Therapeutic reference range for aripiprazole revised: A systematic
                    review and combined analysis

Hart, X.M.; Hiemke, Christoph; Conca, Andreas; Eichentopf, Luzie; Faltraco, Frank; Florio, Vincenzo De; Grüner, Jörg; Havemann-Reinecke, Ursula; Lense, Xenija; Molden, Espen; Paulzen, Michael; Riemer, Thomas; Schoretsanitis, Georgios; Gründer, Gerhard

doi:10.1055/s-0042-1747652

Cited by 3 publications

(3 citation statements)

References 2 publications

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“… 22 , 30 The 95 ng/mL threshold is also broadly in line with a previously described aripiprazole therapeutic threshold of 110 ng/mL, 31 the consensus guidelines for therapeutic drug monitoring stating that the reference range for aripiprazole is 100–350 ng/mL, 21 and the results of a recent systematic review and combined analysis of studies with oral and LAI aripiprazole suggesting that the optimal target range for aripiprazole plasma concentrations is 120–270 ng/mL. 32 It is important to note that variability in aripiprazole plasma concentrations may exist among individual patients receiving identical doses of a given aripiprazole formulation due to factors such as sex, concomitant medications, or cytochrome P450 (CYP)2D6 genotype. 33 Dose adjustments may be required to ensure therapeutic aripiprazole plasma concentrations, particularly in patients who are poor CYP2D6 metabolizers or in those receiving concomitant CYP2D6 inhibitors or CYP3A4 inducers.…”

Section: Discussionsupporting

confidence: 69%

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison

Harlin¹,

Chepke²,

Larsen³

et al. 2023

NDT

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Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a novel long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, developed for the treatment of schizophrenia or maintenance monotherapy treatment of bipolar I disorder in adults (indication will vary by country). Aripiprazole lauroxil 1064 mg (AL 1064) is an LAI formulation of aripiprazole lauroxil, an aripiprazole prodrug, for administration once every 2 months, indicated for the treatment of schizophrenia in adults. This analysis provides an indirect comparison of aripiprazole plasma concentrations following multiple doses of either formulation. Clinical trial data were used to determine average steady-state aripiprazole plasma concentration (C avg,ss ), maximum aripiprazole plasma concentration (C max ), and other pharmacokinetic parameters of either formulation following four administrations (96 patients received Ari 2MRTU 960; 28 patients received AL 1064). All pharmacokinetic parameters were considered in the context of a minimum aripiprazole therapeutic concentration (C min ) of ≥95 ng/mL. An exposure–response analysis using data from two Phase III trials of aripiprazole once-monthly (an aripiprazole monohydrate LAI, administered monthly), showed that patients with a C min ≥95 ng/mL are 4.41 times less likely to relapse than patients with a C min <95 ng/mL. A similar analysis has not been performed for AL 1064. However, consensus guidelines for therapeutic drug monitoring recommend a range of 100–350 ng/mL for aripiprazole. Following four administrations, mean (standard deviation [SD]) C avg,ss over the 2-month dosing interval was 263 (133) ng/mL for Ari 2MRTU 960 and 140.7 (57.3) ng/mL for AL 1064. Mean (SD) C max during the fourth dosing interval was 342 (157) ng/mL for Ari 2MRTU 960 and 188.8 (79.8) ng/mL for AL 1064. This indirect comparison showed that, following four administrations, Ari 2MRTU 960 and AL 1064 delivered mean aripiprazole plasma concentrations that remained above the minimum therapeutic concentration of aripiprazole over the 2-month dosing interval.

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Section: Discussionsupporting

confidence: 69%

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison

Harlin¹,

Chepke²,

Larsen³

et al. 2023

NDT

View full text Add to dashboard Cite

show abstract

“…Limitations of the suggested reference ranges refer to the quality of the underlying study design that highly varies among psychotropic drug trials. As in similar studies on therapeutic reference ranges for other psychotropic drugs before (Eichentopf et al 2022 ; Hart et al 2022b ), the presented information was mostly extracted from naturalistic TDM studies or small non-controlled studies. High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase are missing to support a target range for VEN.…”

Section: Discussionmentioning

confidence: 99%

Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

Lense,

Hiemke,

Funk

et al. 2023

Psychopharmacology

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Introduction The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. Objectives We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. Methods Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. Results High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml. Conclusion VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN’s dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

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“…These included 95 ng/mL (the plasma concentration identified as the lower efficacy threshold for the prevention of impending relapse); this was based on an exposure‐response model analysis for AOM 400 that showed that a patient with schizophrenia and a predicted aripiprazole minimum concentration (C min ) of 95 ng/mL or greater was 4.41 times less likely to relapse than a patient with a C min less than 95 ng/mL 28 . Additionally, a value of 95 ng/mL is consistent with 94 ng/mL, which is the median steady‐state minimum aripiprazole plasma concentration (C min,ss ) for oral aripiprazole 10 mg 29 (ie, the lowest daily dose of oral aripiprazole approved for the treatment of adults with schizophrenia); it is also broadly similar to a therapeutic threshold of approximately 100‐120 ng/mL reported by other researchers 30–32 . A reference line indicating 534 ng/mL (the 75th percentile of simulated maximum concentration at steady state [C max,ss ] values following administration of once‐daily oral aripiprazole 30 mg/day) was also included; this functioned as an indicator of a conservative upper limit of a clinically relevant concentration range, consistent with previous research 33 …”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2‐Month Ready‐to‐Use Long‐Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder

Wang,

Harlin,

Larsen

et al. 2024

Clinical Pharm in Drug Dev

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A ready‐to‐use (RTU) long‐acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once‐monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration‐time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero‐order and lagged first‐order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2‐monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

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Therapeutic reference range for aripiprazole revised: A systematic review and combined analysis

Cited by 3 publications

References 2 publications

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison

Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2‐Month Ready‐to‐Use Long‐Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder

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