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

Genetic polymorphisms in drug metabolizing enzymes and drug–drug interactions are major sources of inadequate drug exposure and ensuing adverse effects or insufficient responses. The current challenge in assessing drug–drug gene interactions (DDGIs) for the development of precise dose adjustment recommendation systems is to take into account both simultaneously. Here, we analyze the static models of DDGI from in vivo data and focus on the concept of phenoconversion to model inhibition and genetic polymorphisms jointly. These models are applicable to datasets where pharmacokinetic information is missing and are being used in clinical support systems and consensus dose adjustment guidelines. We show that all such models can be handled by the same formal framework, and that models that differ at first sight are all versions of the same linear phenoconversion model. This model includes the linear pharmacogenetic and inhibition models as special cases. We highlight present challenges in this endeavor and the open issues for future research in developing DDGI models for recommendation systems. [ABSTRACT FROM AUTHOR]

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary‐derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4‐OH‐solanidine and 3,4‐secosolanidine‐3,4‐dioic acid (SSDA) were determined using a sensitive liquid chromatography‐mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra‐individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α‐OH‐metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day. [ABSTRACT FROM AUTHOR]

Background: The analysis of substrates of polymorphic cytochrome P450 (CYP) enzymes is important information to enable drug–drug interactions (DDIs) analysis and the relevance of pharmacogenetics in this context in large datasets. Our aim was to compare different approaches to assess the substrate properties of drugs for certain polymorphic CYP2 enzymes. Methods: A standardized manual method and an automatic method were developed and compared to assess the substrate properties for the metabolism of drugs by CYP2D6, 2C9, and 2C19. The automatic method used a matching approach to three freely available resources. We applied the manual and automatic methods to a large real-world dataset deriving from a prospective multicenter study collecting adverse drug reactions in emergency departments in Germany (ADRED). Results: In total, 23,878 medication entries relating to 895 different drugs were analyzed in the real-world dataset. The manual method was able to assess 12.2% (n = 109) of drugs, and the automatic method between 12.1% (n = 109) and 88.9% (n = 796), depending on the resource used. The CYP substrate classifications demonstrated moderate to almost perfect agreements for CYP2D6 and CYP2C19 (Cohen's Kappa (κ) 0.48–0.90) and fair to moderate agreements for CYP2C9 (κ 0.20–0.48). Conclusion: A closer look at different classifications between methods revealed that both methods are prone to error in different ways. While the automated method excels in time efficiency, completeness, and actuality, the manual method might be better able to identify CYP2 substrates with clinical relevance. [ABSTRACT FROM AUTHOR]

Ketamine and its enantiomer S‐ketamine (esketamine) are known to produce rapid‐onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short‐term use in anaesthesia and analgesia, the experience with ketamine as long‐term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene‐drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug–drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug–drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long‐term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions. [ABSTRACT FROM AUTHOR]

ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. The genotype distribution met the Hardy–Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin. This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs. [ABSTRACT FROM AUTHOR]

Aims: To assess the validity of self‐reported continuous medication use with drug metabolites measured in plasma by using untargeted mass spectrometric techniques. Methods: In a population‐based cohort in Bonn, Germany, we compared interview‐based, self‐reported medication intake with drug‐specific metabolites measured in plasma (based on participants who completed their study visits between March 2016 and February 2020). Analyses were done stratified by sex and age (<65 years vs ≥65 years). Cohen's kappa (κ) statistics with 95% confidence intervals (CI) were calculated. Results: A total of 13 drugs used to treat hypertension, gout, diabetes, epilepsy and depression were analysed in a sample of 4386 individuals (mean age 55 years, 56.1% women). Eleven drugs showed almost perfect agreement (κ > 0.8), whereas sitagliptin and hydrochlorothiazide showed substantial (κ = 0.8, 95% CI 0.71–0.90) and moderate agreement (κ = 0.61, 95% CI 0.56–0.66), respectively. Frequency of use allowed sex‐ and age‐stratified analyses for eight and nine drugs, respectively. For five drugs, concordance tended to be higher for women than for men. For most drugs, concordance was higher among individuals aged ≥65 years than among individuals aged <65 years, but these age‐related differences were not statistically significant. Conclusion: High concordance rates between self‐reported drug use and metabolites measured in plasma suggest that self‐reported drug use is reliable and accurate for assessing drug use. [ABSTRACT FROM AUTHOR]

