Risperidone-associated adverse drug reactions and CYP2D6 polymorphisms in a South African cohort.
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ABSTRACT:
SUBMITTER: Dodgen TM
PROVIDER: S-EPMC4745369 | biostudies-literature | 2015 Jun
REPOSITORIES: biostudies-literature
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Project description:Cytochrome P450 enzyme especially CYP2D6 plays a major role in biotransformation. The interindividual variations of treatment response and toxicity are influenced by the polymorphisms of this enzyme. This review emphasizes the effect of CYP2D6 polymorphisms in risperidone treatment in terms of basic knowledge, pharmacogenetics, effectiveness, adverse events, and clinical practice. Although the previous studies showed different results, the effective responses in risperidone treatment depend on the CYP2D6 polymorphisms. Several studies suggested that CYP2D6 polymorphisms were associated with plasma concentration of risperidone, 9-hydroxyrisperidone, and active moiety but did not impact on clinical outcomes. In addition, CYP2D6 poor metabolizer showed more serious adverse events such as weight gain and prolactin than other predicted phenotype groups. The knowledge of pharmacogenomics of CYP2D6 in risperidone treatment is increasing, and it can be used for the development of personalized medication in term of genetic-based dose recommendation. Moreover, the effects of many factors in risperidone treatment are still being investigated. Both the CYP2D6 genotyping and therapeutic drug monitoring are the important steps to complement the genetic-based risperidone treatment.
| S-EPMC5138038 | biostudies-literature
Project description:BackgroundThere are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children.MethodsChildren ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers.ResultsFor analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03).ConclusionChildren with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.
| S-EPMC6435416 | biostudies-literature
Project description:BackgroundThis study aimed to investigate the influence of CYP2D6 polymorphisms on risperidone plasma concentrations in patients with schizophrenia. Based on pharmacogenomics, we examined whether plasma concentration of risperidone is associated with clinical response and adverse side-effects.MethodsWe recruited patients with chronic schizophrenia who were then treated with risperidone. The CYP2D6 genotypes were determined using targeted sequencing. All high-frequency mutation sites of the nine exons of the gene were assayed in the present study. Plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-RIS) were measured using high-performance liquid chromatography (HPLC). Psychiatric symptoms were monitored using The Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impression (CGI). Adverse effects were evaluated using the Barnes Akathisia Scale (BAS) and Extrapyramidal Symptom Rating Scale (ESRS). Follow-up visits were scheduled at weeks 2,4, and 8 after treatment initiation.ResultsAmong the 76 patients, 100 C > T (rs1065852), 1038 C > T (rs1081003), 1662 G > C (rs1058164), 2851 C > T (rs16947), and 4181G > C (rs1135840) variants were detected. The most common allele was CYP2D6*10 (81.6%), whereas CYP2D6*2 (9.2%) and CYP2D6*5 (17.1%) were relatively rare. Plasma levels of risperidone and the risperidone/9-OH risperidone ratio (R/9-OH) were significantly increased in individuals with CYP2D6*10 (P < 0.05). The change in PANSS score, weight, high-density lipoprotein (HDL) level, prolactin (PRL) level, and ESRS were significantly different from baseline, between the different genotypes (P < 0.01). Moreover, individuals with CYP2D6*10 homozygous (TT) mutations were associated with higher risperidone concentration and R/9-OH ratio than those with heterozygous mutations (CT) (P < 0.01). A change from baseline in BPRS scores was observed only during week 8 and was different between heterozygous and homozygous mutations. As for the C2851T polymorphism, the incidence of adverse metabolic effects was significantly different between the C/C and C/T genotypes (P < 0.01). Regarding the G4181C polymorphisms, the changes from baseline in GLU and TG, were different between the C/C and C/G genotypes (P < 0.01).ConclusionsThe genotype of CYP2D6 significantly influences the plasma concentration of risperidone and may subsequently influence the adverse side-effects following risperidone treatment, while also exerting a slight influence on clinical outcomes.
