Therapeutic Drug Monitoring of Cariprazine – Updated Values for a Dose-Related Reference Range

• Abstract
• Background
• Methods
• Results
• Conclusion
• References

Abstract

Background

Dose-related reference ranges can be used in therapeutic drug monitoring to monitor pharmacotherapy. The deviation of a measured serum concentration from the expected serum concentration at the corresponding dose can thus be identified early and responded to appropriately. The serum concentrations of patients treated with cariprazine regularly deviated from this dose-related reference range. As this is a relatively new drug with only one recommendation on values for a dose-related reference range, the values were tested for validity using real-world data.

Methods

Serum concentrations of 24 patients receiving cariprazine once daily were analyzed retrospectively. Only patients without pharmacokinetic abnormalities were included. The measured serum concentrations were compared with the values of the dose-related reference range in the guidelines of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie consensus guidelines of 2017 and checked whether a sufficient number of serum concentrations were within the dose-related reference range.

Results

Only 45.8% of the measured serum concentrations were within the dose-related reference range. The C/D ratio was 1.58±0.73. Accordingly, a lower value of 0.85 and an upper value of 2.31 were calculated for the updated dose-related reference range, which is below the currently recommended values.

Conclusion

The results suggest that the current values for the dose-related reference range are too high and require adjustment. The updated dose-related reference range lies between 0.85 and 2.31, with a mean of 1.58±0.73.

Background

Cariprazine is an antipsychotic drug that has been used successfully for years in the treatment of schizophrenia and bipolar disorder and as an augmentation therapy for severe depressive disorder.¹ The efficacy, safety, and tolerability of cariprazine have been demonstrated in several randomized controlled trials and meta-analyses [1] [2] [3] [4] [5] [6] [7].

The use of reference ranges has proven helpful in therapeutic drug monitoring (TDM) [8] [9] [10]. As there is a correlation between efficacy, safety, tolerability, and serum concentration, it is useful to measure a drugʼs serum concentration and refer to reference ranges to provide patients with the best possible therapy [9].

In the most recent update of the consensus guidelines of the AGNP (Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie)-TDM expert group for TDM in psychiatry from 2017, a dose-related reference range (DRR) for cariprazine was specified for the first time [9]. The DRR can be used to consider pharmacokinetic variability in individual patients due to, e. g., drug-drug interactions, comorbidities, genetic variability, or non-adherence; in consequence, using DRR can improve TDM result interpretation [9] [11] [12].

The DRR is defined in the guidelines as the range in which the serum concentration of a patient is expected to be at a specific dose. The range spans from mean±standard deviation (SD) and is derived from pharmacokinetic studies. Therefore, 68% of serum concentrations are expected to be within the lower and upper limits of the DRR. However, this assumption can only be applied to patients considered “normal” according to AGNP guidelines, i. e., 18–65 years of age, without pharmacokinetic abnormalities, and complete adherence to medication intake [9].

In daily clinical practice at the University Hospital Frankfurt, Germany, serum concentrations of patients treated with cariprazine were often outside the currently used DRR. There are several reasons why a patientʼs serum concentrations may consistently fall outside the DRR. Non-adherence and an inadequately defined range are two possibilities [9] [12]. If non-adherence is suspected, but it is due to an inadequate defined DRR, this can lead to a lasting loss of trust in the doctor-patient relationship. Thus, clinicians need to rely on the DRR to provide optimal pharmacotherapy [9]. It is, therefore, essential to review the current DRR of cariprazine based on evidence and adjust it if necessary.

Methods

In this study, we retrospectively analyzed our TDM data within a naturalistic cohort and examined the current DRR values of cariprazine by Hiemke et al. for validity [9].

The sample covered 73 cariprazine serum concentrations from 26 patients who received treatment at the Department of Psychiatry, Psychosomatic Medicine and Psychotherapy at the University Hospital Frankfurt between December 2019 and April 2022. All patients received cariprazine once daily per os. Both inpatients and outpatients were included. Blood was drawn according to the AGNP-TDM expert group recommendations at trough level at steady-state [9]. Serum tubes without gel were used for serum collection. Storage and transport of the samples were conducted at temperatures of 2–8 degree Celsius. The blood samples were analyzed externally with liquid chromatography tandem-mass spectrometry at the TDM laboratory of the University Hospital Würzburg, Germany.

