Rapid Metabolism Underlying Subtherapeutic Serum Levels of Atypical Antipsychotics Preceding Clozapine Treatment: A Retrospective Analysis of Real-World Data.

INTRODUCTION: Adequate antipsychotic treatment intensity is required before diagnosing resistant schizophrenia and initiating clozapine treatment. We aimed to investigate potential rapid drug metabolism underlying low dose-adjusted serum concentration (CD) of non-clozapine atypical antipsychotics preceding clozapine treatment. METHODS: Patients using non-clozapine, atypical antipsychotics (aripiprazole, risperidone, olanzapine, or quetiapine) within 1 year before starting clozapine were included in this study from a therapeutic drug monitoring service in Oslo, Norway, between 2005 and 2023. Patients were assigned into low CD (LCD) and normal CD (NCD) subgroups. Using a reference sample with 147,964 antipsychotic measurements, LCD was defined as CDs below the 25th percentile, while patients with NCD exhibited CDs between the 25th and 75th percentile of the respective reference measurements. Metabolic ratios, doses, and frequency of subtherapeutic levels of non-clozapine antipsychotics were compared between LCD and NCD groups. RESULTS: Preceding clozapine treatment, 110 out of 272 included patients (40.4%) were identified with LCD. Compared with the NCD group, LCD patients exhibited higher metabolic ratios of olanzapine (1.5-fold; p < 0.001), quetiapine (3.0-fold; p < 0.001), and risperidone (6.0-fold; p < 0.001). Metabolic ratio differences were independent of smoking and CYP2D6 genotype for olanzapine (p = 0.008) and risperidone (p = 0.016), respectively. Despite higher doses of olanzapine (1.25-fold; p = 0.054) and quetiapine (1.6-fold; p = 0.001) in LCD versus NCD patients, faster metabolism among the former was accompanied by higher frequencies of subtherapeutic levels of olanzapine (3.3-fold; p = 0.044) and quetiapine (1.8-fold; p = 0.005). CONCLUSION: LCD and associated rapid metabolism of non-clozapine antipsychotics is frequent before starting clozapine treatment. For olanzapine and quetiapine, this is associated with significantly increased risk of having subtherapeutic concentrations.

Effect of the NFIB rs28379954 T>C polymorphism on CYP2D6-catalyzed metabolism of solanidine.

Cytochrome P450 2D6 (CYP2D6) is important for metabolism of 20%-25% of all clinically used drugs. Many known genetic variants contribute to the large interindividual variability in CYP2D6 metabolism, but much is still unexplained. We recently described that nuclear factor 1B (NFIB) regulates hepatic CYP2D6 expression with the minor allele of NFIB rs28379954 T>C significantly increasing CYP2D6-mediated risperidone metabolism. In this study, we investigated the effect of NFIB T>C on metabolism of solanidine, a dietary CYP2D6 substrate. Analyses of solanidine and metabolites (M414, M416, and M444) were performed by ultra-high performance liquid chromatography-high-resolution mass spectrometry in a cohort of 463 CYP2D6-genotyped patients of which with 58 (12.5%) carried NFIB TC (n = 56) or CC (n = 2). Increased metabolism of solanidine was found in CYP2D6 normal metabolizers (NMs; n = 258, 55.7%) carrying the NFIB C variant (n = 27, 5.8%) with 2.83- and 3.38-fold higher M416-to-solanidine (p = 0.039) and M444-to-solanidine (p = 0.046) ratios, respectively, whereas this effect was not significant among intermediate metabolizers (n = 166, 35.9%) (p ≥ 0.09). Importantly, no effect of the NFIB polymorphism on solanidine metabolism was seen in TC or CC carriers lacking CYP2D6 activity (poor metabolizers, n = 30, 6.5%, p ≥ 0.74). Furthermore, the NFIB polymorphism significantly explained variability in solanidine metabolism (M414 p = 0.013, M416 p = 0.020, and M416 and M444 p = 0.009) in multiple linear regression models for each metabolic ratio in the entire population, correcting for covariates (including CYP2D6 genotypes). Thus, the study confirms the effect of NFIB in regulating CYP2D6 activity, suggesting an about 200% increase in CYP2D6-mediated clearance in NMs being NFIB CT or CC carriers, comprising around 6% of Europeans.