| S-EPMC7856706 | biostudies-literature
Project description:BACKGROUND:The high HIV prevalence in South Africa may potentially be shaping the local adverse drug reaction (ADR) burden. We aimed to describe the prevalence and characteristics of serious ADRs at admission, and during admission, to two South African children's hospitals. METHODS:We reviewed the folders of children admitted over sequential 30-day periods in 2015 to the medical wards and intensive care units of each hospital. We identified potential ADRs using a trigger tool developed for this study. A multidisciplinary team assessed ADR causality, type, seriousness, and preventability through consensus discussion. We used multivariate logistic regression to explore associations with serious ADRs. RESULTS:Among 1050 patients (median age 11?months, 56% male, 2.8% HIV-infected) with 1106 admissions we found 40 serious ADRs (3.8 per 100 drug-exposed admissions), including 9/40 (23%) preventable serious ADRs, and 8/40 (20%) fatal or near-fatal serious ADRs. Antibacterials, corticosteroids, psycholeptics, immunosuppressants, and antivirals were the most commonly implicated drug classes. Preterm neonates and children in middle childhood (6 to 11?years) were at increased risk of serious ADRs compared to infants (under 1?year) and term neonates: adjusted odds ratio (aOR) 5.97 (95% confidence interval 1.30 to 27.3) and aOR 3.63 (1.24 to 10.6) respectively. Other risk factors for serious ADRs were HIV infection (aOR 3.87 (1.14 to 13.2) versus HIV-negative) and increasing drug count (aOR 1.08 (1.04 to 1.12) per additional drug). CONCLUSIONS:Serious ADR prevalence in our survey was similar to the prevalence found elsewhere. In our setting, serious ADRs were associated with HIV-infection and the antiviral drug class was one of the most commonly implicated. Similar to other sub-Saharan African studies, a large proportion of serious ADRs were fatal or near-fatal. Many serious ADRs were preventable.
| S-EPMC6942333 | biostudies-literature
Project description:IntroductionEstimating the incidence of antiretroviral discontinuations due to adverse drug reactions (ADRs) is important to inform antiretroviral treatment (ART) regimen recommendations, and to guide prescribing and monitoring policies. Routinely collected clinical data is a useful source of pharmacovigilance data. We estimated the incidences of first-line antiretroviral discontinuations due to ADRs using routine clinical data, and compared them with incidences estimated using data enhanced by folder review, in two South African cohorts.MethodsWe included patients 16 years and older on first-line ART. We selected a stratified random sample of 25% for checking of ART prescription data and reasons for antiretroviral discontinuations retrospectively, including folders reviews where required (enhanced-data sample). We estimated the incidence of antiretroviral discontinuations using Kaplan-Meier and competing risk analyses.ResultsIn 15396 patients, 40% had a first-line antiretroviral discontinuation by three years on ART. We could determine the reason for 65% of discontinuations using routine data only, and 84% of discontinuations, in the enhanced-data sample of 3837 patients. ADR was the most common reason for discontinuations. In the enhanced-data sample, the cumulative incidence of discontinuations due to ADRs by three years was 30.4% (95% CI: 24.4-36.6) for stavudine; 2.0% (95% CI: 1.5-2.6) for tenofovir, and 1.3% (95% CI: 0.8-2.1) for efavirenz. Using routine data only, the cumulative incidences of discontinuations due to ADRs by three years for stavudine, tenofovir, and efavirenz respectively were 23.9% (95% CI: 20.3-27.7), 1.2% (95% CI: 0.9-1.4) and 0.5% (95% CI: 0.3-0.7).ConclusionsAlthough the relative rankings were similar using routine or enhanced data, lack of checking for missing reasons for discontinuation resulted in underestimates of the incidence of antiretroviral discontinuations due to ADRs. Systems to improve data collection of reasons for regimen changes prospectively would increase the capacity of routine data to answer pharmacovigilance questions.
| S-EPMC6124775 | biostudies-literature
Project description:PurposeThe metabolism of antiretroviral drugs is subject to individual variations of the CYP 2B6 gene. The objective of this study was to evaluate the prevalence of CYP 2B6 516 G>T and 983 T>C polymorphisms and investigate their association with the development of adverse drug reactions (ADRs) in people living with HIV/AIDS in Cameroon.Patients and methodsA total number of 122 patients, attending the Yaoundé Central Hospital HIV Day Clinic, consented to take part in this study. Blood specimens were collected and DNA was extracted using the Chelex method. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed for the detection of CYP 2B6 Single-Nucleotide Polymorphisms (SNPs). Genotype frequencies were compared between groups with or without ADRs. Logistic regression analysis was performed to assess association between genotype and adverse effects of antiretroviral therapy (ART).ResultsThree types of metabolizers were identified: extensive, intermediate and slow. For the 516G>T polymorphism, prevalences of 8.2% GG, 65.6% GT and 26.2% TT were obtained. For the 983T>C polymorphism, 89.3% TT, 4.1% CT and 6.6% CC prevalences were obtained. Those homozygous for the wild-type allele (516GG) were less likely to develop ADR with a statistically significant difference (OR=0.885, P=0.029). For the CYP2B6 T983C SNP, homozygous mutants (CC) may present a higher risk (threefold) of developing adverse reactions (OR=2.677, P=0.164).ConclusionThese findings demonstrate that ADRs among HIV/AIDS patients under ART may be associated with the genetic variability of the metabolizing enzyme CYP 2B6. Genotyping for this gene may guide the better administration of Efavirenz and Nevirapine to Cameroonian patients.