We only analyzed samples from patients who could be considered “normal” according to the AGNP guidelines to exclude pharmacokinetic influences as best as possible [9]. The inclusion criteria, therefore, included age between 18 to 65 years, steady state (5 times elimination half-life), and trough level concentrations (Cmin) [9]. The exclusion criteria included simultaneous use of drugs that affect the CYP3A4 enzyme system and liver or kidney disease [9]. To prevent selection bias, only the last sample was considered in the case of several measurements of serum concentrations in one patient.

Patient information was retrieved through the hospitalʼs electronic information system, including sex, age, dose received, measured serum concentration, co-administered medication, comorbidities, and indication for cariprazine administration. As the lower limit of quantification was 2.8 ng/mL, we calculated 1.4 ng/mL if the laboratory reported a serum concentration of<2.8 ng/mL. In addition, it was examined whether there was a correlation between the measured serum concentration and the administered dose, and it was also determined whether there were pharmacokinetically relevant differences between the two sexes.

To calculate the DRR, the dose-related concentration factors (DRC factors) provided by the AGNP-TDM expert group were multiplied by the dose in milligrams. DRC factors, therefore, specify a lower and upper limit depending on the dose and are based on data from pharmacokinetic studies. The DRC factor for cariprazine published with the AGNP guidelines is 2.05±0.49 SD. Thus, we multiplied the different doses (1.5–10.5 mg at 1.5 mg intervals) with 1.56 (lower value) and 2.54 (upper value) and presented this graphically in a scatter plot [9].

The concentration-to-dose ratio (C/D ratio) also indicates the serum concentration per milligram. It can be easily calculated by dividing a measured serum concentration by the dose received [9]. C/D ratios can be used to evaluate pharmacokinetic differences and adherence, as a linear correlation between received dose and serum concentration can be expected [9] [11] [13] [14]. We, therefore, divided the measured serum concentrations by the respective doses received by the patients and calculated a mean value±SD from the C/D ratios [9]. Accordingly, this represents updated DRC factors. IBM SPSS Statistics for Windows, version 29.0.1.1 (IBM, Armonk, N.Y., USA) was used for statistical analysis.

Results

After applying the inclusion and exclusion criteria, 24 serum concentrations were analyzed. A total of 73 samples were initially available, of which one had to be excluded due to duplicate measurements and 46 further samples due to repeated measurements. Two further samples had to be excluded because the patients were not in steady-state condition at the time of blood collection.

Of the 24 patients included, 62.5% (n=15) were female, and 37.5% (n=9) were male, with a mean (±SD) age of 38.0±11.4 years (range 18–63 years). 41.7% (n=10) of the patients were treated for schizophrenia, 50.0% (n=12) for bipolar disorder, and 8.3% (n=2) for major depressive disorder. 50% (n=12) were outpatients and 50% (n=12) were inpatients.

A Pearson correlation coefficient was calculated to evaluate the relationship between serum concentration and dose. There was a significant strong positive relationship between the two variables, r(22)=0.67, p<0.001. A Mann-Whitney U test was performed to evaluate whether C/D Ratios differed between men and women. The results indicated that there was no significant difference between the C/D Ratios of men and women, U=57.00, p=0.558.

The mean dosage administered was 5.2±2.3 mg per day, with the majority of doses ranging from 3 to 6 mg (n=19; 79.2%). The mean serum concentration was 8.2±4.6 ng/mL, the interquartile range was 4.6 to 12.8 ng/mL. The mean C/D ratio was 1.58±0.73. Thus, we calculated a lower value of 0.85 and an upper value of 2.31 for the updated DRR ([Fig. 1]).

