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.

Oxycodone, Morphine, and Fentanyl in Patients With Chronic Pain: Proposal of Dose-Specific Concentration Ranges.

BACKGROUND: Interpreting opioid concentrations is challenging because of the lack of reference ranges. Therefore, the authors aimed to propose dose-specific concentration ranges in serum for oxycodone, morphine, and fentanyl in patients with chronic pain, based on concentration measurements from a large number of patients and supported by theoretical pharmacokinetic calculations and previously published concentrations. METHODS: The opioid concentrations in patients undergoing therapeutic drug monitoring (TDM) for various indications (TDM group) and patients with cancer (cancer group) were investigated. Patients were divided based on the daily opioid doses, and the 10th and 90th percentiles of the concentrations in each dose interval were evaluated. In addition, the expected average serum concentrations were calculated for each dose interval based on published pharmacokinetic data, and a targeted literature search for previously reported dose-specific concentrations was performed. RESULTS: The opioid concentrations in 1054 patient samples were included: 1004 in the TDM group and 50 in the cancer group. In total, 607 oxycodone, 246 morphine, and 248 fentanyl samples were evaluated. The authors proposed dose-specific concentration ranges based mainly on 10th-90th percentiles of the concentrations measured in patient samples, whereas the calculated average concentrations and previously published concentrations were used to adjust the ranges. In general, results from calculations and concentrations retrieved from previous literature were within the 10th-90th percentiles of concentrations from patient samples. However, the lowest calculated average concentrations of fentanyl and morphine were below the 10th percentiles of patient samples in all dose groups. CONCLUSIONS: The proposed dose-specific ranges may be useful for interpreting steady-state opioid serum concentrations in clinical and forensic settings.

Associations of Binge Drinking With the Risks of Ischemic Heart Disease and Stroke: A Study of Pooled Norwegian Health Surveys.

Norwegian health survey data (1987-2003) were analyzed to determine if binge drinking increases the risk of incident major events from ischemic heart disease (IHD) and stroke. Among current drinkers reporting average alcohol intakes of 2.00-59.99 g/day (n = 44,476), frequent binge drinking (≥5 units at least once per month) was not associated with a greater risk of IHD (adjusted hazard ratio (HR) = 0.91, 95% confidence interval (CI): 0.76, 1.09) or stroke (adjusted HR = 0.98, 95% CI: 0.81, 1.19), in comparison with participants who reported that they never or only infrequently (less than once per month) had episodes of binge drinking. Participants with an average alcohol intake of 2.00-59.99 g/day had a lower risk of IHD in comparison with participants with very low intakes (<2.00 g/day), both among frequent binge drinkers (adjusted HR = 0.67, 95% CI: 0.56, 0.80) and among never/infrequent binge drinkers (adjusted HR = 0.75, 95% CI: 0.67, 0.84). The findings suggest that frequent binge drinking, independent of average alcohol intake, does not increase the risk of incident IHD or stroke events. However, the findings should be interpreted in light of the limitations of the study design.

Comparison of the Diagnostic Value of Phosphatidylethanol and Carbohydrate-Deficient Transferrin as Biomarkers of Alcohol Consumption.

BACKGROUND: The aim of this study was to compare the results of Phosphatidylethanol (PEth) and carbohydrate-deficient transferrin (CDT) in blood as biomarkers of alcohol consumption in a large clinical cohort and to evaluate concentrations in relation to age and sex. METHODS: Results of PEth 16:0/18:1 in blood and CDT in serum were included, together with information of age and sex, which were extracted from a clinical chemistry database containing samples mostly from patients of primary care physicians and social care institutions. PEth concentrations were determined using Ultra Performance Convergence chromatography mass spectrometer. CDT was quantified by electrophoretic Capillary System. CDT values ≥ 1.7 %-units and PEth values ≥ 0.31 µmol/L were considered to indicate heavy alcohol consumption. RESULTS: Samples from 6705 patients were included. The median age was 54.5 years, and 34 % were females. Only 47 % of the patients with PEth ≥ 0.31 µmol/L had increased CDT ≥ 1.7 %-units examined in the same specimen (Cohen's kappa was 0.43, p < 0.001). Patients above 50 years had significantly higher concentrations for both CDT (1.0 %-units vs. 0.9 %-units, p < 0.001) and PEth (0.340 µmol/L vs. 0.200 µmol/L, p < 0.001) compared with younger patients. Concentrations of CDT were significantly higher in males compared with females (p = 0.002), while no significant sex differences were seen for PEth (p = 0.465). CONCLUSIONS: A high fraction of the patients had PEth values above the suggested cutoff for heavy drinking and normal CDT values, verifying the superior sensitivity of PEth compared with CDT. The effect of age seems to be minor for both markers. Higher concentrations of CDT, but not PEth, were seen in males, indicating that PEth, as opposed to CDT, might be formed equally in men and women. Therefore, the bias due to sex is possibly present only for CDT, not for PEth.

Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol.

AIMS: To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose-adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose-adjusted serum concentrations in the perphenazine-treated patients. METHODS: Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP-genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose-adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses. RESULTS: Mean dose-adjusted serum concentrations of perphenazine (564 samples) were 3.9-fold and 1.6-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .001 and P < .01). For zuclopenthixol (658 samples), mean dose-adjusted serum concentrations were about 1.5-fold and 1.3-fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .01 and P < .001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose-adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function). CONCLUSIONS: This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles.

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.

Alcohol Consumption, HDL-Cholesterol and Incidence of Colon and Rectal Cancer: A Prospective Cohort Study Including 250,010 Participants.

AIMS: Alcohol consumption has been linked to colorectal cancer (CRC) and also to the high-density lipoprotein cholesterol level (HDL-C). HDL-C has been associated with the incidence of CRC. The aim of this study was to investigate the association between self-reported alcohol consumption, HDL-C and incidence of CRC, separately for the two sites. METHODS: Altogether, 250,010 participants in Norwegian surveys have been followed-up for an average of 18 years with respect to a first-time outcome of colon or rectal cancer. During follow-up, 3023 and 1439 colon and rectal cancers were registered. RESULTS: For men, the HR per 1 drink per day was 1.05 with 95% confidence interval (0.98-1.12) for colon and 1.08 (1.02-1.15) for rectal cancer. The corresponding figures for women were 1.03 (0.97-1.10) and 1.05 (1.00-1.10). There was a positive association between alcohol consumption and HDL-C. HDL-C was inversely associated with colon cancer in men (0.74 (0.62-0.89) per 1 mmol/l) and positively associated with rectal cancer, although not statistically significant (1.15 (0.92-1.44). A robust regression that assigned weights to each observation and exclusion of weights ≤ 0.1 increased the HRs per 1 drink per day and decreased the HR per 1 mmol/l for colon cancer. The associations with rectal cancer remained unchanged. CONCLUSION: Our results support a positive association between alcohol consumption and colon and rectal cancer, most pronounced for rectal cancer. Considering the positive relation between alcohol consumption and HDL-C, the inverse association between HDL-C and colon cancer in men remains unsettled.

Association of coincident self-reported mental health problems and alcohol intake with all-cause and cardiovascular disease mortality: A Norwegian pooled population analysis.

BACKGROUND: The disease burden attributable to mental health problems and to excess or harmful alcohol use is considerable. Despite a strong relationship between these 2 important factors in population health, there are few studies quantifying the mortality risk associated with their co-occurrence in the general population. The aim of this study was therefore to investigate cardiovascular disease (CVD) and all-cause mortality according to self-reported mental health problems and alcohol intake in the general population. METHODS AND FINDINGS: We followed 243,372 participants in Norwegian health surveys (1994-2002) through 2014 for all-cause and CVD mortality by data linkage to national registries. The mean (SD) age at the time of participation in the survey was 43.9 (10.6) years, and 47.8% were men. During a mean (SD) follow-up period of 16.7 (3.2) years, 6,587 participants died from CVD, and 21,376 died from all causes. Cox models estimated hazard ratios (HRs) with 95% CIs according to a mental health index (low, 1.00-1.50; high, 2.01-4.00; low score is favourable) based on the General Health Questionnaire and the Hopkins Symptom Checklist, and according to self-reported alcohol intake (low, <2; light, 2-11.99; moderate, 12-23.99; high, ≥24 grams/day). HRs were adjusted for age, sex, educational level, marital status, and CVD risk factors. Compared to a reference group with low mental health index score and low alcohol intake, HRs (95% CIs) for all-cause mortality were 0.93 (0.89, 0.97; p = 0.001), 1.00 (0.92, 1.09; p = 0.926), and 1.14 (0.96, 1.35; p = 0.119) for low index score combined with light, moderate, and high alcohol intake, respectively. HRs (95% CIs) were 1.22 (1.14, 1.31; p < 0.001), 1.24 (1.15, 1.33; p < 0.001), 1.43 (1.23, 1.66; p < 0.001), and 2.29 (1.87, 2.80; p < 0.001) for high index score combined with low, light, moderate, and high alcohol intake, respectively. For CVD mortality, HRs (95% CIs) were 0.93 (0.86, 1.00; p = 0.058), 0.90 (0.76, 1.07; p = 0.225), and 0.95 (0.67, 1.33; p = 0.760) for a low index score combined with light, moderate, and high alcohol intake, respectively, and 1.11 (0.98, 1.25; p = 0.102), 0.97 (0.83, 1.13; p = 0.689), 1.01 (0.71, 1.44; p = 0.956), and 1.78 (1.14, 2.78; p = 0.011) for high index score combined with low, light, moderate, and high alcohol intake, respectively. HRs for the combination of a high index score and high alcohol intake (HRs: 2.29 for all-cause and 1.78 for CVD mortality) were 64% (95% CI 53%, 74%; p < 0.001) and 69% (95% CI 42%, 97%; p < 0.001) higher than expected for all-cause mortality and CVD mortality, respectively, under the assumption of a multiplicative interaction structure. A limitation of our study is that the findings were based on average reported intake of alcohol without accounting for the drinking pattern. CONCLUSIONS: In the general population, the mortality rates associated with more mental health problems and a high alcohol intake were increased when the risk factors occurred together.

