Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6-mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities of CYP2D6*9, CYP2D6*10, CYP2D6*17, and CYP2D6*41 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D6*10 was shown to be significantly greater than that of CYP2D6*17 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype-phenotype classification systems particularly regarding decreased function alleles and the IM phenotype. Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of ~ 20% of all clinically used drugs. 1 The CYP2D6 gene is highly polymorphic and genetic variations may give rise to reduced, normal or increased activity of the CYP2D6 enzyme. Consequently, there are large interindividual differences in enzymatic activity, which, in turn, may cause differences

Introduction Several blood‐based biomarkers are associated with neuronal injury, but their utility in interventional clinical trials is unclear. This study retrospectively evaluated the utility of plasma neurofilament light (NfL) and total tau (t‐tau) in an 18‐month trial in mild Alzheimer's disease (AD). Methods Correlation and conditional independence analyses and Gaussian graphical models were used to investigate cross‐sectional and longitudinal relations between NfL, t‐tau, and clinical scales. Results NfL had a stronger association than t‐tau with clinical scales; t‐tau did not hold additional information to that given by NfL ( P > 0.05 at all time points). NfL held independent information about shorter‐term (3‐ to 6‐month) progression beyond patient age and clinical scores. However, no meaningful gain in power was found when adjusting a longitudinal analysis of cognitive scores for baseline NfL. Discussion Plasma NfL is superior to t‐tau in mild AD. The ability of NfL to detect changes before clinical manifestations makes it a promising biomarker of drug response in trials of disease‐modifying drugs.

Individual cognitive profiles and correlations between cognitive functions and regional cerebral blood flow (rCBF) were analyzed in 20 consecutive patients with a clinical diagnosis of probable Alzheimer's disease (AD). CBF was measured with high resolution single photon emission computed tomography (SPECT) and [(99m) Tc]d,l-HMPAO. The analysis of cognitive profiles was based on the composite scores for six cognitive domains, derived from a detailed neuropsychological test battery, as compared with corresponding test data obtained in a control group of 28 age-matched healthy volunteers. The cognitive profiles displayed a marked heterogeneity as concerned the general level of cognitive impairment, the number of significantly affected cognitive domains, the spectrum of affected and non-affected cognitive domains, and the severity of each cognitive dysfunction. Statistically significant correlations with rCBF were found for memory scores (right frontal and temporal cortex), abstraction scores (frontal/parietal ratio of rCBF), language scores (left frontal and temporal cortex), visual perception scores (rCBF throughout the right hemisphere), and for visuo-construction scores (side-to-side asymmetry of parietal rCBF). We conclude that the previously observed topographical heterogeneity of rCBF distribution patterns in probable AD was reflected by differences in cognitive profiles. The observed heterogeneities stress the relevance of analyzing individual cognitive and rCBF data, as a supplement to group comparisons of data, in the investigation of diseases with potential heterogeneous affections of the brain.

The cytochrome P450 (CYP) 2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their CYP2D6 genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype‐based dose recommendations. The aim of this study was to quantify and compare the impact of different CYP2D6 genotypes and alleles on CYP2D6 metabolism using a large clinical data set. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6‐dependent metabolite was developed based on pharmacokinetic data from 578 subjects. The CYP2D6‐mediated metabolism was quantified for each subject based on estimates from the final popPK model, and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (CYP2D6*9), 0.34 (CYP2D6*10), 0.01 (CYP2D6*17), 0.65 (CYP2D6*29), and 0.21 (CYP2D6*41). The CYP2D6*17 and CYP2D6*41 alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the CYP2D6*9 allele was shown to be statistically significant (p = 0.02 and p = 0.05, respectively). The study provides new in vivo evidence of the enzyme function of different CYP2D6 genotypes and alleles. Our findings suggest that the activity score assigned to CYP2D6*41 should be revisited, whereas CYP2D6*17 appears to exhibit substrate‐specific behavior. Further studies are needed to confirm the findings and to improve the understanding of CYP2D6 genotype–phenotype relationships across substrates.

Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype-phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM-3411 and DM-3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM-3412, is formed via CYP2D6, the metabolic ratio of DM-3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype-phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n = 183) was associated with only 10% enzyme activity relative to the wild-type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n = 20), 32% for CYP2D6*10 (n = 62), 64% for CYP2D6*14 (n = 1), 4% for CYP2D6*17 (n = 37), 4% for CYP2D6*29 (n = 13), and 9% for CYP2D6*41 (n = 64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate-specific enzyme activity.Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of > 20% of clinically used drugs. 1 As the CYP2D6 gene is highly polymorphic, individuals exhibit varying degrees of CYP2D6 enzyme activity, which may affect the safety and efficacy of drugs cleared and/or activated by CYP2D6. The clinical importance of interindividual differences in

The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine. Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0-infinity) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0-72 h) (40%) of its O-desmethyl metabolite. The mean metabolite/substrate ratio (based on urine excretion) was about 6-times greater in EM than in PM. Treatment with quinidine converted all EM into phenocopies of PM. All pharmacokinetic parameters of brofaromine and O-desmethyl-brofaromine in EM treated with quinidine were similar to those of untreated PM, including the metabolite/substrate ratio. Quinidine treatment of PM did not alter the pharmacokinetics of brofaromine or of its metabolite, nor the metabolite/substrate ratio. The results indicate a role for the debrisoquine type of oxidation polymorphism in the O-demethylation and pharmacokinetics of brofaromine.

Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N = 476), (ii) tedatioxetine (N = 500), and (iii) vortioxetine (N = 1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans.The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Substantial interindividual variability in CYP2D6 activity exists which is largely explained by genetic polymorphism. It has been hypothesized that other factors, such as ethnicity, may also contribute to the variability.

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