Among the samples, 45.8% (n=11) were within, 45.8% (n=11) below, and 8.3% (n=2) above the DRR published by the AGNP-TDM expert group ([Table 1]) [9]. 79.2% (n=19) were within, 12.5% (n=3) below, and 8.3% (n=2) above the updated DRR, based on the C/D ratios of measured serum concentrations ([Table 1]).

Conclusion

To our knowledge, this is the first study to test the established DRR values of cariprazine published by the AGNP-TDM expert group for validity [9]. As cariprazine is a relatively new drug with limited data available, our cohort provides important new data to establish a more precise DRR.

An accurate and evidence-based DRR for cariprazine is essential. The deviation of a measured serum concentration from a DRR may indicate potential abnormalities such as partial non-adherence or drug-drug interactions and may help identify such patients [9]. In such cases, steps could be taken that could have major consequences for the patientʼs medication or even the doctor-patient relationship [8] [9] [12]. Furthermore, an inaccurately defined DRR could lead to clinicians no longer using it in the long term, as far too large a number would be outside the values by default.

The currently used DRR values specified in the AGNP guidelines did not apply to our patient population, as there were only a few serum concentrations within the DRR ([Table 1]). Due to our precise selection process and the exclusion of patients with pharmacokinetic abnormalities, we recommend updated DRR values for cariprazine, as our results accordingly suggest inadequately defined DRR values [9].

It should be noted that 32% of all patients are naturally outside the DRR – therefore, serum concentrations above or below a DRR should not automatically be considered as requiring intervention. However, considerably more patients (n=13; 54.1%) were outside the DRR values of the AGNP guidelines, and only 20.8% (n=5) were outside the updated DRR values ([Table 1]) [9].

It is unclear exactly how the DRR values of the AGNP guidelines were calculated from a study by Nakamura et al. [9] [15]. Another study by Hefner et al. aiming to test the validity of the DRR published in the AGNP guidelines of 2011 and 2017 also found a discrepancy between real-world data on aripiprazole, duloxetine, lamotrigine, risperidone, valproic acid and venlafaxine, and the recommended DRR values, emphasizing that more pharmacokinetic data is needed in the field of TDM [9] [16] [17]. Hefner et al. compared the percentages below, within, and above the DRR specified in the AGNP guidelines to determine whether the minimum 68% of serum concentrations were within the DRR [9] [17].

The consideration of pharmacokinetic studies with a large sample size supports the need for an update, especially since our sample size is relatively small. For example, the measured C_min concentrations from a study by Periclou et al., with a total sample size of 2599, are much more significant [18]. The mean serum concentrations reported here are 22 nM (9.4 ng/mL) at a dosage of 6 mg/day (Table 3 in the study) [18]. If the mean DRC factor (2.05) of the AGNP guidelines were applied at 6 mg, a mean serum concentration of 12.3 ng/mL would be expected, instead of the 9.4 ng/mL measured by Periclou et al. [9] [18]. If the updated mean DRC factor (1.58) were applied at 6 mg, a mean serum concentration of 9.5 ng/mL would be expected, which is very close to the 9.4 ng/mL measured by Periclou et al. [18].

Specifically, regarding the cariprazine data, it was recently recommended that the therapeutic reference range should be lowered, and our results regarding the mean and interquartile range of serum concentrations support this recommendation [19] [20]. This may suggest that the DRR was also not defined correctly and may need to be revised [20].

Some limitations should be noted. Firstly, although the number of patients (n=24) was small, it is identical to the number of patients in the study by Nakamura et al. (n=24), on which the current DRR values of the AGNP guidelines are based [9] [15]. As mentioned above, it remains unclear how exactly the DRR values for cariprazine were determined in the AGNP guidelines; our calculation is more transparent in this respect [9]. Secondly, it would also have been desirable to have the same number of patients or serum concentration measurements for the different doses. Furthermore, data on the active metabolites are missing, as the laboratory did not determine these. The AGNP guidelines also state DRR values for the two active metabolites desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR) in addition to the parent compound for cariprazine [9] [21]. In this study, we could only determine DRR values for the parent compound as the laboratory´s analysis method is only for cariprazine. Further studies would be necessary to determine DRR values for the active metabolites, as these are involved in clinical efficacy [21]. However, as only limited data on serum concentrations are available for cariprazine, our results are valuable for routine clinical practice to improve pharmacotherapy with cariprazine.