Oral Fluid to Blood Concentration Ratios of Different Psychoactive Drugs in Samples from Suspected Drugged Drivers.

BACKGROUND: The ratio between the concentrations of drugs in the oral fluid and blood (OF/B ratio) reflects the transfer of drugs from blood to oral fluid, which is influenced by several factors such as oral fluid contamination. OF/B drug concentration ratios for psychoactive drugs, including interindividual variation, were investigated in this study. For a portion of the material, oral fluid concentrations in both sides of the mouth were compared. METHODS: Samples of whole blood and oral fluid collected using the Intercept device were obtained from 489 suspected drugged drivers. Concentrations of amphetamine, methamphetamine, THC, diazepam, N-desmethyldiazepam, clonazepam, alprazolam, oxazepam, nitrazepam, morphine, buprenorphine, and methadone were determined in blood and oral fluid samples using liquid chromatography-tandem mass spectrometry. RESULTS: Median OF/B ratios were 18.6 for amphetamine, 13.8 for methamphetamine, 3.8 for morphine, 24.8 for buprenorphine, 3.7 for methadone, 0.026 for diazepam, 0.031 for N-desmethyldiazepam, 0.28 for alprazolam, 0.16 for clonazepam, 0.12 for oxazepam, 0.099 for nitrazepam, and 4.3 for THC. Large interindividual variations in OF/B ratios were observed. The median difference in concentrations in oral fluid from both sides of the mouth was less than 20% for all drugs, except THC and buprenorphine, which had median differences of 32%-34%. CONCLUSIONS: High OF/B ratios were found for amphetamines and opioids, reflecting a high degree of drug transfer from blood to oral fluid and a longer detection window in oral fluid than in blood. For benzodiazepines, low OF/B ratios were found. Results of the concentration measurements in oral fluid from both sides of the mouth could indicate that some remnants of THC and buprenorphine were present in the oral cavity. The large variations among individuals and between the 2 sides of the mouth suggest that drug concentrations in oral fluid do not accurately reflect drug concentrations in the blood.

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.

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.

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.

Life course socioeconomic position, alcohol drinking patterns in midlife, and cardiovascular mortality: Analysis of Norwegian population-based health surveys.

BACKGROUND: Socioeconomically disadvantaged groups tend to experience more harm from the same level of exposure to alcohol as advantaged groups. Alcohol has multiple biological effects on the cardiovascular system, both potentially harmful and protective. We investigated whether the diverging relationships between alcohol drinking patterns and cardiovascular disease (CVD) mortality differed by life course socioeconomic position (SEP). METHODS AND FINDINGS: From 3 cohorts (the Counties Studies, the Cohort of Norway, and the Age 40 Program, 1987-2003) containing data from population-based cardiovascular health surveys in Norway, we included participants with self-reported information on alcohol consumption frequency (n = 207,394) and binge drinking episodes (≥5 units per occasion, n = 32,616). We also used data from national registries obtained by linkage. Hazard ratio (HR) with 95% confidence intervals (CIs) for CVD mortality was estimated using Cox models, including alcohol, life course SEP, age, gender, smoking, physical activity, body mass index (BMI), systolic blood pressure, heart rate, triglycerides, diabetes, history of CVD, and family history of coronary heart disease (CHD). Analyses were performed in the overall sample and stratified by high, middle, and low strata of life course SEP. A total of 8,435 CVD deaths occurred during the mean 17 years of follow-up. Compared to infrequent consumption (

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.

Combined Effect of CYP2B6 Genotype and Other Candidate Genes on a Steady-State Serum Concentration of Methadone in Opioid Maintenance Treatment.

