Therapeutic Reference Range Research Articles

Pharmacokinetic interaction of quetiapine and lamotrigine – victim and perpetrator?

ABSTRACT Objective We aimed to investigate the ambiguous findings of earlier research regarding the reduction of quetiapine plasma levels when combined with lamotrigine, most likely via UDP-glucuronosyltransferase induction by lamotrigine. Methods One thousand one hundred and fifty samples, divided into four groups of patients receiving either quetiapine immediate- (IR) or extended-release (XR) without or in combination with lamotrigine were compared regarding absolute and dose-adjusted plasma concentrations. Furthermore, samples of intra-individual controls were analyzed. Results Patients receiving quetiapine IR in combination with lamotrigine showed 31% lower plasma (p = 0.002) and 23% lower dose-adjusted plasma concentrations (p = 0.004) compared to those receiving IR monotherapy. The proportion of patients with quetiapine plasma concentrations below the lower limit of the therapeutic reference range was 50% and 30% in the combination group and in patients receiving monotherapy, respectively (p = 0.03). However, no significant differences regarding plasma concentration (p = 0.13) and dose-adjusted plasma concentration (p = 0.42) were observed in patients with combination vs. monotherapy with the XR formulation of quetiapine. In the intra-individual controls, no trends could be identified, possibly due to insufficient number of samples (p > 0.05). Conclusions The combination of quetiapine IR with lamotrigine is associated with significantly lower drug concentrations of quetiapine, potentially impacting quetiapine effectiveness. For quetiapine ER, a significant interaction is less likely.

Optimizing the individual dosing of paroxetine in major depressive disorder with therapeutic drug monitoring.

Previous studies have examined the correlation between paroxetine concentrations and therapeutic efficacy in patients diagnosed with major depressive disorder (MDD), but findings have been contradictory. This study aimed to investigate the relationships among plasma concentrations, severity of symptoms, and adverse drug reactions (ADRs) to optimize individual dosing. Eighty-seven MDD patients, after completing treatment with paroxetine, were divided into low-concentration (LC, n = 38), medium-concentration (MC, n = 27), and high-concentration (HC, n = 22) groups, based on cutoff value concentrations with the 50% response rate and the laboratory alert level from the 2017 consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology. The severity of depression and anxiety was evaluated using a 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), respectively. Dosage, plasma concentrations, scale scores, and ADRs were recorded across the three groups at different treatment stages to define the therapeutic reference range. The 4-week plasma concentration of paroxetine (65.00 ng/mL) could predict the clinical response in MDD patients at 8 weeks. Symptom relief in patients with 4-week paroxetine concentrations ranging from 65.00 to 120.00 ng/mL at 8 weeks was greater than in those with concentrations below 65.00 ng/mL, with no significant difference observed above this range. In addition, more cases of liver injury and weight gain were observed in patients with high paroxetine concentrations. Our results support that early paroxetine concentration may predict clinical efficacy and the incidence of ADRs, thus improving individual dosing regimens for MDD patients.

Discovering interactions in polypharmacy: Impact of metamizole on the metabolism of quetiapine.

Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations. Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations. The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Association of Lamotrigine Plasma Concentrations With Efficacy and Toxicity in Patients With Epilepsy: A Retrospective Study.

There is limited evidence to support the currently suggested lamotrigine (LTG) therapeutic reference range of 2.5-15 mg/L for the treatment of seizures. The objective of this study was to evaluate the association of LTG plasma concentrations with the efficacy and toxicity of the treatment in patients with epilepsy. Patients whose LTG plasma concentration was measured between January 2013 and February 2022 were included. Efficacy was defined as seizure freedom for at least 6 months around the time of measured LTG concentration. Toxicity was defined as any LTG-related adverse drug effect documented in each patient's health record or when the reason for measuring the LTG concentration was toxicity. In addition, the dose-concentration relationship of LTG was assessed. In total, 549 concentrations from 259 patients with epilepsy were included. The most common reasons for therapeutic drug monitoring were suspected inefficacy (39%) and pregnancy (21%). The LTG plasma concentration was not associated with efficacy (adjusted odds ratio = 0.94; 95% confidence interval, 0.85-1.04). The LTG plasma concentration was positively associated with the incidence of toxicity after adjusting for age, sex, and number of antiepileptic drugs (odds ratio = 1.11; 95% confidence interval, 1.04-1.19). The daily dose had a significant linear correlation with the LTG plasma concentration ( P < 0.001). The LTG plasma concentration was associated with toxicity, whereas no association with efficacy was found. A reference range of 2.5-10 mg/L may be considered to decrease the risk of toxicity while maintaining similar efficacy. Therapeutic drug monitoring may be useful when LTG-related toxicity is suspected and in cases of pharmacokinetic changes (eg, pregnancy and concomitant use of interacting drugs) that can influence the LTG plasma concentration.

