Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.

M3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion.

Drug-disease interactions negatively affect the benefit/risk ratio of drugs for specific populations. In these conditions drugs should be avoided, adjusted, or accompanied by extra monitoring. The motivation for many drug-disease interactions in the Summary of Product Characteristics (SmPC) is sometimes insufficiently supported by (accessible) evidence. As a consequence the translation of SmPC to clinical practice may lead to non-specific recommendations. For the translation of this information to the real world, it is necessary to evaluate the available knowledge about drug-disease interactions, and to formulate specific recommendations for prescribers and pharmacists. The aim of this paper is to describe a standardized method how to develop practice recommendations for drug-disease interactions by literature review and expert opinion.

Tardive dyskinesia (TD) is a common side effect of antipsychotic treatment. This movement disorder consists of orofacial and limb-truncal components. The present study is aimed at investigating the role of serotonin receptors (HTR) in modulating tardive dyskinesia by genotyping patients with schizophrenia.

Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma risperidone levels and risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25-0.75) than normal metabolizer (defined as AS = 1-2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as risperidone/9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the CYP2D6 genotype to phenotype. In addition to validating that CYP2D6 genetic variation significantly impacts risperidone metabolism, we demonstrated that revised value for the CYP2D6*10 was superior for genotype to phenotype translation. However, at least for risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.

Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in patients with cirrhosis.

Background: In 2005, the European Medicines Agency (EMA) released guidance on pharmacokinetic studies in patients with hepatic impairment. This guidance describes the design of these studies and what information should be presented in the Summary of Product Characteristics (SmPC). We aim to evaluate the availability and clinical applicability of information on medicine use in patients with hepatic impairment in SmPCs and registrational dossiers of recently approved medicines. Methods: We reviewed SmPC information on use in patients with hepatic impairment of 51 new medicines authorized between 2015 and 2017. Per medicine, we assessed the availability of nine information items derived from the EMA guidance, i.e. type of hepatic disease studied; stratification by severity of hepatic impairment; influence of hepatic impairment on the pharmacokinetics; safety advice in mild, moderate, and severe hepatic impairments; and dosing recommendation in mild, moderate, and severe hepatic impairments. If unavailable, the European Public Assessment Report (EPAR) and study report were consulted consecutively. Of available items, clinical applicability was assessed by labeling information as "clear" or "ambiguous". Results: Of 51 medicines, 15 had no pharmacokinetic study in patients with hepatic impairment described in their SmPC. The other 36 SmPCs contained on average seven of the nine information items (range 4-9). One SmPC contained all 9 items, and after consulting, the study reports, 11 SmPCs were complete. The item "type of hepatic disease studied" was available in one SmPC, though it could be retrieved in 21 study reports. Regarding clinical applicability, there was no medicine with all information items available and clearly formulated in the SmPC. A total of 12 medicines (33%) contained only clearly formulated information, while 24 (67%) contained at least one ambiguously formulated information item (range 0-4). Items often ambiguously formulated were: "definition of mild, moderate, and severe hepatic impairment" (15 ambiguous SmPCs) and "safety advice in severe hepatic impairment" (17 ambiguous SmPCs). Conclusion: While SmPCs contain a large part of information requested by the EMA, clinical applicability seems low, as it is often unclear to which specific type of hepatic disease patient the advice applies. This can negatively influence the practical use by healthcare professionals.

Patients receive information about their medication from different sources, including prescription labels. These labels are physically attached to each package dispensed to patients and contain the most important instructions on how to use the medication correctly. However, many patients experience difficulties in understanding and applying the instructions on these labels correctly, especially patients with limited health literacy. The aim of this study is to investigate the comprehensibility of prescription label instructions among patients with adequate and limited health literacy skills, and to implement improvements in primary health care.

We investigated the association between genetic variations in pharmacodynamic genes and risperidone-induced increased prolactin levels in children and adolescents with autism spectrum disorder (ASD). In a retrospective study, variants of pharmacodynamic genes were analyzed in 124 ASD patients treated with a risperidone regimen for at least 3 months. To simplify genotype interpretation, we created an algorithm to calculate the dopamine D2 receptor (DRD2) gene genetic risk score. There was no relationship between prolactin levels and single SNPs. However, the H1/H3 diplotype (A2/A2-Cin/Cin-A/G) of DRD2/ankyrin repeat and kinase domain containing 1 (ANKK1) Taq1A, DRD2 -141C indel, and DRD2 -141A>G, which had a genetic risk score of 5.5, was associated with the highest median prolactin levels (23 ng/ml). As the dose-corrected plasma levels of risperidone, 9-OH-risperidone, and the active moiety increased, prolactin levels in patients carrying the H1/H3 diplotype were significantly higher than those of the other diplotypes. DRD2 diplotypes showed significantly high prolactin levels as plasma risperidone levels increased. Lower levels of prolactin were detected in patients who responded to risperidone. This is the first system for describing DRD2 haplotypes using genetic risk scores based on their protein expression. Clinicians should consider using pharmacogenetic-based decision-making in clinical practice to prevent prolactin increase.

