Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.

Purpose Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL. Patients and Methods The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model. Results MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10−9) and rs116855232 in NUDT15 (P = 8.8 × 10−9), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others. Conclusion We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

Although the field of pharmacogenetics has existed for decades, the implementation of, pharmacogenetic testing in clinical care has been slow. There are numerous publications, describing the barriers to clinical implementation of pharmacogenetics. Recently, several freely, available resources have been developed to help address these barriers. In this review we, discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of, patients. Array-based preemptive testing includes a large number of relevant pharmacogenes, that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to, be available prior to any prescribing decision so that genomic variation may be considered as, an inherent patient characteristic in the planning of therapy. This review describes the common, elements among programs that have implemented preemptive genotyping and highlights key, processes for implementation, including clinical decision support.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.

Importance With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is compelling need to mitigate treatment toxicities that can compromise quality of life. Peripheral neuropathy is the major dose-limiting toxicity of the microtubule inhibitor vincristine, an anticancer agent given to every child with ALL. Objective Identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. Design, Setting and Participants All patients had been enrolled in one of two prospective clinical trials for childhood ALL that included treatment with 36–39 doses of vincristine. Genome-wide single nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in all patients from whom DNA was available (n=321 patients); 222 patients (median age at 6.0 years, range 0.1–18.8 years) enrolled between 1994–1998 on the St. Jude Children’s Research Hospital protocol Total XIIIB (St. Jude cohort) with toxicity followed through January 2001, and 99 patients (median age 11.4 years, range 3.0–23.8 years) enrolled between 2007–2010 on the Children’s Oncology Group protocol AALL0433 (COG cohort) with toxicity followed through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. Exposures Treatment with vincristine at a dosage of 1.5 or 2.0 mg/m2 as a component of protocol directed chemotherapy for childhood ALL. Main Outcomes and Measures Vincristine-induced peripheral neuropathy was assessed at each clinic visit using the National Cancer Institute Common Terminology Criteria for Adverse Events and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life-threatening (grade 4). Results Grade 2–4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (n=64 of 222) in the St. Jude cohort and in 22.2% of patients (n=22 of 99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta p =6.3 × 10−9). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%, 95% CI 11.6%–19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 patients (56%, 95% CI 41.2–70.0) developed at least one episode of grade 2–4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotype (58 of 271 patients; 21.4%, 95% CI 16.9–26.7); p=2.4×10−6. The severity (grade) of neuropathy was greater (2.4-fold by Poisson regression (p<0.0001), 2.7-fold based on mean grade of neuropathy (1.23 [95% CI 0.74 – 1.72] versus 0.45 [95% CI 0.3 – 0.6]; t test p=0.004)) in patients homozygous for the CEP72 risk allele (TT genotype), compared to patients with the CC or CT genotype. The CEP72 promoter SNP was show...

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.

• Adherence rates were significantly lower in African Americans (87%) and Asian Americans (90%), as compared with non-Hispanic whites (95%).• Adherence to 6MP at ,90%was associated with a 3.9-fold increased risk of relapse in a multiracial cohort of children with ALL.Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP . Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P 5 .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials. gov as #NCT00268528. (Blood. 2014;124(15):2345-2353

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol‐O‐methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.