Whether the dose-related reference range in the AGNP guidelines is not exclusively based on a C/D ratio needs to be further clarified. The DRC factors were calculated using a formula outlined in the AGNP guidelines (Chapter 2.2 and Table 5 in the guidelines), with the lower and upper DRC factors reflecting variations in the pharmacokinetic parameter total apparent clearance (CL/F) [9] [22]. We have opted for a different approach by using real data and C/D ratios as the basis for calculating the DRC factors as an approximation. However, it can be argued that it is not appropriate to present a range of C/D ratios as a DRR considering the approach used by the AGNP in their guidelines, and especially considering our small sample size [9].

It should also be noted that there was an imbalance of sexes in the sample, with a proportion of 62.5% (n=15) of women. One possible explanation for the lower-than-expected measured values would be the fact that cariprazine is metabolized to a large extent by the CYP3A4 enzyme [9] [23]. This enzyme has been reported to have a higher activity in women [24]. However, in our sample C/D Ratios did not differ between the two sexes.

Our results suggest using lower DRR values than stated in the widely used AGNP consensus guidelines. The values of 2.05±0.49 were found to be too high in our patient population, and we therefore recommend adjusting the values to 1.58±0.73 [9]. However, it is not surprising that an adjustment is necessary – especially since cariprazine is a relatively new drug and the data on pharmacokinetics is not yet comprehensive. Further prospective studies are needed to define and validate evidence-based reference ranges, ideally with larger samples and the active metabolites of cariprazine [9].

When treating with cariprazine, the entire clinical situation of the patient should always be taken into account [25]. However, an evidence-based DRR and TDM-guided dosing can help clinicians ensure a higher level of safety for patients [9] [26].

Conflict of Interest

The authors declare that they have no conflict of interest.

