Chronic Pain Management in a CYP2D6 Poor Metabolizer: A Case Report for Oxycodone.

The objective of this case report is to illustrate pharmacogenomics (PGx)-guided oxycodone treatment, given the conflicting data on the analgesic response from oxycodone in Cytochrome P450 (CYP)2D6 poor metabolizers (PMs). PGx-guided therapy can help improve treatment outcomes. This case report describes a 58-year-old patient who was prescribed oxycodone for chronic pain management. The patient presented with a history of inadequate pain control despite analgesic treatment with oxycodone (morphine milliequivalent [MME] = 22.5). Pharmacogenetic testing revealed that the patient was a CYP2D6 Poor Metabolizer (PM), which may shed light on the observed lack of analgesic response to oxycodone. The clinical pharmacist recommended switching to an alternative opioid not metabolized via the CYP2D6 pathway. The patient was subsequently switched to hydromorphone (MME = 16), resulting in improved pain control and fewer side effects. The newer hydromorphone dose accounted for a 30% MME dose reduction. The patient's initial average and worst pain score were 7 and 9 out of 10, respectively, per the numeric rating scale (NRS). Upon follow-up with the patient in two weeks, her average and worst pain scores improved to 3 and 3.5 out of 10, respectively, per the NRS. Further PGx testing results led to an overall positive outcome, such as her willingness to participate in physical therapy as a result of improved pain scores. This case highlights the importance of considering individual variability in drug metabolism when prescribing medications, particularly opioids such as oxycodone, to ensure optimal therapeutic outcomes and minimize the risk of adverse events in CYP2D6 PMs.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes.

PURPOSE: Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)-positive breast cancer patients under different genotypes. MATERIALS AND METHODS: CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. RESULTS: A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). CONCLUSION: Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

[Study of allelic variants of the CYP2D6 and CYP3A genes on the effectiveness and safety of tamsulosin therapy in patients with BPH: results of a pilot study].

INTRODUCTION: Tamsulosin is a member of the group of selective 1-adrenoblockers. Tamsulosin monotherapy is the most common first-line option in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and can be used regardless on severity of LUTS. The CYP2D6, CYP3A4, and CYP3A5 enzymes are involved in the metabolism of tamsulosin. Carriage of different allelic variants of CYP2D6, CYP3A4 and CYP3A5, involved in its metabolism, may potentially affect the variability of efficacy and safety of the drug. AIM: To evaluate the effect of carriage of allelic variants of cytochrome P450 superfamily enzyme genes (CYP2D6*3, CYP2D6*4, CYP2D6*9, CYP2D6*10, CYP2D6*41, CYP3A4*3, CYP3A4*22 and CYP3A5*3) on the efficiency and safety of tamsulosin in patients with LUTS associated with BPH. MATERIALS AND METHODS: All phases of the study were completed by 106 patients with LUTS/BPH (N40 according to ICD 10). All patients received monotherapy with tamsulosin 0.4 mg/day for a minimum of 8 weeks. Based on the severity of symptoms, they were divided into two groups using the International Prostate Symptom Score (IPSS). In Group 1, there were patients with moderate symptoms (IPSS score of 8-19) (n=57), while Group 2 consisted of those with severe symptoms (IPSS score >20) (n=49). Treatment outcomes were assessed using the IPSS score with determination of quality of life (QoL), transrectal ultrasound with evaluation of prostate volume and residual urine, and uroflowmetry. Follow-up visits were at 2, 4, and 8 weeks after the start of therapy. Genotyping of all patients was performed using polymerase chain reaction to determine the CYP2D6 (*3, *4, *9, *10, and *41), CYP3A4 (*3, *22), and CYP3A5*3 markers. RESULTS: In the group of patients with moderate symptoms, carriers of the CYP2D6*10 and CYP2D6*41 polymorphisms showed a significantly greater reduction in symptoms according to the overall IPSS score at 8 weeks (p=0.046) and in the micturition symptom subscale starting from 4 weeks of treatment (p<0.05). Carriers of the CYP2D6*10 polymorphism in both groups were associated with a decrease in residual urine volume at 8 weeks (p<0.05). The presence of the CYP3A5*3 variant in those with severe symptoms significantly improved quality of life during therapy. Allelic variants of the CYP2D6 and CYP3A genes did not affect the frequency of adverse events. CONCLUSION: The results obtained by calculating the prognostic significance of individual polymorphic markers pointed to the contribution of CYP2D6*10 and CYP2D6*41. Tamsulosin therapy is more effective in patients with LUTS who are carriers of these allele variants. The safety parameters of tamsulosin were not influenced by the studied polymorphic variants. It was found that CYP3A5*3 was associated with an increase in the subjective assessment of the patient's quality of life, but it is too early to draw final conclusions. The issue of the contribution of genetic factors to the efficiency and safety of treatment of LUTS in BPH requires further study with a larger sample size and analyzed parameters.

