Bruce Carleton

Pharmacogenetics of Neonatal Opioid Toxicity Following Maternal Use of Codeine During Breastfeeding: A Case–Control Study

A large number of women receive codeine for obstetric pain while breastfeeding. Following a case of fatal opioid poisoning in a breastfed neonate whose codeine prescribed mother was a CYP2D6 ultrarapid metabolizer (UM), we examined characteristics of mothers and infants with or without signs of central nervous system (CNS) depression following codeine exposure while breastfeeding in a case–control study. Mothers of symptomatic infants (n = 17) consumed a mean 59% higher codeine dose than mothers of asymptomatic infants (n = 55) (1.62 (0.79) mg/kg/day vs. 1.02 (0.54) mg/kg/day; P = 0.004). There was 71% concordance between maternal and neonatal CNS depression. Two mothers whose infants exhibited severe neonatal toxicity were CYP2D6 UMs and of the UGT2B7*2/*2 genotype. There may be a dose–response relationship between maternal codeine use and neonatal toxicity, and strong concordance between maternal‐infant CNS depressive symptoms. Breastfed infants of mothers who are CYP2D6 UMs combined with the UGT2B7*2/*2 are at increased risk of potentially life‐threatening CNS depression.

More Codeine Fatalities After Tonsillectomy in North American Children

In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.

Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy

Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3–125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9–15.9) associated with cisplatin-induced hearing loss in children.

Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children

PURPOSE Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. PATIENTS AND METHODS We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. RESULTS We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. CONCLUSION We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin

Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

Thiazolidinediones and Fractures in Men and Women

BACKGROUND Clinical trials and meta-analyses have found that rosiglitazone maleate, a thiazolidinedione that is prescribed for type 2 diabetes mellitus, increases the risk of fractures in women. The association between the use of thiazolidinediones and fractures in men and women is not adequately understood. METHODS We conducted a prospective cohort study. The primary outcome was peripheral fractures in men and women who were exposed to thiazolidinediones compared with sulfonylureas. We studied 84 339 patients from British Columbia, Canada, who began treatment with a thiazolidinedione or a sulfonylurea. The association between the use of thiazolidinediones and fractures was examined using multivariate-adjusted Cox models. RESULTS The mean age of the patients in the study was 59 years, and 43% were women. In this cohort, treatment with a thiazolidinedione was associated with a 28% increased risk of peripheral fractures compared with treatment with a sulfonylurea (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.10-1.48). The use of pioglitazone hydrochloride was associated with an increased risk of peripheral fracture of 77% in women (HR, 1.76; 95% CI 1.32-2.38). Compared with exposure to sulfonylureas, exposure to pioglitazone was associated with more peripheral fractures in men (HR, 1.61; 95% CI 1.18-2.20), but we did not observe a similar association with exposure to rosiglitazone (HR, 1.00; 95% CI, 0.75-1.34). CONCLUSIONS Both men and women who take thiazolidinediones could be at increased risk of fractures. Pioglitazone may be more strongly associated with fractures than rosiglitazone. Larger observational studies are needed, and fracture data from clinical trials need to be fully published so that fracture risks can be known with greater certainty.

Recommendations for HLA‐B*15:02 and HLA‐A*31:01 genetic testing to reduce the risk of carbamazepine‐induced hypersensitivity reactions

To systematically review evidence on genetic risk factors for carbamazepine (CBZ)–induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA‐B*15:02 and HLA‐A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ‐induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA‐B*15:02 or HLA‐A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?

Phenotype standardization for immune-mediated drug-induced skin injury

Advances in genetic research and molecular biology techniques have made it possible to begin to characterize the underlying genetic factors that predispose patients to serious forms of drug‐induced skin injury (DISI). To facilitate research in this area, we have set out standardized phenotypic definitions for (i) Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), (ii) acute generalized exanthematous pustulosis (AGEP), and (iii) hypersensitivity syndrome (HSS; also known as drug reaction with eosinophilia and systemic symptoms (DRESS) and drug‐induced hypersensitivity syndrome (DIHS)). A DISI Expert Working Group comprising participants with varied expertise reviewed and debated current terminology and diagnostic criteria for DISI and agreed on the minimum phenotypic criteria for selected forms of DISI (SJS/TEN, AGEP, and HSS). In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.

Central nervous system depression of neonates breastfed by mothers receiving oxycodone for postpartum analgesia.

OBJECTIVE To quantify the incidence of central nervous system (CNS) depression in neonates breastfed by mothers medicated with oxycodone as compared with neonates whose breastfeeding mothers used codeine or acetaminophen only. STUDY DESIGN We retrospectively compared 3 cohorts in 533 breastfeeding mother-infant pairs exposed to oxycodone (n = 139), codeine (n = 210), or acetaminophen only (n = 184). Standardized questionnaires were administered to mothers during the postpartum period to identify maternal and neonatal health outcomes temporally related to analgesia exposure. RESULTS Maternal exposure to oxycodone during breastfeeding was associated with a 20.1% rate of infant CNS depression (28/139) compared with 0.5% in the acetaminophen group (1/184; P < .0001; OR, 46.16; 95% CI, 6.2-344.2) and 16.7% in the codeine group (35/210; P > .05; OR, 0.79; 95% CI, 0.46-1.38). Mothers of neonates with symptoms in the oxycodone and codeine cohorts took significantly higher doses of medication compared with mothers of infants with no symptoms in the same cohorts (P = .0005 oxycodone; median, 0.4 mg/kg/day; range, 0.03-4.06 mg/kg/day versus median, 0.15 mg/kg/day; range, 0.02-2.25 mg/kg/day; codeine P < .001; median, 1.4 mg/kg/day; range, 0.7-10.5 mg/kg/day versus 0.9 mg/kg/day; range, 0.18-5.8 mg/kg/day). Mothers were significantly more likely to experience sedative adverse effects from oxycodone as compared with codeine (P < .0001; OR, 17.62; 95% CI, 9.95-31.21). CONCLUSION Oxycodone is not a safer alternative to codeine in breastfed infants.

Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ‐cell tumor, and cranial irradiation) significantly improved the prediction of hearing‐loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin‐induced hearing loss in children.