Serum Concentration-Dose Relationship and Modulation Factors in Children and Adolescents Treated with Fluvoxamine.

Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response. Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations. The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (rs = 0.34, p = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL. These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis

Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype onparoxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P=0.03 and P=0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Exposure to Mycophenolic Acid and Its Clinical Response in an Indian Pediatric Population with Nephrotic Syndrome.

Children with nephrotic syndrome experience many side effects and frequent relapses when treated with steroids and other drugs. Mycophenolic acid (MPA) is one of the effective and least toxic drug for the treatment of nephrotic syndrome. This drug needs to be monitored for maximal efficacy and minimal toxicity. The therapeutic reference range for this drug is not established for the aforementioned patient population of Indian origin. In this observational study, children with nephrotic syndrome on mycophenolate mofetil were followed up for a minimum duration of three months. Following this, their clinical status (relapse/remission) was determined and the mycophenolate exposure was measured for over 12 hours. A total of 34 participants were included, with 17 (50%) in relapse. Median MPA Area under the curve over 12 hours (AUC0-12h) (36.5 µg·h/ml) in the remission group differed significantly compared to that in the relapse group (17.2 µg·h/ml). Higher exposure to MPA AUC0-12h is associated with clinical remission of pediatric nephrotic syndrome.

Assessing Pharmacokinetic Correlates of Escitalopram-Related Adverse Drug Reactions.

To assess the pharmacokinetic correlates of reported adverse drug reactions (ADRs) under antidepressant treatment with escitalopram (ESC) using a large therapeutic drug monitoring database. A large naturalistic sample of inpatients and outpatients prescribed ESC was analyzed. ADRs were classified using the Udvalg for Kliniske Undersogelser side effect rating scale. We compared ESC-treated patients with (n = 35) and without ADRs (n = 273) using ESC plasma concentrations as the primary outcome. We also compared ADR rates in the 2 groups based on 2 cut-off ESC levels reflecting the recommended upper thresholds of the therapeutic reference range of 80 ng/mL, suggested by the consensus therapeutic drug monitoring guidelines, and 40 ng/mL, based on recent meta-analysis data. The effects of age, sex, smoking, daily ESC dose, plasma concentrations, and concentrations corrected for daily dose were included in a binary logistic regression model to predict ADRs. No differences in clinical, demographic, or pharmacokinetic parameters were observed between patients with and without ADRs ( P > 0.05). Patients with ESC-related ADRs were more frequently diagnosed with psychotic disorders than those without (25% vs. 7.1%, P = 0.004). None of the variables was associated with ADR risk. Overall, ADR rates were not significantly different in patients above versus below thresholds of ESC concentrations (ESC concentrations >40 [n = 59] vs. ≤40 ng/mL [n = 249] and >80 [n = 8] vs. ≤80 ng/mL [n = 300]; P = 0.56 and P = 1.0, respectively). No distinct pharmacokinetic patterns underlying ESC-associated ADRs were observed. Further studies with more specific assessments of ADRs in larger cohorts are required to better identify potential underlying patterns.

Analysis of Factors Affecting Concentrations and Concentration-To-Dose Ratios of Trazodone.

Trazodone is prescribed for several clinical conditions. Multiple factors may affect trazodone to reach its therapeutic reference range. The concentration-to-dose (C/D) ratio can be used to facilitate the therapeutic drug monitoring of trazodone. The study aimed to investigate factors on the concentrations and C/D ratio of trazodone. This study analyzed the therapeutic drug monitoring electronic case information of inpatients in the First Hospital of Hebei Medical University from October 2021 to July 2023. Factors that could affect the concentrations and C/D ratio of trazodone were analyzed, including body mass index, sex, age, smoking, drinking, drug manufacturers, and concomitant drugs. A total of 255 patients were analyzed. The mean age was 52.44 years, and 142 (55.69%) were women. The mean dose of trazodone was 115.29 mg. The mean concentration of trazodone was 748.28 ng/mL, which was in the therapeutic reference range (700-1000 ng/mL). 50.20% of patients reached the reference range, and some patients (36.86%) had concentrations below the reference range. The mean C/D ratio of trazodone was 6.76 (ng/mL)/(mg/d). A significant positive correlation was found between daily dose and trazodone concentrations (r 2 = 0.2885, P < 0.001). Trazodone concentrations were significantly affected by dosage, sex, smoking, drinking, and concomitant drugs of duloxetine or fluoxetine. After dosage emendation, besides the above factors, it was influenced by age ( P < 0.05, P < 0.01, or P < 0.001). This study identified factors affecting trazodone concentrations and C/D ratio. The results can help clinicians closely monitor patients on trazodone therapy and maintain concentrations within the reference range.