Pharmacokinetics of single low dose primaquine in Ugandan and Congolese children with falciparum malaria.

BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m-<1 y, n = 12), 582.8 (1-5 y, n = 126), 871.1 (6-9 y, n = 80), and 931.0 (10-11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8-5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.

Sophoricoside attenuates autoimmune­mediated liver injury through the regulation of oxidative stress and the NF­κB signaling pathway.

The prevalence of autoimmune hepatitis (AIH) is increasing, yet specific pharmacotherapies remain to be explored. The present study aimed to investigate the effects of sophoricoside (SOP), a bioactive component of medical herbs, on AIH and to elucidate the underlying mechanisms. Bioinformatic approaches were used to predict the potential targets and underlying regulatory mechanisms of SOP on AIH. The effects of SOP on AIH were evaluated by determining the expression levels of inflammatory cytokines, histological liver injury and hepatic fibrosis in an improved chronic cytochrome P450 2D6 (CYP2D6)­AIH mouse model and in a model of concanavalin­A (ConA)­induced acute immune­mediated liver injury. The antioxidant activity of SOP was detected in in vivo and in vitro experiments. The selected signal targeted by SOP in AIH was further confirmed using western blot analysis and immunofluorescence staining. The results of bioinformatic analysis revealed that the targets of SOP in AIH were related to oxidative stress and the NF­κB gene set. The NF­κB transcription factor family is a key player that controls both innate and adaptive immunity. The activation of the NF­κB signaling pathway is often associated with autoimmune disorders. In the animal experiments, SOP attenuated CYP2D6/ConA­induced AIH, as evidenced by a significant reduction in the levels of hepatic enzymes in serum, inflammatory cytokine expression and histological lesions in the liver. The oxidative response in AIH was also significantly inhibited by SOP, as evidenced by a decrease in the levels of hepatic malondialdehyde, and elevations in the total antioxidant capacity and glutathione peroxidase levels. The results of the in vivo and in vitro experiments revealed that SOP significantly reduced the enhanced expression and nuclear translocation of phosphorylated p65 NF­κB in the livers of mice with AIH and in lipopolysaccharide­stimulated AML12 cells. On the whole, the present study demonstrates the protective role of SOP in AIH, which may be mediated by limiting the oxidative response and the activation of the NF­κB signaling pathway in hepatocytes.

The Utility of CYP2D6 and CYP2C19 Variants to Guide Pharmacological Treatment in Complex Unipolar Major Depression: A Pilot Longitudinal Study.

Major depression is a frequent condition which variably responds to treatment. In view of its high prevalence, the presence of treatment resistance in major depression significantly impacts on quality of life. Tailoring pharmacological treatment based on genetic polymorphisms is a current trend to personalizing pharmacological treatment in patients with major depressive disorders. Current guidelines for the use of genetic tests in major depression issued by the Clinical Pharmacogenomics Implementation Consortium (CPIC) are based on CYP2D6 and CYP2C19 polymorphisms which constitute the strongest evidence for pharmacogenomic guided treatment. There is evidence of increased clinical response to pharmacological treatment in major depression although largely in non-treatment resistant patients from Western countries. In this study, well characterised participants (N = 15) with complex, largely treatment resistant unipolar major depression were investigated, and clinical improvement was measured at baseline and at week-8 after the pharmacogenomics-guided treatment with the Montgomery Åsberg Depression Rating Scale (MÅDRS). Results suggested a statistically significant improvement (p = 0.01) of 16% at endpoint in the whole group and a larger effect in case of changes in medication regime (28%, p = 0.004). This small but appreciable effect can be understood in the context of the level of treatment resistance in the group. To our knowledge, this is the first study from the Middle East demonstrating the feasibility of this approach in the treatment of complex major depressive disorders.

