A systematic review and meta-analysis of the impacts of germline pharmacogenomics on severe toxicity and symptom burden in adult patients with cancer.

The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.

Pharmacogenomic analysis in adrenocortical carcinoma reveals genetic features associated with mitotane sensitivity and potential therapeutics.

Background: Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies. Objective: We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC. Methods: In vitro mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing. Results: PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs. Conclusion: ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.

Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.

INTRODUCTION: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse. METHODS AND ANALYSIS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out. ETHICS AND DISSEMINATION: The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission. TRIAL REGISTRATION NUMBER: NCT05667766.

Pharmacogenomics, Race, and Treatment Outcome in Pediatric Acute Myeloid Leukemia.

Importance: Disparities in outcomes exist between Black and White patients with acute myeloid leukemia (AML), with Black patients experiencing poorer prognosis compared with their White counterparts. Objective: To assess whether varying intensity of induction therapy to treat pediatric AML is associated with reduced disparities in treatment outcome by race. Design, Setting, and Participants: A comparative effectiveness analysis was conducted of 86 Black and 359 White patients with newly diagnosed AML who were enrolled in the AML02 trial from 2002 to 2008 or the AML08 trial from 2008 to 2017. Statistical analysis was conducted from July 2023 through January 2024. Interventions: Patients in AML02 were randomly assigned to receive standard low-dose cytarabine-based induction therapy or augmented high-dose cytarabine-based induction therapy, whereas patients in AML08 received high-dose cytarabine-based therapy. Main Outcomes and Measures: Cytarabine pharmacogenomic 10-single-nucleotide variant (ACS10) scores were evaluated for association with outcome according to race and treatment arm. Results: This analysis included 86 Black patients (mean [SD] age, 8.8 [6.5] years; 54 boys [62.8%]; mean [SD] leukocyte count, 52 600 [74 000] cells/µL) and 359 White patients (mean [SD] age, 9.1 [6.2] years; 189 boys [52.6%]; mean [SD] leukocyte count, 54 500 [91 800] cells/µL); 70 individuals with other or unknown racial and ethnic backgrounds were not included. Among all patients without core binding factor AML who received standard induction therapy, Black patients had significantly worse outcomes compared with White patients (5-year event-free survival rate, 25% [95% CI, 9%-67%] compared with 56% [95% CI, 46%-70%]; P = .03). By contrast, among all patients who received augmented induction therapy, there were no differences in outcome according to race (5-year event-free survival rate, Black patients, 50% [95% CI, 38%-67%]; White patients, 48% [95% CI, 42%-55%]; P = .78). Among patients who received standard induction therapy, those with low ACS10 scores had a significantly worse 5-year event-free survival rate compared with those with high scores (42.4% [95% CI, 25.6%-59.3%] and 70.0% [95% CI, 56.6%-83.1%]; P = .004); however, among patients who received augmented induction therapy, there were no differences in 5-year event-free survival rates according to ACS10 score (low score, 60.6% [95% CI, 50.9%-70.2%] and high score, 54.8% [95% CI, 47.1%-62.5%]; P = .43). Conclusions and Relevance: In this comparative effectiveness study of pediatric patients with AML treated in 2 consecutive clinical trials, Black patients had worse outcomes compared with White patients after treatment with standard induction therapy, but this disparity was eliminated by treatment with augmented induction therapy. When accounting for ACS10 scores, no outcome disparities were seen between Black and White patients. Our results suggest that using pharmacogenomics parameters to tailor induction regimens for both Black and White patients may narrow the racial disparity gap in patients with AML.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients.

BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer.

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and ß-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.

Pharmacogenomic study-A pilot study of the effect of pharmacogenomic phenotypes on the adequate dosing of verapamil for migraine prevention.

OBJECTIVE: To investigate factors affecting the efficacy and tolerability of verapamil for migraine prevention using individual pharmacogenomic phenotypes. BACKGROUND: Verapamil has a wide range of dosing in headache disorders without reliable tools to predict the optimal doses for an individual. METHODS: This is a retrospective chart review examining adults with existing pharmacogenomic reports at Mayo Clinic who had used verapamil for migraine. Effects of six cytochrome P450 phenotypes on the doses of verapamil for migraine prevention were assessed. RESULTS: Our final analysis included 33 migraine patients (82% with aura). The mean minimum effective and maximum tolerable doses of verapamil were 178.2(20-320) mg and 227.9(20-480) mg. A variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes were found, without significant association with the verapamil doses after adjusting for age, sex, body mass index, and smoking status. CONCLUSIONS: We demonstrated a wide range of effective and tolerable verapamil doses used for migraine in a cohort with various pharmacogenomic phenotypes.

Review of Personalized Medicine and Pharmacogenomics of Anti-Cancer Compounds and Natural Products.