Background Cancer patients are at risk of secondary therapy–related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)–associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH–associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. Methods We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH–associated genes (ASXL1 , DNMT3A , GNAS , JAK2 , PPM1D , SF3B1 , SH2B3 , SRSF2 , TET2 , TP53). Results were analyzed according to the BRCA1/2 germline (g BRCA1/2) mutation status. All statistical tests were 2-sided. Results Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH–associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for g BRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D : odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P  =  .007; TP53 : odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P  =  .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in g BRCA1/2 mutation carriers vs noncarriers (PPM1D : mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P  <  .001; TP53 : mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P  <  .001). No interaction between platinum-based chemotherapy and g BRCA1/2 mutation status with the occurrence of CH–associated gene mutations was observed. Conclusions A positive g BRCA1/2 mutation status is not a risk factor to acquire CH–associated gene mutations. OC patients may benefit from monitoring CH–associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks. [ABSTRACT FROM AUTHOR]

Introduction: Bupropion is metabolized to its active metabolite, hydroxybupropion (HB), by the genetically polymorphic cytochrome P450 2B6 (CYP2B6) enzyme. Despite its significant role in bupropion metabolism, the magnitude of the impact of CYP2B6 genotype on the exposure of bupropion has not been quantified. Objectives: A systematic review and meta‐analysis was conducted to quantify the association of bupropion and HB exposure with CYP2B6 variant alleles and genotype‐defined metabolizer phenotypes. Methods: MEDLINE, EMBASE, Web of Science, Scifinder, PsycINFO, and CENTRAL were screened to identify studies that met the following inclusion criteria (search updated on February 2021): (1) area under the plasma drug concentration‐time curve (AUC) of bupropion and/or HB in relation to CYP2B6 genotypes was studied, and (2) study participants were genotyped for common CYP2B6 variant alleles including at least CYP2B6*6. The Newcastle Ottawa Scale was used to assess risk of bias in each included study. The ratio of means (RoM) between CYP2B6 genotype or genotype‐defined phenotype groups for bupropion exposure was calculated for each study and combined in a meta‐analysis. Results: Eleven studies met the inclusion criteria for this systematic review, and 10 (including N = 413 participants) were included in the meta‐analysis. All 10 studies involved healthy adult volunteers, where other medications were not allowed. The AUCs of HB and the active moiety (bupropion + HB) were significantly reduced in CYP2B6*6 carriers compared with the non‐carriers (HB: RoM 0.77, 95% CI 0.71–0.83; active moiety: RoM 0.81, 95% CI 0.75–0.88). Both CYP2B6 poor and intermediate metabolizers had significantly decreased exposures to HB and the active moiety than normal metabolizers. Conclusion: The CYP2B6*6 allele and genotype‐determined CYP2B6 poor and intermediate metabolizer phenotypes are associated with significantly lower exposures to HB and the total active moiety. The findings of this study suggest opportunities to further study precision dosing strategies for bupropion therapy based on CYP2B6 genotype. [ABSTRACT FROM AUTHOR]

Abstract Background Prevention of colorectal cancer is a major health care issue. People who have undergone colonoscopy screening and had colorectal polyps removed have a higher risk of being diagnosed with polyps again compared to the normal population. Therefore, it would be ideal to find appropriate means that effectively help to prevent the reoccurrence of polyps after polypectomy. So far, pharmaceutical chemoprevention with NSAIDs including aspirin has been shown to be effective but not gained general acceptance due to side effects. Nutraceuticals such as polyphenols from tea plants have demonstrated remarkable therapeutic and preventive effects in molecular, epidemiological and clinical trials. However, placebo-controlled trials demonstrating the efficacy of nutraceuticals for the (secondary) prevention of colorectal polyps as precursors for colorectal cancer are missing. Methods/Design We present the design of a randomized, placebo controlled, multicentre trial to investigate the effect of diet supplementation with green tea extract containing 300 mg epigallocatechin gallate (EGCG), the major polyphenol in green tea, on the recurrence of colon adenomas. Patients who have undergone polypectomy for colonic polyps will be randomized to receive either green tea extract containing 150 mg EGCG two times daily or a placebo over the course of three years. After a one month run-in period in which all patients will receive the active intervention, 2534 patients will be randomized, and 2028 patients are expected to complete the whole study course. Incidence, number and histology of adenoma at endpoint colonoscopy at three years will be compared in both groups. Discussion The beneficial safety profile of decaffeinated green tea extract, the quantifiable and known active content EGCG, and the accumulating evidence of its cancer preventive potential require, in our view, a validation of this compound for the nutriprevention of colorectal adenoma. Good accessibility and low costs might render this neutraceutical a top candidate for wider use as food supplement in colon cancer prevention. Trial registration ClinicalTrials.gov: NCT01360320

