of aripiprazole are consistent with the fact that CYP2D6 and CYP3A4 are the primary enzymes involved in the metabolism of aripiprazole [13].

Comedication with valproate caused a 24% decrease in the C/D ratio. This result is in accordance with a previous study, in which valproate reduced the AUC for aripiprazole by exactly the same value, 24%[3]. Aripiprazole is highly protein-bound, and it has been speculated that the reason for the lowered concentrations is displacement from its plasma protein binding sites by valproate [3]. Then, due to the compensatory increased clearance of free drug, there will be no change in the unbound plasma concentration whereas the measured plasma concentration (reflecting the concentration of free+protein-bound drug) will decrease. If this hypothesis is correct, the lowered aripiprazole concentrations do not require dose increments, as only free drug can be transported to the target organ and exert a pharmacological effect.

Comedication with lithium increased the C/D ratio of aripiprazole by 34%. Lithium is neither metabolized nor bound to plasma proteins in humans, and no pharmacokinetic interactions with drugs metabolized by CYP2D6 or CYP3A4 are expected. Nevertheless, in a previous study, coadministration of lithium increased the aripiprazole AUC with 15%[3]. Comedication with lamotrigine increased the C/D ratio of aripiprazole by 51%, whereas coadministration with citalopram or escitalopram increased the C/D ratio by 39%. Lamotrigine is metabolized predominantly by glucuronidation, and does not have any effects on the activity of CYP enzymes [5]. Citalopram and escitalopram are weak inhibitors of CYP2D6 in vitro, but this effect is clinically negligible [2] [18]. The effects of these drugs on the pharmacokinetics of aripiprazole have not been studied previously.

We cannot see any obvious mechanism for the apparent effects of lithium, lamotrigine, citalopram and escitalopram on aripiprazole metabolism. The findings could simply be coincidental due to the low number of samples studied. Alternatively, the effects might be caused by non-pharmacological factors, such as the possibility that patients receiving mood stabilizers or antidepressants have a better adherence to aripiprazole treatment than average. More studies are needed to explore these issues further.

As we were unable to retrieve the active metabolite dehydroaripiprazole from the manufacturer of aripiprazole, dehydroaripiprazole was not analyzed in the samples included in this study. As CYP3A4 has been shown to be the predominant enzyme involved in the metabolism of dehydroaripiprazole [13] one can make some assumptions regarding the consequences of the different comedications on the concentration of dehydroaripiprazole. It is likely that coadministration with carbamazepine will affect the level of dehydroaripiprazole in the same direction and in the same order of magnitude as for aripiprazole, as indicated in the study with the CYP3A4 inhibitor itraconazole [13]. In the same study [13] the AUC for aripiprazole was 39% higher in CYP2D6 intermediate metabolizers than in extensive metabolizers, whereas the AUC for aripiprazole plus dehydroaripiprazole was only 18% higher. Thus, it could be expected that the impact of CYP2D6 inhibition on aripiprazole plus dehydroaripiprazole would be lower than we have found for aripiprazole in the present study, as the direction of change in the concentration of the active metabolite tends to offset the effect on the parent drug.

The results of this study should be interpreted very cautiously. First, the study is small, particularly when it comes to the subgroups treated with various comedications. Second, the routine TDM setting did not allow us to control patient adherence to the treatment or to cross-check the information given with regard to dosage, comedications, and whether a steady-state condition was achieved. The patients included in the study were not genotyped, and one cannot exclude that some of the high aripiprazole C/D ratios (e.g., in column 2 in [Fig. 1]) are a result of low CYP2D6 activity. Nevertheless, the results on the effects of genetically determined concomitant therapy with drugs causing CYP3A4 induction and CYP2D6 inhibition are consistent with the findings from previous studies performed in a controlled setting in a few healthy volunteers and patients with schizophrenia.

In conclusion, this study adds evidence to the results from experimental studies indicating that comedication with drugs inhibiting or inducing CYP2D6 and CYP3A4 affects the serum levels of aripiprazole. A lower aripiprazole concentration during comedication with valproate, which previously has been suggested to be caused by protein binding displacement and thus being clinically insignificant, was also observed in the present study. The findings regarding lamotrigine, citalopram/escitalopram and lithium should be considered as preliminary and have to be replicated in a larger material before any firm conclusions can be drawn.