The impact of endoxifen-guided tamoxifen dose reductions on endocrine side-effects in patients with primary breast cancer.

BACKGROUND: Tamoxifen is important in the adjuvant treatment of hormone-sensitive breast cancer and substantially reduces recurrence; however, almost 50% of patients are non-compliant mainly due to side-effects. The aim of this study was to investigate whether endoxifen-guided tamoxifen dose reduction could lead to fewer side-effects. MATERIALS AND METHODS: Effects of tamoxifen dose reduction were investigated in patients with bothersome side-effects and endoxifen levels ≥32 nM and compared to patients with side-effects who remained on tamoxifen 20 mg. Endocrine symptoms and health-related quality of life (HR-QOL) were assessed after 3 months with the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire. RESULTS: Tamoxifen dose was reduced in 20 patients, 17 of whom were assessable for side-effect analyses. A clinically relevant improvement of >6 points was observed in endocrine symptoms and HR-QOL in 41% and 65% of the patients, respectively. In total, there was a significant and clinically relevant improvement in endocrine symptoms [5.7, 95% confidence interval (CI) -0.5-11.5] and HR-QOL (8.2, 95% CI 0.9-15.4) after dose reduction. This was not seen in patients whose doses were not reduced (n = 60). In 21% of patients, endoxifen dropped slightly below the 16-nM threshold (12.8, 15.5, 15.8, 15.9 nM). CONCLUSIONS: Endoxifen-guided dose reduction of tamoxifen significantly improved tamoxifen-related side-effects and HR-QOL. Nearly 80% of patients remained above the most conservative endoxifen threshold.

[A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring]. / æ‰˜èŽ«è¥¿æ±€åœ¨æ³¨æ„åŠ›ç¼ºé™·å¤šåŠ¨éšœç¢æ‚£å„¿ä¸­çš„ç²¾å‡†è¯å­¦ç ”ç©¶ï¼šCYP2D6åŸºå› æ£€æµ‹å’Œæ²»ç–—è¯ç‰©ç›‘æµ‹.

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

Evidence Regarding Pharmacogenetics in Pain Management and Cancer.

Patients experience interindividual variation in response to analgesics, which may be partially explained by genetics. This commentary discusses a recently published trial on COMT genotype and opioid dose requirements and describes the potential role for COMT and other genes (eg, CYP2D6) on opioid therapy and the current evidence for germline pharmacogenetics and resources for opioid pharmacogenetics.

Acute liver injury induced by drug interaction between dacomitinib and metoprolol due to the inhibition of CYP2D6 by dacomitinib.

INTRODUCTION: In recent years, oral antineoplastic agents are commonly used in antitumor therapy. The interaction between drugs may affect the efficacy of drugs or lead to adverse reactions. We describe the case of a patient who presented acute liver injury, possibly induced by the concomitant use of metoprolol and dacomitinib. CASE REPORT: A 62-year-old male patient with non-small cell lung cancer was admitted for anti-cancer treatment. He regularly took metoprolol tartrate 12.5 mg, 2/day for hypertension. He was treated with dacomitinib according to EGFR Exon21 L858R positive. After 3 days of dacomitinib, the patient's alanine aminotransferase (ALT) and glutathione aminotransferase (AST) increased, and the heart rate and systolic blood pressure of the patient decreased significantly. The patient was diagnosed with acute liver injury. MANAGEMENT AND OUTCOMES: Dacomitinib was discontinued and glutathione, magnesium isoglycyrrhizinate were given to treat acute liver injury. Two days after discontinued dacomitinib, the patient's heart rate increased, but the ALT and AST of the patient elevated again. Metoprolol tartrate was subsequently discontinued and the ALT and AST gradually decreased and the patient discharged from the hospital eight days later with his liver function improved. DISCUSSION: To our knowledge, this is the first case in the literature of acute liver injury possibly induced by the interaction between metoprolol and dacomitinib. The interaction most likely arose because dacomitinib is a CYP2D6 strong inhibitor and could therefore impair the metabolism of metoprolol (a CYP2D6 substrate) and increase its serum concentration. Therefore, hepatic function should be carefully monitored in patients treated with dacomitinib and metoprolol and other inhibitors or inducers of CYP2D6.

[CYP2D6 gene polymorphic markers role in determining the optimal treatment tactics for portal hypertension in patients with liver cirrhosis].