Adverse drug reactions (ADRs) are one of the major causes of morbidity and mortality worldwide. It is well-known that individual genetic make-up is one of the causative factors of ADRs. Approximately 14 million single nucleotide polymorphisms (SNPs) are distributed throughout the entire human genome and every patient has a distinct genetic make-up which influences their response to drug therapy. Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of antiretroviral, antimalarial, anticancer, and antidepressant drugs. These drug classes are commonly in use worldwide and face specific population variability in side effects and dosing. Parts of this variability may be caused by single nucleotide polymorphisms (SNPs) in the CYP2B6 gene that are associated with altered protein expression and catalytic function. Population variability in the CYP2B6 gene leads to changes in drug metabolism which may result in adverse drug reactions or therapeutic failure. So far more than 30 non-synonymous variants in CYP2B6 gene have been reported. The occurrence of these variants show intra and interpopulation variability, thus affecting drug efficacy at individual and population level. Differences in disease conditions and affordability of drug therapy further explain why some individuals or populations are more exposed to CYP2B6 pharmacogenomics associated ADRs than others. Variabilities in drug efficacy associated with the pharmacogenomics of CYP2B6 have been reported in various populations. The aim of this review is to highlight reports from various ethnicities that emphasize on the relationship between CYP2B6 pharmacogenomics variability and the occurrence of adverse drug reactions. In vitro and in vivo studies evaluating the catalytic activity of CYP2B6 variants using various substrates will also be discussed. While implementation of pharmacogenomic testing for personalized drug therapy has made big progress, less data on pharmacogenetics of drug safety has been gained in terms of CYP2B6 substrates. Therefore, reviewing the existing evidence on population variability in CYP2B6 and ADR risk profiles suggests that, in addition to other factors, the knowledge on pharmacogenomics of CYP2B6 in patient treatment may be useful for the development of personalized medicine with regards to genotype-based prescription. [ABSTRACT FROM AUTHOR]

Aim: High medication use may contribute to the efficiency of drug therapy in general, but it could also increase the burden of adverse drug reactions. We aimed to assess medication use and the prevalence of three risk factors for adverse drug reactions: the use of polypharmacy, potentially inappropriate medication in the elderly and pharmacogenomic polymorphisms affecting the metabolism of drugs. Methods: Cross‐sectional interview‐based medication data (including over‐the‐counter drugs) was collected in a large population‐based cohort (≥30 years of age) in Bonn, Germany. Results: Analyses were based on the first 5000 participants of the Rhineland Study (mean age 55 years, 57% women). Of our participants, 66.0% reported the use of a drug regularly, which increased to 87.4% in participants aged ≥65 years (n = 1301). The rates of use of polypharmacy, potentially inappropriate medication and pharmacogenomic drugs were 15.9%, 6.4% and 20.5%, respectively. In participants <65 years, 16.0% (95% CI 14.8, 17.3) had at least one risk factor. In participants aged ≥65 years, 54.1% (95% CI 51.4, 56.8) had at least one and 27.4% (95% CI 25.0, 29.9) had at least two risk factors. Extrapolating these numbers to the German population implies that around 9 million of the 17 million individuals aged 65 years or older are potentially at an elevated risk for adverse drug reactions, of which 4.6 million are at a potentially highly elevated risk for adverse drug reactions. Conclusion: Our study shows that drug use is common and the individual risk for an adverse drug reaction in our population is high. This suggests room for improvement in general medication use. [ABSTRACT FROM AUTHOR]