Long-Acting Injectable Second-Generation Antipsychotics in Seriously Ill Patients with Schizophrenia: Doses, Plasma Levels, and Treatment Outcomes.

This research studies the dose-plasma level (PL) relationship of second-generation antipsychotics, together with the treatment outcomes achieved, in seriously ill people with schizophrenia. An observational, prospective, one-year follow-up study was carried out with patients (N = 68) with severe schizophrenia treated with paliperidone three-month (PP3M) or aripiprazole one-month (ARIM). Participants were divided into standard-dose or high-dose groups. PLs were divided into "standard PL" and "high PL" (above the therapeutic reference range, TRR) groups. The dose/PL relationship, and severity, hospitalizations, tolerability, compliance, and their relationship with doses and PLs were evaluated. There was no clear linear relationship between ARIM or PP3M doses and the PLs achieved. In half of the subjects, standard doses reached PLs above the TRR. The improvements in clinical outcomes (decrease in clinical severity and relapses) were related to high PLs, without worse treatment tolerability or adherence. All participants remained in the study, regardless of dose or PL. Clinical severity and hospitalizations decreased significantly more in those patients with high PLs. Considering the non-linear dose-PL relationship of ARIM and PP3M in people with severe schizophrenia, PLs above the TRR are linked to better treatment outcomes, without worse tolerability. The need in a notable number of cases for high doses to reach those effective PLs is highlighted.

Recommendation for a Therapeutic Reference Range of Cariprazine-A Short Communication.

Therapeutic reference ranges are essential for therapeutic drug monitoring to evaluate results and adjust pharmacotherapy. The measured serum concentrations of cariprazine-treated patients have frequently been found to lie beyond the currently used therapeutic reference range; furthermore, reliable data for establishing evidence-based therapeutic ranges are scarce. The current therapeutic reference ranges have only been estimated; however, real-world data on cariprazine are missing. Individual serum concentrations were analyzed, and the validity of the currently used reference ranges was assessed. Serum concentrations of 19 psychiatric patients treated with cariprazine without pharmacokinetic abnormalities were retrospectively analyzed. Only the last measurement per patient was included in the analysis, and patients who underwent a dose adjustment in the subsequent 2 weeks after sampling were excluded (assuming that the target dose and response had been achieved at that time). Serum concentrations were compared with the therapeutic reference range (10-20 ng/mL) of the Arbeitsgemeinschaft für Neuropsychiatrie und Pharmakotherapie consensus guidelines of 2017 and with a recent recommendation for a lower therapeutic reference range (5-15 ng/mL). The mean serum concentration was 9.1 ± 4.1 SD ng/mL. A total of 47.4% of the values were within the therapeutic reference range of 10-20 ng/mL, and 78.9% fell within the range of 5-15 ng/mL. These results support previous recommendations for lowering the therapeutic reference range to 5-15 ng/mL. The calculated therapeutic reference range was 5.0-13.2 ng/mL. It may even be potentially lower because clinicians may have tried to titrate the dose to a serum concentration within the current therapeutic reference range of 10-20 ng/mL.

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

IntroductionThe 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.ObjectivesWe 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.MethodsFour 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.ResultsHigh-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.ConclusionVEN 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.