• References

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Correspondence

Publication History

Received: 11 August 2024

Accepted: 26 December 2024

Article published online:
29 January 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Cooper H, Mishriky R, Reyad AA. Efficacy and safety of cariprazine in acute management of psychiatric disorders: a meta-analysis of randomized controlled trials. Psychiatr Danub 2020; 32: 36-45
  CrossrefPubMedSearch in Google Scholar
• 2 Calabrese JR, Keck PE, Starace A. et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: A double-blind, placebo-controlled study. J Clin Psychiatry 2015; 76: 284-292
  CrossrefPubMedSearch in Google Scholar
• 3 Durgam S, Earley W, Guo H. et al. Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: A randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder. J Clin Psychiatry 2016; 77: 371-378
  CrossrefPubMedSearch in Google Scholar
• 4 Durgam S, Greenberg WM, Li D. et al. Safety and tolerability of cariprazine in the long-term treatment of schizophrenia: Results from a 48-week, single-arm, open-label extension study. Psychopharmacology (Berl) 2017; 234: 199-209
  CrossrefPubMedSearch in Google Scholar
• 5 Kane JM, Zukin S, Wang Y. et al. Efficacy and safety of cariprazine in acute exacerbation of schizophrenia: Results from an international, phase III clinical trial. J Clin Psychopharmacol 2015; 35: 367-373
  CrossrefPubMedSearch in Google Scholar
• 6 Ketter TA, Sachs GS, Durgam S. et al. The safety and tolerability of cariprazine in patients with manic or mixed episodes associated with bipolar I disorder: A 16-week open-label study. J Affect Disord 2018; 225: 350-356
  CrossrefPubMedSearch in Google Scholar
• 7 Vieta E, Earley WR, Burgess MV. et al. Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder. Int Clin Psychopharmacol 2019; 34: 76-83
  CrossrefPubMedSearch in Google Scholar
• 8 Haen E, Greiner C, Bader W. et al. Wirkstoffkonzentrationsbestimmungen zur therapieleitung. Ergänzung therapeutischer Referenzbereiche durch dosisbezogene Referenzbereiche. Nervenarzt 2008; 79: 558-566
  PubMedSearch in Google Scholar
• 9 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: e1-e62
  Thieme ConnectPubMedSearch in Google Scholar
• 10 Hiemke C. Concentration-effect relationships of psychoactive drugs and the problem to calculate therapeutic reference ranges. Ther Drug Monit 2019; 41: 174-179
  CrossrefPubMedSearch in Google Scholar
• 11 Haen E. Dose-related reference range as a tool in therapeutic drug monitoring. Ther Drug Monit 2022; 44: 475-493
  CrossrefPubMedSearch in Google Scholar
• 12 Ritscher S, Hoyer M, Wunder C. et al. Evaluation of the dose-related concentration approach in therapeutic drug monitoring of diuretics and β-blockers – drug classes with low adherence in antihypertensive therapy. Sci rep 2019; 9: 15652
  CrossrefPubMedSearch in Google Scholar
• 13 Rancic N, Dragojevic-Simic V, Vavic N. et al. Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication. Vojnosanit Pregl 2015; 72: 813-822
  CrossrefPubMedSearch in Google Scholar
• 14 van Gelder T, Meziyerh S, Swen JJ. et al. The clinical impact of the C0/D ratio and the CYP3A5 genotype on outcome in tacrolimus treated kidney transplant recipients. Front Pharmacol 2020; 11: 1142
  CrossrefPubMedSearch in Google Scholar
• 15 Nakamura T, Kubota T, Iwakaji A. et al. Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des Devel Ther 2016; 10: 327-338
  PubMedSearch in Google Scholar
• 16 Hiemke C, Baumann P, Bergemann N. et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: Update 2011. Pharmacopsychiatry 2011; 44: 195-235
  Thieme ConnectPubMedSearch in Google Scholar
• 17 Hefner G, Hahn M, Buenger M. et al. Comparison of dose-related-reference ranges with individual psychotropic drug serum concentrations in clinical practice – AGNP consensus guidelines 2011 and 2017. J Pharmacol Pharm Res 2017; 1: 001
  PubMedSearch in Google Scholar
• 18 Periclou A, Phillips L, Ghahramani P. et al. Population pharmacokinetics of cariprazine and its major metabolites. Eur J Drug Metab Pharmacokinet 2021; 46: 53-69
  CrossrefPubMedSearch in Google Scholar
• 19 Schoretsanitis G, Kane JM, Correll CU. et al. Blood levels to optimize antipsychotic treatment in clinical practice: A joint consensus statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie. J Clin Psychiatry 2020; 81: 81
  CrossrefPubMedSearch in Google Scholar
• 20 Sattaf F, Scherf-Clavel M, Unterecker S. et al. Recommendation for a therapeutic reference range of cariprazine-a short communication. Ther drug monit 2024; 46: 270-273
  CrossrefPubMedSearch in Google Scholar
• 21 Kiss B, Némethy Z, Fazekas K. et al. Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine. Drug Des Devel Ther 2019; 13: 3229-3248
  CrossrefPubMedSearch in Google Scholar
• 22 Fekete S, Hiemke C, Gerlach M. Dose-related concentrations of neuroactive/psychoactive drugs expected in blood of children and adolescents. Ther Drug Monit 2020; 42: 315-324
  CrossrefPubMedSearch in Google Scholar
• 23 Hart XM, Gründer G, Ansermot N. et al. Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics. World J Biol Psychiatry 2024; 25: 451-536
  CrossrefPubMedSearch in Google Scholar
• 24 Tanaka E. Gender-related differences in pharmacokinetics and their clinical significance. J Clin Pharm Ther 1999; 24: 339-346
  CrossrefPubMedSearch in Google Scholar
• 25 Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med 2009; 24: 1-10
  CrossrefPubMedSearch in Google Scholar
• 26 Haen E. Therapeutic drug monitoring in pharmacovigilance and pharmacotherapy safety. Pharmacopsychiatry 2011; 44: 254-258
  Thieme ConnectPubMedSearch in Google Scholar