| S-EPMC6941599 | biostudies-literature
Project description:We sought to determine the prevalence at admission and incidence during hospitalization of antibiotic-associated suspected adverse drug reactions (aa-ADRs) among Ugandan inpatients; and to characterize these aa-ADRs. We conducted a prospective cohort study of 762 consented adults admitted on medical and gynecological wards of the 1790-bed Mulago National Referral Hospital. Thirty percent were known HIV-seropositive (232/762). Nineteen percent (148/762; 95% CI: 17-22%) of inpatients experienced at least one aa-ADR. At hospital admission, 6% (45/762; 95% CI: 4-8%) of patients had at least one aa-ADR; and 15% (45/300; 11-20%) of those who had received antibiotics in the 4-weeks preadmission. Twenty-four (53%) of these 45 patients had serious aa-ADRs. The incidence of aa-ADRs was 19% (117/629; 95% CI: 16-22%) of patients who received antibiotics [community-acquired: 9% (27/300; 95% CI: 6-13%); hospital-acquired: 16% (94/603; 95% CI: 13-19%)]: 39 (33%) of 117 patients had serious aa-ADRs. Of 269 aa-ADRs, 115 (43%) were community-acquired, 66 (25%) probable/definite, 171 (64%) preventable, 86 (32%) serious, and 24 (9%) rare. Ceftriaxone was the most frequently implicated for serious hospital-acquired aa-ADRs. Cotrimoxazole, isoniazid, rifampicin, ethambutol, and pyrazinamide were the most frequently linked to serious community-acquired aa-ADRs. Fatal jaundice (isoniazid), life-threatening difficulty in breathing with shortness of breath (rifampicin) and disabling itchy skin rash with numbness of lower swollen legs (ethambutol, isoniazid) were observed. Pharmaceutical quality testing of implicated antibiotics could be worthwhile. Periodic on-ward collection and analysis of antibiotic-safety-data standardized by consumption is an efficient method of tracking antibiotics with 1%-risk for serious aa-ADRs.
| S-EPMC5368962 | biostudies-literature
Project description:Olanzapine, aripiprazole and risperidone are atypical antipsychotics or neuroleptics widely used for schizophrenia treatment. They induce various adverse drug reactions depending on their mechanisms of action: metabolic effects, such as weight gain and alterations of glucose and lipid metabolism; hyperprolactinemia and extrapyramidal effects, such as tremor, akathisia, dystonia, anxiety and distress. In this review, we listed polymorphisms associated with individual response variability to olanzapine, aripiprazole and risperidone. Olanzapine is mainly metabolized by cytochrome P450 enzymes, CYP1A2 and CYP2D6, whereas aripiprazole and risperidone metabolism is mainly mediated by CYP2D6 and CYP3A4. Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics. The three antipsychotics act on dopamine and serotonin receptors, among others, and several studies found associations between polymorphisms in these genes and variations in the incidence of adverse effects and in the response to the drug. Since olanzapine is metabolized by CYP1A2, a lower starting dose should be considered in patients treated with fluvoxamine or other CYP1A2 inhibitors. Regarding aripiprazole, a reduced dose should be administered in CYP2D6 poor metabolizers (PMs). Additionally, a reduction to a quarter of the normal dose is recommended if the patient is treated with concomitant CYP3A4 inhibitors. Risperidone dosage should be reduced for CYP2D6 PMs and titrated for CYPD6 ultrarapid metabolizers (UMs). Moreover, risperidone dose should be evaluated when a CYP2D6, CYP3A4 or ABCB1 inhibitor is administered concomitantly.
| S-EPMC8316766 | biostudies-literature
Project description:We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient's pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.
| S-EPMC8233787 | biostudies-literature
Project description:We conducted a quantitative assessment of drug-inducible cis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs were identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) .
2024-07-24 | GSE272109 | GEO