In recent years, the FDA has approved numerous anti-cancer drugs that are mutation-based for clinical use. These drugs have improved the precision of treatment and reduced adverse effects and side effects. Personalized therapy is a prominent and hot topic of current medicine and also represents the future direction of development. With the continuous advancements in gene sequencing and high-throughput screening, research and development strategies for personalized clinical drugs have developed rapidly. This review elaborates the recent personalized treatment strategies, which include artificial intelligence, multi-omics analysis, chemical proteomics, and computation-aided drug design. These technologies rely on the molecular classification of diseases, the global signaling network within organisms, and new models for all targets, which significantly support the development of personalized medicine. Meanwhile, we summarize chemical drugs, such as lorlatinib, osimertinib, and other natural products, that deliver personalized therapeutic effects based on genetic mutations. This review also highlights potential challenges in interpreting genetic mutations and combining drugs, while providing new ideas for the development of personalized medicine and pharmacogenomics in cancer study.

Clinical prediction of opioid use disorder in chronic pain patients: a cohort-retrospective study with a pharmacogenetic approach.

BACKGROUND: Opioids are widely used in chronic non-cancer pain (CNCP) management. However, they remain controversial due to serious risk of causing opioid use disorder (OUD). Our main aim was to develop a predictive model for future clinical translation that include pharmacogenetic markers. METHODS: An observational study was conducted in 806 pre-screened Spanish CNCP patients, under long-term use of opioids, to compare cases (with OUD, N.=137) with controls (without OUD, N.=669). Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were analyzed. Socio-demographic, clinical and pharmacological outcomes were also registered. A logistic regression model was performed. The model performance and diagnostic accuracy were calculated. RESULTS: OPRM1-AA genotype and CYP2D6 poor and ultrarapid metabolizers together with three other potential predictors: 1) age; 2) work disability; 3) oral morphine equivalent daily dose (MEDD), were selected with a satisfactory diagnostic accuracy (sensitivity: 0.82 and specificity: 0.85), goodness of fit (P=0.87) and discrimination (0.89). Cases were ten-year younger with lower incomes, more sleep disturbances, benzodiazepines use, and history of substance use disorder in front of controls. CONCLUSIONS: Functional polymorphisms related to OPRM1 variant and CYP2D6 phenotypes may predict a higher OUD risk. Established risk factors such as young age, elevated MEDD and lower incomes were identified. A predictive model is expected to be implemented in clinical setting among CNCP patients under long-term opioids use.

Opioid use disorder in pediatric populations: considerations for perioperative pain management and precision opioid analgesia.

INTRODUCTION: Opioids are commonly used for perioperative analgesia, yet children still suffer high rates of severe post-surgical pain and opioid-related adverse effects. Persistent and severe acute surgical pain greatly increases the child's chances of chronic surgical pain, long-term opioid use, and opioid use disorder. AREAS COVERED: Enhanced recovery after surgery (ERAS) protocols are often inadequate in treating a child's severe surgical pain. Research suggests that 'older' and longer-acting opioids such as methadone are providing better methods to treat acute post-surgical pain. Studies indicate that lower repetitive methadone doses can decrease the incidence of chronic persistent surgical pain (CPSP). Ongoing research explores genetic components influencing severe surgical pain, inadequate opioid analgesia, and opioid use disorder. This new genetic research coupled with better utilization of opioids in the perioperative setting provides hope in personalizing surgical pain management, reducing pain, opioid use, adverse effects, and helping the fight against the opioid pandemic. EXPERT OPINION: The opioid and analgesic pharmacogenomics approach can proactively 'tailor' a perioperative analgesic plan to each patient based on underlying polygenic risks. This transition from population-based knowledge of pain medicine to individual patient knowledge can transform acute pain medicine and greatly reduce the opioid epidemic's socioeconomic, personal, and psychological strains globally.

Polypharmacy as Formal Training and a Model of Practice.

Traditional definitions of polypharmacy may largely not account for the market proliferation of herbal and dietary supplements, cannabis products, or incorporate the new science of pharmacogenomics (PGx). Polypharmacy is encountered by most pharmacists providing patient care in many settings. The "polypharmacist" can assist patients and providers with solving medication-related problems (MRPs) in this new and challenging environment of supplements and cannabis products by utilizing traditional pharmacology and pharmacokinetic principles, including PGx, broadly across many medical disciplines. One may encounter polypharmacy more in the geriatric population, though in an age of supplements and cannabis proliferation, polypharmacy is increasingly being encountered at younger ages. Not only is polypharmacy training at best fragmented in pharmacy curricula, but it may also not account for the above-mentioned products that may use the same metabolic pathways to increase drug interactions and adverse drug reactions (ADRs) regarding prescription medications. Polypharmacy being more formally prioritized in pharmacist training may better prepare pharmacists for commonly encountered polypharmacy and can be a viable model of practice.

Implementing Whole Genome Sequencing (WGS) in Clinical Practice: Advantages, Challenges, and Future Perspectives.