Impact of age, sex and cytochrome P450 genotype on quetiapine and N-desalkylquetiapine serum concentrations: A study based on real-world data from 8118 patients.

AIMS: To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N-desalkylquetiapine (NDQ). METHODS: Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. RESULTS: The average age of the included population (n = 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged >50 years compared to those aged 18-30 years, with 28 and 29% increase, respectively, for patients aged >70 years (P < .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P < .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males (P < .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males <65 years (P < .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P = .012) and poor (+17%, P = .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. CONCLUSION: This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose-dependent side effects of NDQ during QUE treatment.

Polygenic overlap with body-mass index improves prediction of treatment-resistant schizophrenia.

Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR <0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

Effect of CYP2D6 and CYP2C19 genotypes on atomoxetine serum levels: A study based on therapeutic drug monitoring data.

AIMS: Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced-function CYP2C19 genotype on atomoxetine concentrations in real-world settings. METHODS: Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced-function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfunctional or reduced variant alleles comprised CYP2D6*3-*6, *9-*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose-adjusted serum atomoxetine concentration was the exposure measure. RESULTS: Using a patient cohort (n = 315), it was found that CYP2D6 IM and PM patients had 1.9-fold (95% confidence interval: 1.4-2.7) and 9.6-fold (5.9-16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5-fold (1.1-2.2) higher atomoxetine exposure than noncarriers regardless of CYP2D6 genotype. CONCLUSION: CYP2D6 genotype has a great impact on atomoxetine exposure, where our real-world data suggest atomoxetine dose requirements to be around half and 1/10 in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre-emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

Metabolite Profiling of Clozapine in Patients Switching Versus Maintaining Treatment: A Retrospective Pilot Study.

PURPOSE/BACKGROUND: Pharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations. METHODS/PROCEDURES: Adult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018-2020. Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last clozapine intake, and (3) detectable levels of N -desmethylclozapine, clozapine -N -oxide, clozapine-5 N -glucuronide, or clozapine- N + - glucuronide. Patients comedicated with cytochrome P450 enzyme inducers, inhibitors, or valproic acid were excluded. The high-resolution mass spectrometry assay enabled detection of 21 clozapine metabolites. Metabolite profiles were compared between patients switching treatment (switchers), measured as clozapine being replaced by another antipsychotic drug in blood samples, versus maintaining clozapine treatment (nonswitchers) during the study period. FINDINGS/RESULTS: Of the 84 patients fulfilling the study criteria, 7 patients (8.3%) were identified as clozapine switchers. After correcting for smoking habits, the clozapine-5 N -glucuronide/clozapine ratio was 69% lower ( P < 0.001), while the clozapine- N + -glucuronide/clozapine-5 N -glucuronide ratio was 143% higher ( P = 0.026), respectively, in switchers versus nonswitchers. The other metabolite ratios did not significantly differ between switchers and nonswitchers. IMPLICATIONS/CONCLUSIONS: The present study found a significantly reduced 5 N -glucuronidation phenotype in patients switching from clozapine at therapeutic serum concentrations (>1070 nmol/L) to other antipsychotic drugs. This may indicate that glucuronidation, as a potential detoxification mechanism, is related to clozapine tolerability. However, the causality of this observation needs to be investigated in future studies with larger patient populations.

The Polymorphic Nuclear Factor NFIB Regulates Hepatic CYP2D6 Expression and Influences Risperidone Metabolism in Psychiatric Patients.

The genetic background for interindividual variability of the polymorphic CYP2D6 enzyme activity remains incompletely understood and the role of NFIB genetic polymorphism for this variability was evaluated in this translational study. We investigated the effect of NFIB expression in vitro using 3D liver spheroids, Huh7 cells, and the influence of the NFIB polymorphism on metabolism of risperidone in patients in vivo. We found that NFIB regulates several important pharmacogenes, including CYP2D6. NFIB inhibited CYP2D6 gene expression in Huh7 cells and NFIB expression in livers was predominantly nuclear and reduced at the mRNA and protein level in carriers of the NFIB rs28379954 T>C allele. Based on 604 risperidone treated patients genotyped for CYP2D6 and NFIB, we found that the rate of risperidone hydroxylation was elevated in NFIB rs28379954 T>C carriers among CYP2D6 normal metabolizers, resulting in a similar rate of drug metabolism to what is observed in CYP2D6 ultrarapid metabolizers, with no such effect observed in CYP2D6 poor metabolizers lacking functional enzyme. The results indicate that NFIB constitutes a novel nuclear factor in the regulation of cytochrome P450 genes, and that its polymorphism is a predictor for the rate of CYP2D6 dependent drug metabolism in vivo.