AIM: To study the polymorphic markers CYP2D6*4 (G1846A, rs3892097), CYP2D6*6 (T1707del, rs5030655), CYP2D6*10 (C100T, rs1065852), CYP2D6*41 (G2988A, rs28371725) and CYP2D6*3 (A2549del, rs4986774) role in treatment optimization of portal hypertension with propranolol in patients with liver cirrhosis (LC). MATERIALS AND METHODS: The study included 60 patients with LC who received propranolol therapy at a daily dose of 30 mg for 14 days. The efficacy of treatment was assessed by ultrasonography measuring the linear blood flow velocity of portal vein. Genotyping of CYP2D6*4, CYP2D6*6, CYP2D6*10, CYP2D6*41 and CYP2D6*3 was carried out by real-time polymerase chain reaction. Evaluation of the CYP2D6 activity was carried out by determining the ratio of pinoline and its metabolite concentration in morning urine using high performance liquid chromatography with mass spectrometry. RESULTS: Positive hemodynamics in the form of any increase in the mean linear blood flow velocity of the portal vein compared to baseline was observed in 41 patients. Portal vein mean linear blood flow rate increased from 10.43.9 to 14.74.3 cm/s (p0.001). Of these, 29 patients showed an increase in this indicator by 20% from the initial one with a dynamic of 5.5 cm/s (p0.001). The regression analysis constructed by us revealed the presence of a statistically significant effect of the CYP2D6 gene polymorphic marker G1846A carriage on the propranolol therapeutic effect (p0.05). There was no statistically significant effect of polymorphic markers T1707del, C100T, G2988A, and A2549del of the CYP2D6 gene (p0.05). No convincing reliable dependence of CYP2D6 activity on the severity of LC was revealed (p0.05). CONCLUSION: An association was found between CYP2D6 gene polymorphic marker G1846A carriage and the hemodynamic effect of propranolol in patients with LC of the Russian population. There is a more significant positive dynamics of manifestations of portal hypertension on the background of propranolol therapy in carriers of the homozygous GG CYP2D6*4 genotype, in contrast to patients with the heterozygous GA genotype. Based on the results of the study, an algorithm has been developed for personalizing the treatment of patients with LC with nonselective b-adrenergic blockers using the method of CYP2D6 genotyping. Carriage of polymorphic markers T1707del, C100T, G2988A and A2549del gene CYP2D6 does not affect the effectiveness of propranolol therapy in patients with LC.

The Pharmacogenetic Impact on the Pharmacokinetics of ADHD Medications.

ADHD is a common condition in both children and adults. The most prescribed medications for the treatment of ADHD include methylphenidate, mixed amphetamine salts, atomoxetine, guanfacine, and clonidine. While each of these medications have their own distinct pharmacokinetic profile, the extent to which pharmacogenetics effects their pharmacokinetic parameters is best described in atomoxetine, followed by methylphenidate. Atomoxetine is predominantly metabolized by cytochrome p450 2D6 (CYP2D6), while methylphenidate is metabolized by carboxylesterase 1 (CES1). Both CYP2D6 and CES1 have multiple variants resulting in varying levels of enzyme activity; however, to date, the functional consequence of variants and alleles for CYP2D6 is better characterized as compared to CES1. Regarding CYP2D6, individuals who are poor metabolizers prescribed atomoxetine experience up to ten-fold higher exposure as compared to normal metabolizers at comparable dosing. Additionally, individuals prescribed methylphenidate with the rs71647871 variant may experience up to 2.5-fold higher exposure as compared to those without. Having this pharmacogenetic information available may aid clinicians and patients when choosing medications and doses to treat ADHD.

Pharmacogenomics of Alzheimer's Disease: Novel Strategies for Drug Utilization and Development.