An established theory for the pathogenesis of tardive dyskinesia is disturbed dopaminergic receptor sensitivity and/or dopaminergic intracellular signaling. We examined associations between genetic variants of neurotransmitter receptors and tardive dyskinesia.

Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis.

Metoprolol (a CYP2D6 substrate) is often co-prescribed with paroxetine/fluoxetine (a CYP2D6 inhibitor) because the clinical relevance of this drug-drug interaction (DDI) is still unclear. This review aimed to systematically evaluate the available evidence and quantify the clinical impact of the DDI.

There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression.

Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of drug response. Hyperprolactinemia (HPRL), a common adverse effect of antipsychotics, is attributed to blockade of dopamine D2 receptors. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. We examined whether the functional polymorphism rs2734849 in the ANKK1 gene is associated with antipsychotic-induced HPRL.

The aim of this study is to evaluate the potential association between N-acetyltransferase type 2 (NAT2) polymorphisms and drug-induced liver injury during anti-TB treatment (AT-DILI).

Major depressive disorder has become a prominent cause of disability, as lifetime prevalence has increased to ~15% in the Western world. Pharmacological effects of serotonin (5-hydroxytryptamine, 5-HT) are mediated through 5-hydroxytryptamine receptor (5-HTR) binding. Serotonin regulation of amygdala activity is attained through activation of three 5-HT2 family receptor subtypes, 5-HT2A, 5-HT2B, and 5-HT2C. Specifically, HT2A and the HT2C receptors have similar gross cerebral distribution and function, with higher constitutive activity found in HT2C than in HT2A. We investigated the possible association of 5-HTR gene polymorphisms to specific and non-specific antidepressant treatment responses in treatment-free patients in Siberia. 156 patients, aged between 18-70 years and clinically diagnosed with depressive disorders, were treated with antidepressants for 4 weeks. Patients were genotyped for a subset of 29 SNPs from the following 5-HT Receptor genes: HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B and HTR6. Primary outcome was measured by differences in Hamilton Depression Rating Scale (ΔHAM-D 17) scores between baseline/week two, week two/week four and baseline/week four. Univariate linear regression was initially conducted to determine the 5-HTR SNPs to be studied within the multiple linear regression. Multiple linear regression analyses over the three time periods were conducted for ΔHAM-D 17 with independent factors including: age, gender, depression diagnosis, antidepressant treatment and selected 5-HTR SNPs. We found improved ∆HAM-D 17 in patients taking tricyclic antidepressants (0-4 weeks: B = 4.85, p = 0.0002; 0-2 weeks: B = 3.58, p = 0.002) compared to patients taking SSRIs. Over the course of study, significant associations between 5-HT receptors SNPs and antidepressant response were not identified.

Guidelines advise the use of antibacterials (ABs) in the management of COPD exacerbations. COPD patients often have multiple comorbidities, such as diabetes mellitus and cardiac diseases, leading to polypharmacy. Consequently, drug-drug interactions (DDIs) may frequently occur, and may cause serious adverse events and treatment failure.

Hyperprolactinaemia, a common adverse effect of antipsychotic drugs, is primarily linked to blockade of dopamine D2 receptors in the pituitary gland. Certain antipsychotic drugs, such as, for example risperidone and paliperidone, are more likely to induce hyperprolactinaemia compared to others. This effect is probably caused by a relatively high blood/brain concentration ratio, a consequence of being a substrate of P-glycoprotein. Genetic variants of P-glycoprotein with changed functional activity might influence the potential of risperidone and paliperidone to cause hyperprolactinaemia as the altered blood/brain concentration ratio would lead to a reduced therapeutic drug level within essential brain areas making dose adaptations necessary. This increases exposure of dopamine D2 receptors within the pituitary gland.

Metabolic syndrome (MetS) is characterized by abdominal obesity, hyperglycaemia, dyslipidaemia and hypertension. FTO gene has been implicated in the pathogenesis of obesity, but the available scientific data concerning their relationship to antipsychotic drug-induced obesity and metabolic syndrome is still incomplete and inconsistent, which indicates that continuing the investigation of this gene's role is necessary.

Many antidepressants are substrates of P-glycoprotein, an efflux transporter in the blood-brain-barrier encoded by the ABCB1 gene. Genetic variations might influence the transport rate of antidepressants and hence their pharmacological effects. This study investigates the influence of eight polymorphisms in the ABCB1 gene on antidepressant treatment response.