Effects of a Novel UGT2B Haplotype and UGT1A4*3 Allele Variants on Glucuronidation of Clozapine In vivo.

BACKGROUND: Glucuronidation is an important metabolic pathway of clozapine (CLZ), but the impact of various uridine 5'diphospho-glucuronosyltransferases (UGT) polymorphisms on the exposure and metabolism of CLZ in vivo is unclear. OBJECTIVE: The objective of this study was to investigate the impact of UGT2B haplotype and UGT1A4*3 allele variants on the formation of CLZ glucuronide metabolites (5N- and N+-glucuronide) and CLZ exposure in patients' serum after adjusting for sex, age, and smoking habits. METHODS: The study was based on serum samples from CLZ-treated patients (n=79) subjected to routine therapeutic drug monitoring (TDM) at Diakonhjemmet Hospital, Oslo, Norway. From the same patients, the following UGT variants were genotyped using Real-Time PCR: UGT2B:GA haplotype (defined as UGT2B:GA; rs1513559A>G and rs416593T>A) and UGT1A4*3 (rs2011425T>G). Serum concentrations of CLZ 5N- and N+-glucuronide were measured by UPLC high-resolution mass spectrometry. RESULTS: None of the genotypes had significant impact on CLZ exposure (p>0.05). However, compared to UGT2B:AT/AT and UGT1A4*1/*1, the 5N-glucuronide exposure was reduced in UGT2B:GA/GA carriers (-75 %, p=0.03) while the exposure was non-significantly increased in UGT1A4*3 carriers (+100 %, p=0.14), respectively. The N+-glucuronide exposure was unchanged in UGT1A4*3 vs. noncarriers (p=0.28), but significantly reduced in heterozygous (-50 %, p=0.016) and homozygous carriers (-70 %, p=0.021) of UGT2B:GA compared to UGT2B:AT/AT carriers, respectively. CONCLUSION: The UGT2B:GA and UGT1A4*3 variants had no impact on CLZ exposure but were associated with differences and preferences in CLZ glucuronidation. The latter might be of potential relevance for CLZ tolerability since levels of the N+-glucuronide metabolite may reflect the generation and trapping of reactive metabolites involved in CLZ-induced toxicity.

Effect of Valproic Acid on the Metabolic Spectrum of Clozapine in Patients With Schizophrenia.

BACKGROUND: Valproic acid (VPA) is frequently used with clozapine (CLZ) as mood stabilizer and/or seizure prophylaxis. Valproic acid is known to reduce N-desmethylclozapine (N-DMC) but not CLZ levels. This leads to the hypothesis that VPA induces the CLZ metabolism via non-N-desmethylation pathways. Therefore, we aimed to investigate the effect of concurrent VPA use on the serum concentrations of a spectrum of CLZ metabolites in patients, adjusting for smoking. METHODS: In total, 288 patients with an overall number of 737 serum concentration measurements of CLZ and metabolites concurrently using VPA (cases, n = 22) or no interacting drugs (controls, n = 266) were included from a routine therapeutic drug monitoring service. Linear mixed model analyses were performed to compare the dose-adjusted concentrations (C/D) of CLZ, N-DMC, CLZ 5N/N+-glucuronides, and metabolite-to-parent ratios in cases versus controls. RESULTS: After adjusting for covariates, the N-DMC (-40%, P < 0.001) and N+-glucuronide C/Ds (-78%, P < 0.001) were reduced in cases versus controls, while the CLZ C/D was unchanged (P > 0.7). In contrast, the 5N-glucuronide C/D (+250%, P < 0.001) and 5N-glucuronide-to-CLZ ratios (+120%, P = 0.01) were increased in cases versus controls. CONCLUSIONS: Our findings show that complex changes in CLZ metabolism underly the pharmacokinetic interaction with VPA. The lower levels of N-DMC seem to be caused by VPA-mediated induction of CLZ 5N-glucuronide formation, subsequently leading to reduced substrate availability for N-desmethylation. Whether the changes in CLZ metabolism caused by VPA affects the clinical outcome warrants further investigation.

