Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

Effect of CYP2D6 genotype on duloxetine serum concentration.

Duloxetine is metabolized by cytochrome P450 (CYP)1A2 and CYP2D6. The aim of this study was to investigate the effect of the CYP2D6 genotype on duloxetine serum concentration adjusting for age and sex. Patients were included retrospectively from a therapeutic drug monitoring service. Multiple linear regression analysis was used to investigate the effect of CYP2D6 genotype, age and sex on the duloxetine concentration-to-dose (C/D) ratio. In total, 269 patients were included and assigned to the following genotype-predicted phenotype subgroups: CYP2D6 poor metabolizers (PMs, n = 23), intermediate metabolizers (IMs, n = 121), normal metabolizers (NMs, n = 120) and ultrarapid metabolizers (UMs, n = 5). Multiple linear regression analysis revealed a 95% higher duloxetine C/D ratio in PMs compared with NMs (p = 0.009). Patients ≥65 years had a 56% higher C/D ratio than younger patients (p = 0.01), while women had a 46% higher C/D ratio than men (p = 0.04). In conclusion, the CYP2D6 PM phenotype is associated with a twofold higher concentration at recommended dosing compared with the NM phenotype. CYP2D6 PM females above 65 years are at particular risk of high duloxetine levels as they may obtain a threefold higher C/D ratio compared with younger, male NMs.

Impact of CYP2D6 Genotype on Paroxetine Serum Concentration.

BACKGROUND: Paroxetine is a selective serotonin reuptake inhibitor metabolized by cytochrome P450 (CYP)2D6. Only small-scale studies have reported the impact of CYP2D6 genotype on paroxetine exposure, and international guidelines differ in their recommendations on whether paroxetine should be administered according to CYP2D6 genotype. To clarify this issue, the aim of the present study was to investigate the impact of CYP2D6 genotype on paroxetine serum concentration in a large population of patients after adjusting for CYP2C19 genotype, age, and sex. METHODS: Patients from a therapeutic drug monitoring database with records on their paroxetine serum concentrations and CYP2D6 and CYP2C19 genotyping between 2010 and 2021 were included in the study. The impact of CYP2D6 and CYP2C19 genotypes, age, and sex on the paroxetine concentration-to-dose (C/D) ratio was investigated by multiple linear regression analysis. Patients treated with relevant CYP inhibitors or inducers were excluded. RESULTS: In total, 304 patients were included in the study: 17 CYP2D6 poor metabolizers (PMs), 114 intermediate metabolizers (IMs), 168 extensive metabolizers (EMs), and 5 ultrarapid metabolizers. Multiple linear regression analysis showed that CYP2D6 IMs and PMs had 2.2-fold and 3.8-fold higher paroxetine C/D-ratios than extensive metabolizers, respectively ( P < 0.001). Patients who were CYP2C19 IMs (n = 70) or PMs (n = 13) had 1.6-fold higher paroxetine C/D ratio than extensive metabolizers ( P = 0.04). An age ≥65 years was associated with a 2.9-fold increased C/D ratio ( P < 0.001), whereas sex was not significantly associated with paroxetine exposure. CONCLUSIONS: The present study showed that CYP2D6 genotype is of significant importance for paroxetine dose adjustments. For CYP2D6 PMs, 25% of the regular paroxetine starting dose may be sufficient, whereas CYP2D6 IMs could receive 50% of the regular dosage. This well-powered study shows that the guidelines should consider the importance of CYP2D6 genotype for personalized dosing of paroxetine.

Genotyping of patients treated with selective serotonin reuptake inhibitors. / Genotyping av pasienter behandlet med selektive serotoninreopptakshemmere.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are used by over 180,000 people in Norway. The enzymes CYP2D6 and CYP2C19 are key in the metabolism of SSRI antidepressants. The serotonin transporter coded by SLC6A4 may be significant for the efficacy of the drugs. MATERIAL AND METHOD: All patients who had undergone genotyping for CYP2D6, CYP2C19 and SLC6A4 at the Centre for Psychopharmacology in 2020 were included, irrespective of indication. For those patients where data were available, CYP2C19 genotype was linked to serum concentration measurement of escitalopram, which is the most commonly used SSRI drug. RESULTS: Out of 3,492 patients, 432 (12.4 %) had a combination of genotypes of CYP2D6, CYP2C19 and SLC6A4 considered to lead to the most favourable metabolism and efficacy of SSRI antidepressants. The dose requirement in patients with poor CYP2C19 metabolism was more than halved to achieve the same concentration of escitalopram compared to patients with normal metabolism. INTERPRETATION: Our findings demonstrate the low prevalence of the most favourable genotype combination for response to SSRIs. Genotype combinations probably contribute to the wide variation between individuals in the efficacy of these drugs and the fact that treatment does not produce the desired outcome in many patients.

Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression.

PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.

A Novel CYP2C-Haplotype Associated With Ultrarapid Metabolism of Escitalopram.

Escitalopram is one of the most commonly used antidepressant drugs but exhibits a substantial interindividual variation in clinical response. A key factor underlying response differences is the polymorphic nature of the CYP2C19 gene encoding the major enzyme responsible for escitalopram metabolism. Although pre-emptive CYP2C19 genotyping may improve escitalopram treatment outcome by dose individualization, much of the interindividual variability cannot be assigned to the currently known CYP2C19 gene variants. The aim of the present study was to search for novel CYP2C-haplotypes for better genetic prediction of escitalopram metabolism. First, the CYP2C18/CYP2C19 locus was sequenced from gDNA obtained from 24 patients previously genotyped as CYP2C19*1/*1 showing consistently low serum concentrations of escitalopram (< 25 nM/10 mg). Three new haplotypes of the CYP2C locus (CYP2C:TG, CYP2C:TA, and CYP2C:CG) were here identified, and their functional roles were evaluated using gDNA from 875 previously genotyped escitalopram-treated patients. The CYP2C:CG and CYP2C:TA haplotypes had no significant impact on escitalopram concentration. Based on the estimated effects of the novel CYP2C-haplotypes on escitalopram exposure, the predicted serum concentrations of escitalopram in homozygous CYP2C:TG and CYP2C19*17 carriers were 24.8% and 17.3% lower compared with the baseline (CYP2C:CG and CYP2C:TA), respectively. In conclusion, a novel CYP2C-haplotype defined by rs2860840T and rs11188059G associated with ultrarapid metabolism of escitalopram was identified. Further studies should clarify the genetic basis for the enhanced escitalopram metabolism and the impact of the CYP2C:TG haplotype on the metabolism of other CYP2C19 substrates like omeprazole, voriconazole, and clopidogrel.

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.

The Influence of Combined CYP2D6 and CYP2C19 Genotypes on Venlafaxine and O-Desmethylvenlafaxine Concentrations in a Large Patient Cohort.

PURPOSE: The antidepressant venlafaxine is largely O-desmethylated by CYP2D6, whereas CYP2C19 mediates an alternative metabolic route of venlafaxine through N-desmethylation. The aim of this study was to investigate the combined effect of genotype-predicted CYP2D6 and CYP2C19 phenotypes on serum concentrations of venlafaxine and metabolites in a large patient population. METHODS: Patients were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital in Oslo (Norway) between January 01, 2007, and December 31, 2017. The study population was divided into different phenotype subgroups according to the combinations of CYP2D6/CYP2C19 phenotypes; intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers, and compared using combined normal metabolizers (NMs) as reference. FINDINGS: The dose-adjusted serum concentration of venlafaxine was 4- and 13-fold increased in combined CYP2D6 IM/CYP2C19 PMs and combined PMs, respectively, compared with combined NMs (P < 0.001). The sum concentration of venlafaxine + ODV (pharmacological active moiety) was increased 1.9 and 3.6-fold, respectively, in the same phenotype groups. Furthermore, the dose-adjusted active moiety exposure was similar in combined IMs as combined CYP2D6 PM/CYP2C19 NMs. CYP2D6 and CYP2C19 phenotypes explained 46% of the interindividual variability in dose-adjusted venlafaxine serum concentrations, whereas CYP2D6 alone explained 24%. CONCLUSIONS: The combined CYP2D6/CYP2C19 phenotype has a significant impact on serum concentrations of venlafaxine and also on the active moiety of venlafaxine + ODV, than CYP2D6 alone. In clinical practice, it is therefore important to take into account phenotype variabilities of both enzymes when assessing the risk of dose-dependent adverse effects during venlafaxine treatment.

Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients.

Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into CYP2C19 genotype-predicted phenotype subgroups, i.e. normal (NMs), ultra rapid (UMs), intermediate (IMs), and poor metabolisers (PMs). The differences in dose-harmonized serum concentrations of sertraline and N-desmethylsertraline-to-sertraline metabolic ratio were compared between the subgroups, with CYP2C19 NMs set as reference. The patient proportions outside the therapeutic concentration range were also compared between the subgroups with NMs defined as reference. Compared with the CYP2C19 NMs, the sertraline serum concentration was increased 1.38-fold (95% CI 1.26-1.50) and 2.68-fold (95% CI 2.16-3.31) in CYP2C19 IMs and PMs, respectively (p < 0.001), while only a marginally lower serum concentration (-10%) was observed in CYP2C19 UMs (p = 0.012). The odds ratio for having a sertraline concentration above the therapeutic reference range was 1.97 (95% CI 1.21-3.21, p = 0.064) and 8.69 (95% CI 3.88-19.19, p < 0.001) higher for IMs and PMs vs. NMs, respectively. CYP2C19 IMs and PMs obtain significantly higher serum concentrations of sertraline than NMs. Based on the relative differences in serum concentrations compared to NMs, dose reductions of 60% and 25% should be considered in PMs and IMs, respectively, to reduce the risk of sertraline overexposure in these patients.

Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism.

BACKGROUND: Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. METHODS: A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. RESULTS: The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). CONCLUSIONS: The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4ß-Hydroxycholesterol-an Interaction Study in Healthy Volunteers.

4ß-Hydroxycholesterol (4ßOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4ßOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4ßOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4ßOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4ßOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1 week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4ßOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.

Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study.

BACKGROUND: The polymorphic CYP2D6 enzyme metabolises the antipsychotic drugs risperidone and aripiprazole to their active metabolites, 9OH-risperidone and dehydroaripiprazole. The aim of this study was to quantify the effect of CYP2D6 genetic variability on risperidone and aripiprazole exposure and treatment in a large patient population. METHODS: We retrospectively obtained patient data from a routine therapeutic drug monitoring database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between Jan 1, 2005, and Oct 15, 2018. Individuals included in our analyses were CYP2D6-genotyped patients treated with risperidone or aripiprazole. Inclusion criteria for measurement of pharmacokinetic parameters (drug and metabolite serum concentrations) were oral administration of risperidone or aripiprazole, information known about prescribed daily dose and comedications, and aged older than 18 years. Exclusion criteria included polypharmacy with drugs known to be CYP2D6 inhibitors or CYP3A4 inducers or inhibitors. Treatment failure was analysed in all patients treated with risperidone or aripiprazole without these criteria. The first endpoint in our analysis was the metabolism of risperidone to 9OH-risperidone and aripiprazole to dehydroaripiprazole, estimated by the log-transformed ratio between the concentrations of metabolite and parent drug (ie, the metabolic ratio for risperidone [9OH-risperidone]/[risperidone] and the metabolic ratio for aripiprazole [dehydroaripiprazole]/[aripiprazole]). Endpoint two was measurement of drug exposure, quantified by the dose-normalised sum of parent drug and active metabolite serum concentrations (ie, active moiety). The third endpoint of treatment failure was measured as the number of patients switched from risperidone or aripiprazole to another antipsychotic drug within 1 year after the last therapeutic drug monitoring analysis of risperidone or aripiprazole. Patient subgroups were defined by CYP2D6 genotype-determined metaboliser status: poor metabolisers, intermediate metabolisers, normal metabolisers, and ultrarapid metabolisers. ANOVA was used to assess the differences in metabolic ratios, active moieties, and daily doses between individual metaboliser categories, and risperidone and aripiprazole therapeutic failures were compared by logistic regression using the normal metaboliser subgroup as a reference. FINDINGS: 1288 risperidone-treated patients and 1334 aripiprazole-treated patients were included in the study, of whom 725 (56%) risperidone-treated and 890 (67%) aripiprazole-treated patients were eligible for the pharmacokinetic analyses. CYP2D6 genotype significantly changed risperidone and aripiprazole metabolism resulting in an approximately 1·6-times and 1·4-times increase in risperidone and aripiprazole active moiety exposure in poor and intermediate metabolisers compared with normal metabolisers, respectively (odds ratios [OR] for the risperidone dose-normalised active moiety concentration 1·568, 95% CI 1·401-1·736, and 1·373, 1·213-1·532; and for the aripiprazole dose-normalised active moiety concentration 1·585, 1·447-1·724, and 1·476, 1·263-1·688, respectively; p<0·0001 for all). Compared with doses for normal metabolisers, clinicians reduced daily doses of risperidone and aripiprazole administered to poor metabolisers by 19% (95% CI 5-35, p=0·010) and 15% (95% CI 1-28, p=0·033) respectively. The incidence of switching from risperidone to another antipsychotic was increased in ultrarapid metabolisers (OR 2·934, 95% CI 1·437-5·989, p=0·003) and poor metabolisers (1·874, 1·128-3·112, p=0·015); by contrast, the incidence of switching from aripiprazole to another antipsychotic was not significantly related to CYP2D6 metaboliser status. INTERPRETATION: CYP2D6 genotype had a substantial clinical effect on risperidone and aripiprazole exposure and on the therapeutic failure of risperidone. Pre-emptive CYP2D6 genotyping would be valuable for individualising risperidone and aripiprazole dosing and treatment optimisation. FUNDING: H2020 program U-PGx, The Swedish Research Council, the Swedish Brain foundation, and the South-Eastern Norway Regional Health Authority.

Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients.

AIMS: CYP2D6*9, CYP2D6*10 and CYP2D6*41 are the most frequent reduced-function CYP2D6 alleles in Caucasians. Despite lacking in vivo evidence, they are collectively classified with an enzyme activity score of 0.5. Thus, the aim of this study was to compare the functional impact of CYP2D6*9, CYP2D6*10 and CYP2D6*41 on CYP2D6 metabolism in a large patient population. METHODS: A total of 1003 patients (mainly Caucasians) with data on CYP2D6 genotype and serum concentrations of venlafaxine and metabolites were included from a therapeutic drug monitoring service in Oslo, Norway. The O-desmethyl-to-N-desmethyl-venlafaxine metabolic ratio (MR) was applied as CYP2D6 biomarker and compared (Mann-Whitney) between carriers of CYP2D6*9-10 (merged) and CYP2D6*41, either combined with CYP2D6*1 or non-coding (null) alleles. MR subgroup estimates were obtained by multiple linear regression for calculations of CYP2D6*9-10 and CYP2D6*41 activity scores. RESULTS: MR was significantly lower in carriers of CYP2D6*41 than CYP2D6*9-10 (P < 0.002). The majority of CYP2D6*41/null carriers (86.7%) had MR in the observed range of CYP2D6null/null carriers compared with the minority of CYP2D6*9-10/null carriers (17.4%). CYP2D6 genotype explained 60.7% of MR variability in the multivariate analysis providing subgroup estimates of 9.54 (95% CI; 7.45-12.20), 3.55 (2.06-6.10), 1.33 (0.87-2.05) and 0.47 (0.35-0.61) in carriers of CYP2D6*1/null (n = 269), CYP2D6*9-10/null (n = 17), CYP2D6*41/null (n = 30) and CYP2D6null/null (n = 95), respectively. Based on these estimates, the calculated activity score of CYP2D6*41 was 0.095 compared to 0.34 for CYP2D6*9-10. CONCLUSIONS: CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine ratio is significantly lower in Scandinavian carriers of CYP2D6*41 vs. CYP2D6*9-10. Thus, these alleles should be differentiated when classifying CYP2D6 phenotype from genotype.

Age Impacts Olanzapine Exposure Differently During Use of Oral Versus Long-Acting Injectable Formulations: An Observational Study Including 8,288 Patients.

PURPOSE: Olanzapine is a commonly prescribed antipsychotic available as oral and long-acting injectable (LAI) formulations. Data are lacking on the use and safety of olanzapine-LAI in older patients. The aim of this study was to investigate the effect of increasing age on olanzapine exposure during oral versus LAI administration in a real-life setting. METHODS: This observational study was based on routine therapeutic drug monitoring data collected during 2005-2017. As a measure of exposure, absolute concentrations and concentration/dose ratios of olanzapine were defined as outcome variables. Linear mixed-model analyzes were used to allow for inclusion of multiple samples per patient and adjustment for covariate effects. RESULTS: Olanzapine concentrations and doses from 8,288 patients (21,378 measurements) were included. The number of patients on oral treatment was 7,893 (42%, 50 years or older), while 395 were using olanzapine-LAI (27%, 50 years or older). In contrast to oral use, where the dose-adjusted concentration of olanzapine increased significantly for patients 50 years or older (P < 0.001), increasing age had no effect on olanzapine concentration following LAI administration (P = 0.550). The effects of smoking habits and gender were equal in oral and olanzapine-LAI users. CONCLUSION: While the dose-adjusted systemic exposure of olanzapine increases by age after oral administration, these novel findings from a large patient population show that systemic exposure of olanzapine-LAI is unaffected by age, probably due to the lacking influence of age-related changes in gastrointestinal absorption and/or presystemic metabolism. From a pharmacokinetic point of view, it is therefore no reason to restrict the use of olanzapine-LAI in older patients requiring long-term treatment.