References

• 1 Adson DE, Kushner MG, Fahnhorst TA. Treatment of residual anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake inhibitors.  J Affective Disord. 2005;  86 99-104
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  CrossrefPubMedSearch in Google Scholar
• 14 Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers.  J Clin Pharmacol. 2004;  44 179-187
  PubMedSearch in Google Scholar
• 15 McGavin JK, Goa KL. Aripiprazole.  CNS Drugs. 2002;  16 779-786
  PubMedSearch in Google Scholar
• 16 Nickel MK, Muehlbacher M, Nickel C, Kettler C, Gil FP, Bachler E. et al . Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study.  Am J Psychiatry. 2006;  163 833-838
  CrossrefPubMedSearch in Google Scholar
• 17 Papakostas GI, Petersen TJ, Kinrys G, Burns AM, Worthington JJ, Alpert JE. et al . Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder.  J Clin Psychiatry. 2005;  66 1326-1330
  PubMedSearch in Google Scholar
• 18 von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram.  Drug Metab Dispos. 2001;  29 1102-1109
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Correspondence

I. CastbergMD 

Department of Forensic Psychiatry Brøset

P.O.Box 1803 Lade

7440 Trondheim

Norway

Phone: +47/73/865 000

Email: ingrid.castberg@stolav.no

References

• 1 Adson DE, Kushner MG, Fahnhorst TA. Treatment of residual anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake inhibitors.  J Affective Disord. 2005;  86 99-104
  CrossrefPubMedSearch in Google Scholar
• 2 Brøsen K, Naranjo CA. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram.  Eur Neuropsychopharmacol. 2001;  11 275-283
  CrossrefPubMedSearch in Google Scholar
• 3 Citrome L, Josiassen R, Bark N, Salazar DE, Mallikaarjun S. Pharma- cokinetics of aripiprazole and concomitant lithium and valproate.  J Clin Pharmacol. 2005;  45 89-93
  CrossrefPubMedSearch in Google Scholar
• 4 Connor KM, Payne VM, Gadde KM, Zhang W, Davidson JR. The use of aripiprazole in obsessive-compulsive disorder: preliminary observations in 8 patients.  J Clin Psychitary. 2005;  66 49-51
  PubMedSearch in Google Scholar
• 5 Dickens M, Chen C. Lamotrigine. Chemistry, biotransformation and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors, Antiepileptic drugs. Philadelphia: Lippincott Williams & Wilkins 2002: 370-379
  Search in Google Scholar
• 6 El-Sayeh H, Morganti C. Aripiprazole for schizophrenia.  Cochrane Database Syst Rev. 2004;  , CD004578.pub2
  PubMedSearch in Google Scholar
• 7 El-Sayeh H, Morganti C. Aripiprazole for schizophrenia.  Cochrane Database Syst Rev. 2006;  , CD004578
  PubMedSearch in Google Scholar
• 8 Grunder G, Kugel M, Ebrecht M, Gorocs T, Modell S. Aripiprazole: pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia.  Pharmacopsychiatry. 2006;  39 ((Suppl 1)) 21-25
  Thieme ConnectPubMedSearch in Google Scholar
• 9 Hiemke C, Draqievic A, Grunder G, Hatter S, Sachse J, Vernaleken I. et al . Therapeutic drug monitoring of new antipsychotic drugs.  Ther Drug Monit. 2004;  26 156-160
  CrossrefPubMedSearch in Google Scholar
• 10 http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=18494
• 11 Kane JM, Carson WH, Saha AR, McQuade RD, Ingento GG, Zimbroff DL. et al . Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.  J Clin Psychiatry. 2002;  63 763-771
  CrossrefPubMedSearch in Google Scholar
• 12 Keck PE, Calabrese JR, McQuade RD, Carson WH, Carlson BX, Rollin LM. et al . For the aripiprazole study group. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder.  J Clin Psychiatry. 2006;  67 626-637
  PubMedSearch in Google Scholar
• 13 Kubo M, Koue T, Inaba A, Takeda H, Maune H, Fukuda T. et al . Influence of itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic aripiprazole.  Drug Metab Pharmacokinet. 2005;  20 55-64
  CrossrefPubMedSearch in Google Scholar
• 14 Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers.  J Clin Pharmacol. 2004;  44 179-187
  PubMedSearch in Google Scholar
• 15 McGavin JK, Goa KL. Aripiprazole.  CNS Drugs. 2002;  16 779-786
  PubMedSearch in Google Scholar
• 16 Nickel MK, Muehlbacher M, Nickel C, Kettler C, Gil FP, Bachler E. et al . Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study.  Am J Psychiatry. 2006;  163 833-838
  CrossrefPubMedSearch in Google Scholar
• 17 Papakostas GI, Petersen TJ, Kinrys G, Burns AM, Worthington JJ, Alpert JE. et al . Aripiprazole augmentation of selective serotonin reuptake inhibitors for treatment-resistant major depressive disorder.  J Clin Psychiatry. 2005;  66 1326-1330
  PubMedSearch in Google Scholar
• 18 von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram.  Drug Metab Dispos. 2001;  29 1102-1109
  PubMedSearch in Google Scholar

Correspondence

I. CastbergMD 

Department of Forensic Psychiatry Brøset

P.O.Box 1803 Lade

7440 Trondheim

Norway

Phone: +47/73/865 000

Email: ingrid.castberg@stolav.no