Absolute and Dose-Adjusted Serum Concentrations of Clozapine in Patients Switching vs. Maintaining Treatment: An Observational Study of 1979 Patients.

BACKGROUND: Clozapine is an effective drug for the management of schizophrenia that has not responded to other agents, but some patients experience insufficient or adverse effects and discontinue treatment. OBJECTIVE: We investigated a potential association between clozapine serum concentrations and switching to other antipsychotics in a large real-world patient population from a therapeutic drug monitoring service. METHODS: Absolute and dose-adjusted serum concentrations (concentration-to-dose ratios [C/D ratios]) of clozapine during dosing between 100 and 1000 mg/day were measured in 1979 Norwegian patients during the period 2005-2019. These variables were compared in patients switching to other antipsychotic drugs versus maintaining clozapine treatment using linear mixed models. Smoking habits were known for 49% of the patients. To prevent potential nonadherence affecting clozapine switching, only patients with serum concentrations above 50% of the lower reference range were included. RESULTS: In total, 190 patients (9.6%) switched from clozapine to another antipsychotic drug during the study period, whereas the remaining patients were not detected as switchers and were interpreted as maintaining treatment. Patients switching treatment had 23.5% lower absolute concentrations (954 vs. 1245 nmol/L; p < 0.001) and 15.7% lower daily doses (305 vs. 362 mg/day; p < 0.001) of clozapine than did nonswitchers, making the clozapine C/D ratio 9.7% lower in switchers than in nonswitchers after correcting for smoking habits (2.80 vs. 3.10 nmol/L/mg/day; p = 0.032). CONCLUSIONS: The present study suggests that decreased absolute and dose-adjusted serum concentrations of clozapine were associated with clozapine discontinuation. The significantly reduced clozapine concentrations regardless of prescribed dose in switchers versus nonswitchers may indicate a pharmacokinetic mechanism underlying the risk of clozapine discontinuation.

Impact of age and gender on paliperidone exposure in patients after administration of long-acting injectable formulations-an observational study using blood samples from 1223 patients.

PURPOSE: Paliperidone palmitate is an antipsychotic medication available as long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age and gender on paliperidone exposure after administration of LAI formulations. METHODS: Data on serum concentrations of paliperidone from patients using LAI during were included retrospectively from a therapeutic drug monitoring (TDM) service. Information about dose was obtained from the requisition forms. As a measure of exposure, daily dose-adjusted serum concentration (C/D ratio) was used. Based on initial analysis of C/D ratios versus age, a breaking point close to 50 years was observed, thus deciding the grouping of patients as older (≥50 years) or younger (15-49 years). Linear mixed model analyses, allowing multiple measurements per patients, were used. RESULTS: In total, 1223 patients were included, whereof 1158 patients used paliperidone LAI in once-monthly intervals. In these patients (27.9% older), older patients had significantly higher paliperidone C/D ratio than younger patients (+20%, p<0.001). Compared to males, females had higher C/D ratio (+14%; p<0.001). Subsequently, older female users of once-monthly LAI intervals had 41% higher paliperidone C/D ratios compared to younger males (15.0 vs. 21.2 nM/mg; p<0.001). Compared to females aged 21-30 years, females with high age (≥70 years) had at least 105% higher paliperidone C/D ratio (p<0.001). CONCLUSION: The present study shows that older age and female gender are associated with higher paliperidone exposure than younger age and males, respectively. Particularly, older female patients (>50 years) are likely exposed to high concentration and cautious dosing in this subgroup is required.

Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation-an observational study including 2044 patients.

PURPOSE: Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment for CYP2D6 genotype. METHODS: Data on serum concentrations of zuclopenthixol and CYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005-2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18-64 years). Linear mixed model analyses without and with adjustment for CYP2D6 genotype were used. RESULTS: Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25-33%, p < 0.001) and oral formulation (+ 25-29%, p ≤ 0.003) without and with adjustment for CYP2D6 genotype. The doses were lower in older versus younger patients (oral: - 30%; LAI: - 20%; p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%, p < 0.001). CONCLUSION: The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users.

Correction: Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients-a genome-wide association study adjusting for smoking habits.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Undetectable or subtherapeutic serum levels of antipsychotic drugs preceding switch to clozapine.