Guía internacional para una dosificación más segura de la clozapina en adultos mediante el uso de 6 titulaciones personalizadas de dosis basados en la etnicidad, la proteína C reactiva y los niveles de clozapina

This is the Spanish translation of an international guideline which proposes improving clozapine package inserts worldwide by using ancestry-based: 1) dosing and 2) titration. Adverse drug reaction (ADR) databases suggest clozapine: 1) is the third most toxic drug in the United States (US), and 2) produces worldwide pneumonia mortality four times greater than that of agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers require the lowest dose and male smokers the highest dose). Poor metabolizer (PM) status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity or inflammation with C-reactive protein (CRP) elevations. People with ancestry from Asia (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/ml. Daily doses of 300-600 mg/day are recommended in the US. Slow personalized titration may prevent early ADRs (including syncope, myocarditis and pneumonia). The core of this guideline consists of six personalized titration schedules for inpatients: 1) Asian/Amerindian ancestry with lower metabolism (in cases of obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) Asian/Amerindian ancestry with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (in cases of obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US of non-Asian/Amerindian ancestry with lower clozapine metabolism (in cases of obesity or valproate) needing 150-300 mg/day, and 6) in the US of non-Asian/Amerindian ancestry with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least 4 weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

A 5-year retrospective study of amisulpride steady-state plasma concentration in patients with schizophrenia in real-life settings based on therapeutic drug monitoring data.

Here, we present a retrospective analysis of the last 5 years' data collected in real-life settings as direct evidence to evaluate the optimal therapeutic window of amisulpride (AMI) for psychiatric patients. Retrospective analysis of the therapeutic drug monitoring (TDM) results of AMI in outpatients and inpatients were obtained from the Xi'an Mental Health Center from 2017 to 2021. The interquartile (P25-P75) AMI concentrations ranged 212.20-574.25ng/mL. The results showed that the proportion of outpatients who received TDM once was significantly higher than that of inpatients who received TDM once (P<0.001), whereas the reverse was true for those who experienced TDM more than twice (P<0.001). Higher estimated plasma concentrations were identified in inpatients, female patients, and patients over 59 years of age. Nearly 57.21% of the samples had high concentrations (>320ng/mL). The optimal therapeutic reference range for AMI may require reconstruction to guide the use of AMI for the treatment of schizophrenia.

Therapeutic drug monitoring in adolescents with anorexia nervosa for safe treatment with adjunct olanzapine.

Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best-evidenced substance used off-label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP-guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age- and disorder-specific therapeutic reference range. Sixty-five adolescents with AN (aged 10-18) treated with OLZ (98% female; 97.5% AN-restricting-type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p<0.001)/0.65 (**p<0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5kg/m2 (t=10.6, p<0.001). A preliminary therapeutic reference range is 11.9 and 39.9ng/mL. OLZ in the hands of specialists is a well-tolerated and safe treatment adjunct for adolescents with AN.

Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.

Therapeutic Reference Range for Olanzapine in Schizophrenia: Systematic Review on Blood Concentrations, Clinical Effects, and Dopamine Receptor Occupancy.

The Association Between Clozapine Plasma Concentration, CYP2D6 (*10, *2) Polymorphisms and Risk of Adverse Reactions.

The aim of this article was to study the relationships between the risk of adverse reactions, plasma concentration, and cytochrome P450 2D6 rs1065852 (*10) and rs16947 (*2) polymorphisms for clozapine. The steady-state clozapine plasma concentration of 100 Chinese inpatients with schizophrenia was determined using 2-dimensional liquid chromatography. The polymorphisms of cytochrome P450 2D6 (*10 and *2) were determined using fluorescent in situ hybridization protocols. The decreased percentages of white blood cells and neutrophils and the elevated percentages of creatine kinase, alanine aminotransferase, and aspartate transferase in patients treated with clozapine for 6 months were linearly associated with clozapine plasma concentration. Compared with the corresponding groups, the clozapine plasma concentrations of individuals with the *10TT genotype and individuals with the *2CC genotype were the highest (P < .05). The decreased percentages of white blood cells and neutrophils and elevated percentages of creatine kinase, alanine aminotransferase, and aspartate transferase for patients with the *10TT genotype were significantly higher than those for patients with the *10CC and *10CT genotypes (P < .05). The decreased percentages of white blood cells and neutrophils and increased percentages of creatine kinase, alanine aminotransferase, and aspartate transferase for patients with the *2CC genotype were significantly higher than those of the other groups (P < .05). The therapeutic reference range of clozapine for Chinese patients with schizophrenia was defined as 102.5-483.1 ng/mL. This study demonstrated that the determination of cytochrome P450 2D6 polymorphisms and therapeutic drug monitoring of clozapine might be beneficial for identifying patients with a higher risk of adverse reactions.