Clinically Relevant Effect of UGT1A4*3 on Lamotrigine Serum Concentration Is Restricted to Postmenopausal Women-A Study Matching Therapeutic Drug Monitoring and Genotype Data From 534 Patients.

BACKGROUND: Previous studies have reported inconsistent findings regarding the impact of the UGT1A4*3 variant allele on lamotrigine (LTG) exposure. As no studies have controlled for nongenetic factors, the aim of this study was to compare serum concentrations of LTG in carriers versus noncarriers of UGT1A4*3 adjusting for differences in age, sex, and valproic acid (VPA) comedication. METHODS: Matched data on serum concentration of LTG and UGT1A4 genotype patients with known information about VPA comedication were included retrospectively from a therapeutic drug monitoring service. Linear mixed-model analysis was used to evaluate the impact of the UGT1A4*3 variant on dose-adjusted serum concentrations (C/D ratio) of LTG. Subanalyses were performed to assess the impact of UGT1A4*3 in relation to age, sex, and VPA comedication. RESULTS: In total, 534 patients (1735 LTG serum concentrations) were included. In the study population, UGT1A4*3 carriers (n = 87; 16.3%) were estimated to have a 13% lower LTG C/D ratio compared with noncarriers (P = 0.01). Subanalyses showed that the quantitative impact of UGT1A4*3 was greatest in postmenopausal women (>50 years) without VPA comedication. In these patients (n = 99), UGT1A4*3 carriers displayed a 40% lower LTG C/D ratio than noncarriers (P = 0.001). The UGT1A4*3 variant had no significant effect on LTG C/D ratio in the other subpopulations (P > 0.1). Regardless of patient subgroup, the concomitant use of VPA was the strongest determinant of LTG exposure by increasing the C/D ratio 2.5-fold (P < 0.001). CONCLUSIONS: This study shows that UGT1A4*3 generally has a modest impact on LTG exposure, but it could lead to clinically relevant lowering in LTG serum concentration among postmenopausal women. The clinical impact of UGT1A4*3 in these patients needs to be assessed in relation to comedication with VPA, which is associated with a substantial increase in serum concentration of LTG.

Comparison of CYP3A4-Inducing Capacity of Enzyme-Inducing Antiepileptic Drugs Using 4ß-Hydroxycholesterol as Biomarker.

BACKGROUND: Enzyme-inducing antiepileptic drugs (EIAEDs) are among the clinically most important inducers of cytochrome P450 (CYP) 3A4, but there is limited evidence regarding the comparative potency of each EIAED in raising CYP3A4 activity. The aim of this study was to estimate CYP3A4-inductive potency of EIAEDs by comparing CYP3A4 activity in patients treated with carbamazepine, phenobarbital, or phenytoin. METHODS: Residual serum samples from patients treated with EIAEDs or levetiracetam were collected from a therapeutic drug monitoring service for analysis of 4ß-hydroxycholesterol (4ßOHC), which is an indicator of CYP3A4 activity. The samples were collected between January and September 2016 at Diakonhjemmet Hospital, Oslo, Norway. Concentration of 4ßOHC, EIAEDs, and levetiracetam was measured by ultra-performance liquid chromatography tandem mass spectrometry. Kruskal-Wallis and Mann-Whitney tests were used for comparison of 4ßOHC levels between the subgroups. RESULTS: In total, 4ßOHC measurements for 343 and 339 patients treated with EIAEDs and levetiracetam, respectively, were included in the study. Compared with levetiracetam-treated patients, the median 4ßOHC concentration was 3.3-fold, 5.8-fold, and 6.9-fold higher in patients using phenobarbital, phenytoin, or carbamazepine, respectively (P < 0.0001). Phenytoin users (n = 65) and carbamazepine users (n = 225) had 1.8- and 2.1-fold higher median 4ßOHC concentration than phenobarbital users (n = 28), respectively (P ≤ 0.0001). CONCLUSIONS: This study shows that phenytoin and carbamazepine have approximately twice the CYP3A4-inducing potency of phenobarbital. The results indicate that 2-fold higher doses of CYP3A4-metabolized drugs may generally be required during concurrent treatment with phenytoin or carbamazepine compared with phenobarbital.

Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients.

OBJECTIVE: The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. METHOD: A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. RESULTS: Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. CONCLUSIONS: The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.