Adequate antipsychotic treatment intensity is required for defining treatment-resistant schizophrenia (TRS) and justifying clozapine treatment. We investigated the occurrence of undetectable or subtherapeutic serum levels of oral antipsychotics preceding switch to clozapine as an endpoint of TRS. For patients starting clozapine, 12-month retrospective reviews of antipsychotic serum concentration measurements were performed in a Norwegian therapeutic drug monitoring (TDM) database from 2005 to 2017. Undetectable levels in high-sensitive analytical assays defined 'no drug use', while levels <50% of the lower reference range defined 'subtherapeutic use'. Similar data were collected for patients switching to long-acting injectable (LAI) antipsychotics, as a reference of 'no or subtherapeutic drug use'. Nineteen of 353 patients initiating clozapine (5.4%) had a recent history of undetectable antipsychotic drug levels compared to 91 of 1048 (8.7%) initiating LAI. Another 19 patients starting clozapine (5.4%) had recent events of subtherapeutic levels. In conclusion, the present retrospective study may indicate that every 10th patient starting clozapine has a recent history of undetectable or subtherapeutic serum levels of oral antipsychotics. The clinical implications of the present study for the assessment of TRS should be investigated prospectively in further studies.

Identification of a novel polymorphism associated with reduced clozapine concentration in schizophrenia patients-a genome-wide association study adjusting for smoking habits.

Clozapine (CLZ) is the superior antipsychotic drug for treatment of schizophrenia, but exhibits an extensive interpatient pharmacokinetic variability. Here, we conducted a genome-wide association study (GWAS) of CLZ serum concentration adjusting for known smoking habits, which is a major nongenetic factor reducing CLZ levels. The study included 484 patients with 10,283 steady-state serum concentrations of CLZ and N-desmethylclozapine, prescribed dosing, co-medications and known smoking habits (n = 422; 9284 serum samples) from a therapeutic drug monitoring (TDM) service. The GWAS analyses were performed with and without smoking habits as covariate, where possible hits were assessed in relation to the target CLZ concentration range applied in the TDM service (300-2500 nmol/L). The smoking-independent analysis of N-desmethylclozapine serum concentration and the CLZ-to-N-desmethylclozapine ratio replicated the previously identified locus on chromosome 4. After adjusting for smoking habits in patients confirmed as 'smokers' (61%) or 'nonsmokers' (39%), a novel variant (rs28379954; minor T>C allele frequency 4.1%; 7.6% CT carriers in the population) within the gene encoding the nuclear factor 1 B-type (NFIB) was significantly associated with reduced CLZ serum concentration (p = 1.68 × 10-8, beta = -0.376; explained variance 7.63%). There was no significant association between rs28379954 and N-desmethylclozapine concentration in the GWAS analysis (p = 5.63 × 10-5). The fraction of CLZ TDM samples below 300 nmol/L was significantly higher in carriers vs. noncarriers of the rs28379954 minor C allele [12.0% (95% CI: 9.4-14.7) vs. 6.2% (95% CI: 5.7-6.8), p < 0.001]. We identified a novel variant in the NFIB gene associated with reduced CLZ levels and increased risk of subtherapeutic serum concentrations. This warrants testing of clinical relevance of screening for this gene variant, and also experimental studies to investigate the biological mechanisms of NFIB involvement in CLZ pharmacokinetics.

Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation: relevance of poor and intermediate metabolizer status.

PURPOSE: Tailoring medication dosing for the individual patient is complex, and many factors can influence drug exposure. We investigated the effect of age and CYP2D6 genotype on aripiprazole and dehydroaripiprazole exposure in patients using long-acting injectable (LAI) or oral aripiprazole. METHODS: Matched data on serum concentration of aripiprazole and CYP2D6 genotype of patients using oral or LAI aripiprazole were included retrospectively from a therapeutic drug monitoring service. The patients were divided into the following CYP2D6 genotype-defined categories: poor metabolizers (PMs), intermediate metabolizers (IMs), normal metabolizers (NMs), and ultrarapid metabolizers (UMs). Linear mixed model analyses were used to evaluate the impact of CYP2D6 genotype on dose-adjusted serum concentrations of the active moiety of aripiprazole+dehydroaripiprazole in relation to age and formulation. RESULTS: We identified 635 patients (mean age = 40.1 years, 9.4% ≥ 65 years, 53.7% females) using LAI (n = 166) or oral formulation (n = 469). The genotype-predicted CYP2D6 phenotype subgroups were 2.4% UMs, 82.0% NMs, 8.0% IMs, and 7.2% PMs. Age did not significantly affect exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (p = 0.071) or oral (p = 0.14) subgroups. Compared with CYP2D6 NMs, PMs and IMs had significantly increased exposure of the active moiety of aripiprazole+dehydroaripiprazole in the LAI (1.7-fold higher, p < 0.001, and 1.5-fold higher, p < 0.001) and oral (1.7-fold higher, p < 0.001, and 1.6-fold higher, p < 0.001) subgroups. CONCLUSIONS: In conclusion, doses should be adjusted according to CYP2D6 genotype when initiating treatment with aripiprazole LAI or tablets, while advanced age do not affect the exposure of the active moiety of aripiprazole treatment regardless of formulation.

