Association of UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic polymorphisms with irinotecan‐induced toxicity in Asian cancer patients: Meta‐analysis

Effects of UGT1A1*6 and UGT1A1*28 genetic polymorphisms on irinotecan‐induced severe toxicities in Asian cancer patients are inconclusive. Also, ABCC2 c.3972C>T may affect toxicity of irinotecan. The aim was to assess the aggregated risk of neutropenia or diarrhea in Asian cancer patients taking irinotecan and inherited UGT1A1*6, UGT1A1*28, or ABCC2 c.3972C>T genetic variants. A PubMed literature search for eligible studies was conducted. Odds ratios (ORs) were measured using RevMan software where p values <0.05 were statistically significant. Patients that inherited both UGT1A1*6 and UGT1A1*28 genetic variants (heterozygous: UGT1A1*1/*6 + *1/*28 and homozygous: UGT1A1*6/*6 + *28/*28) were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1 (neutropenia: OR 2.89; 95% CI 1.97–4.23; p < 0.00001; diarrhea: OR 2.26; 95% CI 1.71–2.99; p < 0.00001). Patients carrying homozygous variants had much stronger effects in developing toxicities (neutropenia: OR 6.23; 95% CI 3.11–12.47; p < 0.00001; diarrhea: OR 3.21; 95% CI 2.13–4.85; p < 0.00001) than those with heterozygous variants. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with neutropenia (OR 1.67; 95% CI 0.98–2.84; p = 0.06) and were significantly associated with a reduction in irinotecan‐induced diarrhea (OR 0.31; 95% CI 0.11–0.81; p = 0.02). Asian cancer patients should undergo screening for both UGT1A1*6 and UGT1A1*28 genetic variants to reduce substantially irinotecan‐induced severe toxicities.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cancer patients taking irinotecan and inheriting either UGT1A1*6 or UGT1A1*28 genetic polymorphisms or a combination of these variants (UGT1A1*6 + UGT1A1*28) are associated with severe toxicities such as neutropenia or diarrhea, but the aggregated risk is highly inconsistent, especially in Asian cancer patients. Also, the ABCC2 c.3972C>T genetic polymorphism is associated with irinotecan‐induced toxicities.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Is the combination of UGT1A1*6 and UGT1A1*28 genetic polymorphisms or ABCC2 c.3972C>T genetic variant associated with severe neutropenia or diarrhea in Asian cancer patients?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Asian cancer patients, irrespective of the type of cancer, who carried both the UGT1A1*6 and UGT1A1*28 genetic variants were significantly associated with increased risk of neutropenia and diarrhea compared to patients with UGT1A1*1/*1, and the effects were even more striking in cancer patients with homozygous variants than those with heterozygous variants. In addition, dose‐dependent analysis indicated that a high dose of irinotecan (>150 mg/m²) was significantly associated with diarrhea in cancer patients that carried both the UGT1A1*6 and UGT1A1*28 genetic variants compared to patients on medium and low doses of irinotecan. However, patients carrying the ABCC2 c.3972C>T genetic variant were not significantly associated with irinotecan‐induced toxicities.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The results presented in this meta‐analysis will greatly enhance the clinical practice of irinotecan therapy considering UGT1A1*6 and UGT1A1*28 pharmacogenetics. The findings of this study will also assist clinicians in suggesting genotyping for UGT1A1*6 and UGT1A1*28 polymorphisms prior to administering irinotecan therapy as part of standard care and may advance the translation of irinotecan pharmacogenetics to the bedside.     

9‐Hydroxyrisperidone‐Induced Hyperprolactinaemia in Thai Children and Adolescents with Autism Spectrum Disorder

Although our previous study revealed an association between prolactin level and risperidone dosage, data regarding the plasma concentration of risperidone are lacking. Therefore, this study aimed to investigate the association between plasma drug concentrations of risperidone, 9‐hydroxyrisperidone and serum prolactin level in Thai children and adolescents with autism spectrum disorder (ASD). The individuals for this study were 103 children and adolescents with ASD (90 males and 13 females). In the 12th hour after the last risperidone dose, blood samples were collected for analysis. Serum prolactin, plasma risperidone and 9‐hydroxyrisperidone levels were measured. Patients' clinical data were collected from medical records – age, weight, height, body mass index, dose of risperidone and duration of treatment. Serum prolactin level was significantly positively correlated with plasma 9‐hydroxyrisperidone level (r_s = 0.355, p < 0.001). The median concentration of 9‐hydroxyrisperidone in individuals with hyperprolactinaemia (7.59 ng/ml; IQR 4.86–15.55) was significantly higher than non‐hyperprolactinaemic individuals (5.18 ng/ml; IQR 2.10–8.99) after risperidone treatment (p = 0.006). By multivariate analysis, high prolactin level was correlated to high 9‐hydroxyrisperidone level (p = 0.010). The results of this study showed that serum prolactin levels, especially in autistic individuals with hyperprolactinaemia during risperidone treatment, were significantly correlated with the level of 9‐hydroxyrisperidone. These results suggest that hyperprolactinaemia may develop during risperidone treatment.     