BACKGROUND: A considerable interindividual variability in methadone pharmacokinetics is seen in patients on methadone maintenance treatment. The aim of this study was to clarify the impact of the reduced function CYP2B6*6 variant allele together with variants in other candidate genes on a steady-state methadone concentration in a naturalistic setting. METHODS: Information of methadone serum concentration, dose, age, sex, and CYP2C9, CYP2C19, and CYP2D6 genotypes were collected from a routine therapeutic drug monitoring database, whereas variant alleles in CYP2B6 and CYP3A5 were retrospectively genotyped. Linear mixed model analyses were used to study the impact of gene variants on methadone serum concentration/dose (C/D) ratios, including age, sex, and time since the last dose intake as covariates. RESULTS: Overall, 155 serum samples from 62 patients were included in this study. The estimated mean methadone C/D ratios was 17.8 nmol·L·mg for homozygous carriers of CYP2B6*6, which was significantly (P < 0.001) higher than noncarriers (9.2 nmol·L·mg). There was no difference in C/D ratios between heterozygous carriers of CYP2B6*6 (9.1 nmol·L·mg) and noncarriers. An increase in mean methadone C/D ratios was also seen for homozygous carriers of CYP3A5*3 and heterozygous carriers of CYP2C9*2 or *3 and CYP2C19*2 or *3. CONCLUSIONS: Patients homozygous for CYP2B6*6 had a >90% higher methadone C/D ratio. Genotyping of CYP2B6 may therefore be of value when assessing dose requirements in methadone maintenance treatment.

Ethyl Glucuronide Elimination Kinetics in Fingernails and Comparison to Levels in Hair.

AIMS: Measurement of ethyl glucuronide (EtG) in nail, as a biomarker for alcohol intake, has recently been suggested as alternative to measurement in hair. The aim of this study was to compare levels of EtG in nail and hair, and to investigate the elimination kinetics of EtG in fingernails during an alcohol abstinent period. METHODS: Overall, 40 subjects (median estimated daily intake of ethanol (EDI) 92.5 g/day) were recruited from an alcohol rehabilitation clinic. Nail and hair samples were collected at inclusion and nail clippings were collected every 7-10th day for up to 12 weeks. RESULTS: All patients showed higher nail EtG/EDI ratios compared to hair EtG/EDI ratios (P < 0.001). The median value of the ratios between EtG in nail and EtG in hair was 5.0 (range: 1.07-56.1). There was a significant correlation between nail EtG/EDI and hair EtG/EDI (Spearman's ρ = 0.638, P < 0.001). EtG disappeared from nails after ~2 months of abstinence and the median calculated EtG half-life in nail clippings was 13.3 days (range: 5.5-29.0). There was a significant correlation between the time elapsed to last positive sample for nail EtG and nail EtG levels at time of inclusion (Spearman's ρ = 0.449, P = 0.004). CONCLUSION: The present data indicate that EtG cut-off levels in nails should be higher compared to the established 30 pg/mg EtG cut-off in hair representing heavy drinking. EtG may disappear faster from nail than expected from nail growth physiology. SHORT SUMMARY: Nails are an alternative matrix to hair when measuring ethyl glucuronide (EtG). The present study indicate that EtG cut-off levels in nails should be higher compared to the established 30 pg/mg EtG cut-off in hair representing heavy drinking, and EtG may disappear faster from nail than expected.

Levels of Hair Ethyl Glucuronide in Patients with Decreased Kidney Function: Possibility of Misclassification of Social Drinkers.

BACKGROUND: The use of hair ethyl glucuronide (EtG) levels as a biomarker for chronic high intake of ethanol (EtOH) is increasing, and misclassification of alcohol consumption may have large implications for the patient. The aim of this study was to compare levels of hair EtG in patients with reduced kidney function to levels seen in a comparable control group and to investigate whether the hair EtG levels among kidney failure patients who are social drinkers may lead to a false-positive diagnosis of heavy drinking. METHODS: A total of 41 patients with reduced kidney function and 42 healthy volunteers were included in the study. Both patients and the healthy volunteers reported moderate alcohol intake. The levels of EtG in hair (corrected for estimated daily intake of EtOH [EDI]) were compared between the 2 groups. RESULTS: There was no significant difference between the groups regarding EDI. Despite this, there were significant higher levels of hair EtG (corrected for EDI) in the patient group compared to the control group (p < 0.001). Eight subjects (20%) in the patient group showed EtG levels in hair above 30 pg/mg, in contrast to no subjects among healthy volunteers (p = 0.002). In the patient group, there was significant correlation between levels of EtG in hair and both estimated glomerulus filtration rate and serum creatinine levels. CONCLUSIONS: This study documents an increased risk of obtaining a false-positive diagnosis of heavy drinking among renal disease patients who are social drinkers. Interpretation of EtG levels in hair among patients with reduced kidney function must be performed with caution.