Prescribing of antipsychotic drugs to older patients living at home 2006­18. / Forskrivning av antipsykotika til hjemmeboende eldre 2006­18.

BACKGROUND: It is generally agreed that prescribing of antipsychotic drugs to older patients should be reduced, but figures for the prescribing of these drugs to older patients living at home in Norway are not available. The study aimed to investigate developments in prescribing of antipsychotic drugs among older patients living at home from 2006 to 2018, and whether there were differences in prescribing rates between the age groups 65-74 years, 75-84 years and 85 years or older. MATERIAL AND METHOD: Data were retrieved from the Norwegian Prescription Database. All persons aged 65 years or older who were dispensed at least one antipsychotic drug in 2006, 2010, 2014 and 2018 were included, and gender-specific prevalence for the ten most widely used antipsychotic drugs was calculated. RESULTS: The proportion of patients aged 65 or older who were prescribed antipsychotic drugs in the period decreased for both sexes. For the age group 65-74 years, an increase was found from 2014 to 2018. There was a clear decrease in the prescribing rate for prochlorperazine and levomepromazine, whereas prescriptions for quetiapine increased. INTERPRETATION: Attention should be paid to the increase in prescribing of antipsychotic drugs for the youngest age group of older patients (65-74 years) in the last four years, along with the increase in prescribing of quetiapine for older patients.

The Effect of Valproic Acid on Olanzapine Serum Concentration: A Study Including 2791 Patients Treated With Olanzapine Tablets or Long-Acting Injections.

BACKGROUND: The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting. METHODS: From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included. RESULTS: The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003). IMPLICATIONS: These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.

Synthesis of a novel legumain-cleavable colchicine prodrug with cell-specific toxicity.

Conventional chemotherapy has undesirable toxic side-effects to healthy tissues due to low cell selectivity of cytotoxic drugs. One approach to increase the specificity of a cytotoxic drug is to make a less toxic prodrug which becomes activated at the tumour site. The cysteine protease legumain have remarkable restricted substrate specificity and is the only known mammalian asparaginyl (Asn) endopeptidase. Over-expression of legumain is reported in cancers and unstable atherosclerotic plaques, and utilizing legumain is a promising approach to activate prodrugs. In this study we have synthesized the legumain-cleavable peptide sequence N-Boc-Ala-Ala-Asn-Val-OH. The peptide was subsequently conjugated to deacetyl colchicine during three steps to produce Suc-Ala-Ala-Asn-Val-colchicine (prodrug) with >90% chemical purity. Several cell lines with different expressions and activities of legumain were used to evaluate the general toxicity, specificity and efficacy of the microtubule inhibitor colchicine, valyl colchicine and the legumain-cleavable colchicine prodrug. The prodrug was more toxic to the colorectal cancer HCT116 cells (expressing both the 36kDa active and 56kDa proform of legumain) than SW620 cells (only expressing the 56kDa prolegumain) indicating a relationship between toxicity of the prodrug and activity of legumain in the cells. Also, in monoclonal legumain over-expressing HEK293 cells the prodrug toxicity was higher compared to native HEK293 cells. Furthermore, co-administration of the prodrug either with the potent legumain inhibitor cystatin E/M or the endocytosis inhibitor Dyngo-4a inhibited cell death, indicating that the prodrug toxicity was dependent on both asparaginyl endopeptidase activity and endocytosis. This colchicine prodrug adds to a legumain-activated prodrug strategy approach and could possibly be of use both in targeted anticancer and anti-inflammatory therapy.