Alzheimer's disease (AD) is a priority health problem in developed countries with a high cost to society. Approximately 20% of direct costs are associated with pharmacological treatment. Over 90% of patients require multifactorial treatments, with risk of adverse drug reactions (ADRs) and drug-drug interactions (DDIs) for the treatment of concomitant diseases such as hypertension (>25%), obesity (>70%), diabetes mellitus type 2 (>25%), hypercholesterolemia (40%), hypertriglyceridemia (20%), metabolic syndrome (20%), hepatobiliary disorder (15%), endocrine/metabolic disorders (>20%), cardiovascular disorder (40%), cerebrovascular disorder (60-90%), neuropsychiatric disorders (60-90%), and cancer (10%).For the past decades, pharmacological studies in search of potential treatments for AD focused on the following categories: neurotransmitter enhancers (11.38%), multitarget drugs (2.45%), anti-amyloid agents (13.30%), anti-tau agents (2.03%), natural products and derivatives (25.58%), novel synthetic drugs (8.13%), novel targets (5.66%), repository drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and other compounds (<1%).Pharmacogenetic studies have shown that the therapeutic response to drugs in AD is genotype-specific in close association with the gene clusters that constitute the pharmacogenetic machinery (pathogenic, mechanistic, metabolic, transporter, pleiotropic genes) under the regulatory control of epigenetic mechanisms (DNA methylation, histone/chromatin remodeling, microRNA regulation). Most AD patients (>60%) are carriers of over ten pathogenic genes. The genes that most frequently (>50%) accumulate pathogenic variants in the same AD case are A2M (54.38%), ACE (78.94%), BIN1 (57.89%), CLU (63.15%), CPZ (63.15%), LHFPL6 (52.63%), MS4A4E (50.87%), MS4A6A (63.15%), PICALM (54.38%), PRNP (80.7059), and PSEN1 (77.19%). There is also an accumulation of 15 to 26 defective pharmagenes in approximately 85% of AD patients. About 50% of AD patients are carriers of at least 20 mutant pharmagenes, and over 80% are deficient metabolizers for the most common drugs, which are metabolized via the CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 enzymes.The implementation of pharmacogenetics can help optimize drug development and the limited therapeutic resources available to treat AD, and personalize the use of anti-dementia drugs in combination with other medications for the treatment of concomitant disorders.

Association of genetic polymorphisms of CYP3A4 and CYP2D6 with gefitinib-induced toxicities.

Dermatological, gastrointestinal and hepatic toxicities are the most common adverse events associated with gefitinib use. Gefitinib is metabolized by cytochrome P450. Inconsistent associations of single nucleotide genetic polymorphisms of CYP450 and gefitinib-induced adverse effects were reported. We aim to investigate the association between CYP450 genetic polymorphism and the development of gefitinib-associated adverse events. A retrospective cohort study of Chinese patients with metastatic nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations who received first-line gefitinib treatment was conducted. Single nucleotide polymorphisms (SNPs) of CYP2D6, CYP3A4 and CYP3A5 were assayed using a multiplex SNP microarray. Risks of development of gefitinib-induced toxicities associated with different SNPs were determined. Among the 152 patients treated with gefitinib, 52 (34.2%) had gefitinib-induced hepatotoxicity, 113 (74.3%) had cutaneous reactions and 53 (34.9%) had gastrointestinal adverse effects. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes were significantly associated with hepatic, cutaneous and gastrointestinal adverse effects [odds ratio (OR) 3.773; (95% confidence interval {CI},1.046-13.610; P = 0.043), 3.368 (95% CI, 1.000-11.345; P = 0.050) and 20.000 (95% CI, 2.381-167.965; P = 0.006), respectively]. CYP2D6*41 CT, CYP2D6*10 AA and CYP3A4*1/*1G TT genotypes may be associated with increased risks of gefitinib-induced toxicities in the liver, skin and gastrointestinal tract.

Effects of CYP2D6 genotypes on Plasmodium vivax recurrence after primaquine treatment: A meta-analysis.

OBJECTIVES: To elucidate the relationship between CYP2D6 polymorphisms and Plasmodium vivax recurrence in patients receiving primaquine-based treatment through systematic review and meta-analysis. METHODS: We searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases for eligible studies published up to August of 2021. We included studies investigating the associations between CYP2D6 polymorphisms and P. vivax recurrence. We evaluated the pooled odds ratio (OR) and 95% confidence interval (CI). RESULTS: Data from nine studies, including 970 patients, were analyzed. We found that CYP2D6 poor metabolizers (PMs), intermediate metabolizers (IMs), or normal metabolizers slow (NM-Ss) were associated with a 1.8-fold (95% CI, 1.34-2.45; P = 0.0001) higher recurrence of P. vivax than normal metabolizers fast (NM-Fs), extensive metabolizers (EMs), or ultrarapid metabolizer (UMs). Subgroup analysis showed that studies on both Brazilian and Southeast or East Asian individuals had similar results to the main results. Sensitivity analysis by sequentially excluding individual studies also showed robust results (OR range: 1.63-2.01). CONCLUSIONS: This meta-analysis confirmed that CYP2D6 PMs, IMs, or NM-Ss increased the risk of P. vivax recurrence compared to NM-Fs, EMs, or UMs. The results of this study could be used to predict P. vivax recurrence and suggest CYP2D6 genotype-based primaquine dosing.