Fractional CO2 laser-assisted Botulinum toxin type A delivery for the treatment of primary palmar hyperhidrosis

Lasers in Medical Science - Intradermal injections of botulinum toxin type A (BTX-A) have been used successfully to treat patients with primary palmoplantar hyperhidrosis (PPH). However, problems...     

Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.     

Combined effects of curcumin and vitamin C to protect endothelial dysfunction in the iris tissue of STZ-induced diabetic rats

This study was aimed to evaluate the combined effect of curcumin with vitamin C supplementation on hyperglycemic and dyslipidemia conditions and endothelial cell dysfunction induced in diabetic rats. Wistar Furth rats were used and divided into four groups: control (single injection of 0.9% sterile saline), STZ (streptozotocin, Sigma, 55 mg/kg.BW, i.v.), STZ-vitC (1 g/l ascorbic acid mixed in drinking water), STZ-cur (daily oral treatment of 300 mg/kg.BW curcumin; Cayman Chemical Co., USA), and STZ-cur+vitC (1 g/l ascorbic acid mixed in drinking water and oral treatment of 300 mg/kg.BW curcumin). On 8th week after STZ-injection, the microcirculation in the iris tissue was observed using intravital fluorescence videomicroscopy, and also leukocyte adhesion in the venule was examined for each group. Blood glucose (BG), lipid profiles, glycosylated hemoglobin (HbA1c) were measured in blood samples collected at the end of each experiment. The contents of liver malondialdehyde (MDA) were also quantified for each group. Feeding curcumin (STZ-cur) could decrease BG, HbA1c, dyslipidemia, and MDA significantly, compared to STZ. In cases of feedings curcumin with vitamin C, these results were more effective in all aspects, including leukocyte adhesion. In conclusion, curcumin might increase the effect of vitamin C in protecting the function of endothelial cells through its anti-oxidant with hypoglycemic and hypolipidemic actions.     

Pharmacogenomics and Efficacy of Risperidone Long‐Term Treatment in Thai Autistic Children and Adolescents

The purpose of this study was to evaluate the association of pharmacogenomic factors and clinical outcome in autistic children and adolescents who were treated with risperidone for long periods. Eighty‐two autistic subjects diagnosed with DSM‐IV and who were treated with risperidone for more than 1 year were recruited. Pharmacogenomics and clinical outcome (CGI‐I, aggressive, overactivity and repetitive score) were evaluated. Almost all patients showed stable symptoms on aggressive behaviour (89.02%), overactivity (71.95%), repetitive (70.89%) behaviour and all clinical symptoms (81.71%). Only 4.48% of patients showed minimally worse CGI‐I score. Patients in the non‐stable symptom group had DRD2 Taq1A non‐wild‐type (TT and CT) frequencies higher than the clinically stable group (p = 0.04), whereas other gene polymorphisms showed no significant association. Haplotype ACCTCAT (rs6311, rs1045642, rs1128503, rs1800497, rs4436578, rs1799978, rs6280) showed a significant association with non‐stable clinical outcome (χ² = 6.642, p = 0.010). Risperidone levels showed no association with any clinical outcome. On the other hand, risperidone dose, 9‐OH risperidone levels and prolactin levels were significantly higher in the non‐stable compared to the stable symptom group (p = 0.013, p = 0.044, p = 0.030). Increased appetite was the most common adverse drug reaction and associated with higher body‐weight, whereas it was not significantly associated with genetic variations and non‐genetic information. In conclusion, risperidone showed efficacy to control autism, especially aggressive symptoms in long‐term treatment. However, Taq1A T – carrier of dopamine 2 receptor gene – is associated with non‐stable response in risperidone‐treated patients. This study supports pharmacogenomics testing for personalized therapy with risperidone in autistic children and adolescents.