Therapeutic drug monitoring and the therapeutic reference range of levetiracetam for Chinese patients: Problems and issues

BackgroundLevetiracetam (LEV) is widely used in the clinical monotherapy or multi-drug combination treatment of seizures due to its good tolerability and efficacy. Due to a lack of large-scale clinical studies, the relationship between levetiracetam concentrations, disease activity and adverse is unclear, limiting the usefulness of therapeutic drug monitoring (TDM) based LEV plasma levels. This study was intended to investigate factors influencing the pharmacokinetics of and the appropriate reference range of LEV concentration using available LEV TDM data. MethodsA rapid, accurate and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method was established to determine LEV plasma concentrations. In this study, the levetiracetam plasma concentration monitoring data from 352 samples (taken from 248 patients) were used to explore the relationship between levetiracetam dose, age, combined administration with other antiseizure medications in patients with epilepsy. ResultsAge and combined administration emerged as important affecting factors for the correlation of LEV concentration and dose. The correlation between concentration and dose was better in monotherapy. Combined administration may affect LEV concentration, especially when LEV is combined with oxcarbazepine, which might decrease the LEV concentration. ConclusionThese findings emphasize the need to monitor LEV routinely LEV, especially among children and older adults when other antiseizure comedications are prescribed in the treatment regimen. LEV TDM is a well-established tool for the management of patients with epilepsy.

Discovering interactions in augmentation strategies: Impact of duloxetine on the metabolism of aripiprazole.

We aimed to unravel potential pharmacokinetic interactions between aripiprazole and duloxetine. Plasma concentrations of aripiprazole in two groups of 78 patients each, receiving aripiprazole as a monotherapy or combined with duloxetine, were compared. A potential impact of duloxetine on the metabolism of aripiprazole was expected in higher plasma concentrations of aripiprazole and higher dose-adjusted plasma concentrations. Patients co-medicated with duloxetine showed significantly higher plasma concentrations of aripiprazole by 54.2% (p= 0.019). Dose-adjusted plasma concentrations were 45.6% higher (p= 0.001); 12.8% of these patients exhibited aripiprazole plasma concentrations above the upper limit of the therapeutic reference range, in the control group this was only the case for 10.3% of the patients. A positive relationship was found between the daily dose of duloxetine and dose-adjusted plasma concentrations of aripiprazole (p= 0.034). As dehydroaripiprazole concentrations were not available, conclusions for the active moiety (aripiprazole plus dehydroaripiprazole) could not be drawn. Combining duloxetine and aripiprazole leads to significantly higher drug concentrations of aripiprazole, most likely via an inhibition of cytochrome P450 CYP2D6 and to a lesser extent of CYP3A4 by duloxetine. Clinicians have to consider increasing aripiprazole concentrations when adding duloxetine to a treatment regimen with aripiprazole.

Defining the therapeutic reference range for cariprazine

IntroductionAccording to the Consensus Guideline, the “therapeutic reference range” (TRR) defines ranges of drug blood concentrations that specify a lower limit below which a drug-induced therapeutic response is unlikely to occur and an upper limit above which tolerability decreases or the therapeutic improvement ceases. The TRR can be obtained from concentration measurements (trough (pre-dose) plasma concentration under steady-state conditions) in studies at therapeutically effective doses.ObjectivesThe aim is to examine the TRR for cariprazine (CAR: 1.5 mg/day to 6 mg/day) in schizophrenia studies.MethodsThe population based TRR for CAR is derived by PK/PD evaluation from phase 2/3 schizophrenia efficacy studies with sparse PK sampling. The population PK simulated TRR is compared to the actually measured values obtained from two PK studies. As the two active metabolites of cariprazine also contribute to the drug effect, plasma exposure is given for Total cariprazine (CAR + DCAR + DDCAR) and the parent drug (CAR).ResultsPK/PD analyses demonstrated an increase in efficacy with increasing exposure. These efficacy results are related to Total cariprazine trough concentrations of ca. 30 nM and 100 nM that determine the lower and upper TRR limits. For the parent drug, the pre-dose mean plasma concentration at 6 mg/day was between 5.7-10 ng/mL in different studies, while at 1.5 mg/day it was 1.9 ng/mL.ConclusionsThe TRR of the trough plasma levels at steady state is ca. 30 – 100 nM for Total cariprazine and ca. 2-10 ng/mL for the parent drug (unchanged drug) for schizophrenia treatment.Disclosure of InterestM. Kapás Employee of: Gedeon Richter Plc., A. Horváth Employee of: Gedeon Richter Plc., D. Djuric Employee of: Gedeon Richter Plc., R. Csehi Employee of: Gedeon Richter Plc., Á. Barabássy Employee of: Gedeon Richter Plc.