Four Times of Relapse of Plasmodium vivax Malaria Despite Primaquine Treatment in a Patient with Impaired Cytochrome P450 2D6 Function.

Plasmodium vivax exhibits dormant liver-stage parasites, called hypnozoites, which can cause relapse of malaria. The only drug currently used for eliminating hypnozoites is primaquine. The antimalarial properties of primaquine are dependent on the production of oxidized metabolites by the cytochrome P450 isoenzyme 2D6 (CYP2D6). Reduced primaquine metabolism may be related to P. vivax relapses. We describe a case of 4 episodes of recurrence of vivax malaria in a patient with decreased CYP2D6 function. The patient was 52-year-old male with body weight of 52 kg. He received total gastrectomy and splenectomy 7 months before the first episode and was under chemotherapy for the gastric cancer. The first episode occurred in March 2019 and each episode had intervals of 34, 41, and 97 days, respectively. At the first and second episodes, primaquine was administered as 15 mg for 14 days. The primaquine dose was increased with 30 mg for 14 days at the third and fourth episodes. Seven gene sequences of P. vivax were analyzed and revealed totally identical for all the 4 samples. The CYP2D6 genotype was analyzed and intermediate metabolizer phenotype with decreased function was identified.

The effects of cytochrome P450 2D6 inhibitors on a high-dose tramadol taper for medically supervised opioid withdrawal: a retrospective chart review.

Background: Tramadol is used off-label for medically supervised opioid withdrawal. Tramadol is metabolized by CYP2D6 to an active metabolite with significantly more pharmacologic activity compared to the parent compound.Objectives: The objective of this study is to evaluate the effects of CYP2D6 inhibitors on patient response to a tramadol taper for medically supervised opioid withdrawal.Methods: A retrospective chart review of patients who received a tramadol taper for medically supervised opioid withdrawal was conducted comparing patients who received concomitant moderate-to-strong CYP2D6 inhibitors to patients without concomitant therapy. The primary outcome was the change in Clinical Institute Narcotic Assessment (CINA) scores from baseline to discharge. Secondary outcomes included area under the curve of CINA scores over time, additional CINA outcomes, length of stay, and readmissions.Results: Of 100 charts reviewed, 30 patients received a concomitant moderate-to-strong CYP2D6 inhibitor. There were no statistically significant differences between the baseline demographics of the two groups. Change from baseline CINA to discharge did not differ significantly between the Non-2D6 group and the 2D6 group (-4.0 ± 3.83 and -4.5 ± 4.48 respectively; p = 0.606). The average CINA score for nausea and vomiting was significantly higher in the Non-2D6 group compared to the 2D6 group (0.34 ± 0.35 and 0.18 ± 0.33 respectively; p = 0.019). Otherwise there were no significant differences found in any secondary outcomes.Conclusions: Based on these results, moderate-to-strong CYP2D6 inhibitors do not appear to have a significant impact on the withdrawal course for patients treated with a high-dose tramadol taper.

Case report: recurrence of Plasmodium vivax malaria due to defective cytochrome P450 2D6 function in Pos Lenjang, Pahang, Malaysia.

Five children in Pos Lenjang, Pahang, Malaysia were PCR-positive for vivax malaria and were admitted to the hospital from 5 to 26 July 2019. One of the patients experienced three episodes of recurrence of vivax malaria. Microsatellite analysis showed that reinfection is unlikely. Drug resistance analysis indicated that Riamet (artemether-lumefantrine) is effective. Cytochrome P450 2D6 (CYP2D6) testing showed that this patient has defective CYP2D6 function. Primaquine failure to clear the Plasmodium vivax hypnozoites may be the cause of recurring infections in this patient. This report highlights the need for the development of liver-stage curative antimalarials that do not require metabolism by the CYP2D6 enzyme.