The integration of whole genome sequencing (WGS) into all aspects of modern medicine represents the next step in the evolution of healthcare. Using this technology, scientists and physicians can observe the entire human genome comprehensively, generating a plethora of new sequencing data. Modern computational analysis entails advanced algorithms for variant detection, as well as complex models for classification. Data science and machine learning play a crucial role in the processing and interpretation of results, using enormous databases and statistics to discover new and support current genotype-phenotype correlations. In clinical practice, this technology has greatly enabled the development of personalized medicine, approaching each patient individually and in accordance with their genetic and biochemical profile. The most propulsive areas include rare disease genomics, oncogenomics, pharmacogenomics, neonatal screening, and infectious disease genomics. Another crucial application of WGS lies in the field of multi-omics, working towards the complete integration of human biomolecular data. Further technological development of sequencing technologies has led to the birth of third and fourth-generation sequencing, which include long-read sequencing, single-cell genomics, and nanopore sequencing. These technologies, alongside their continued implementation into medical research and practice, show great promise for the future of the field of medicine.

Pharmacogenetics of tamoxifen in breast cancer patients of African descent: Lack of data.

Tamoxifen, a selective estrogen receptor modulator, is used to treat hormone receptor-positive breast cancer. Tamoxifen acts as a prodrug, with its primary therapeutic effect mediated by its principal metabolite, endoxifen. However, tamoxifen has complex pharmacokinetics involving several drug-metabolizing enzymes and transporters influencing its disposition. Genes encoding enzymes involved in tamoxifen disposition exhibit genetic polymorphisms which vary widely across world populations. This review highlights the lack of data on tamoxifen pharmacogenetics among African populations. Gaps in data are described in this study with the purpose that future research can address this dearth of research on the pharmacogenetics of tamoxifen among African breast cancer patients. Initiatives such as the African Pharmacogenomics Network (APN) are crucial in promoting comprehensive pharmacogenetics studies to pinpoint important variants in pharmacogenes that could be used to reduce toxicity and improve efficacy.

Uncoupling of Cytochrome P450 2B6 and stimulation of reactive oxygen species production in pharmacogenomic alleles affected by interethnic variability.

Cytochrome P450 mediated substrate metabolism is generally characterized by the formation of reactive intermediates. In vitro and in vivo reaction uncoupling, results in the accumulation and dissociation of reactive intermediates, leading to increased ROS formation. The susceptibility towards uncoupling and altered metabolic activity is partly modulated by pharmacogenomic alleles resulting in amino acid substitutions. A large variability in the prevalence of these alleles has been demonstrated in CYP2B6, with some being predominantly unique to African populations. The aim of this study is to characterize the uncoupling potential of recombinant CYP2B6*1, CYP2B6*6 and CYP2B6*34 metabolism of specific substrates. Therefore, functional effects of these alterations on enzyme activity were determined by quantification of bupropion, efavirenz and ketamine biotransformation using HPLC-MS/MS. Determination of H2O2 levels was performed by the AmplexRed/horseradish peroxidase assay. Our studies of the amino acid substitutions Q172H, K262R and R487S revealed an exclusive use of the peroxide shunt for the metabolism of bupropion and ketamine by CYP2B6*K262R. Ketamine was also identified as a trigger for the peroxide shunt in CYP2B6*1 and all variants. Concurrently, ketamine acted as an uncoupler for all enzymes. We further showed that the expressed CYP2B6*34 allele results in the highest H2O2 formation. We therefore conclude that the reaction uncoupling and peroxide shunt are directly linked and can be substrate specifically induced with K262R carriers being most likely to use the peroxide shunt and R487S carrier being most prone to reaction uncoupling. This elucidates the functional diversity of pharmacogenomics in drug metabolism and safety.

Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients.

This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer.Patients administered DOX (60 mg/m2) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities.The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12-0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07-0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs.Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.

Large-scale next generation sequencing based analysis of SLCO1B1 pharmacogenetics variants in the Saudi population.

BACKGROUND: SLCO1B1 plays an important role in mediating hepatic clearance of many different drugs including statins, angiotensin-converting enzyme inhibitors, chemotherapeutic agents and antibiotics. Several variants in SLCO1B1 have been shown to have a clinically significant impact, in relation to efficacy of these medications. This study provides a comprehensive overview of SLCO1B1 variation in Saudi individuals, one of the largest Arab populations in the Middle East. METHODS: The dataset of 11,889 (9,961 exomes and 1,928 pharmacogenetic gene panel) Saudi nationals, was used to determine the presence and frequencies of SLCO1B1 variants, as described by the Clinical Pharmacogenetic Implementation Consortium (CPIC). RESULTS: We identified 141 previously described SNPs, of which rs2306283 (50%) and rs4149056 (28%), were the most common. In addition, we observed six alleles [*15 (24.7%) followed by *20 (8.04%), *14 (5.86%), *5 (3.84%), *31 (0.21%) and *9 (0.03%)] predicted to be clinically actionable. Allele diplotype to phenotype conversion revealed 41 OATP1B1 diplotypes. We estimated the burden of rare, and novel predicted deleterious variants, resulting from 17 such alterations. CONCLUSIONS: The data we present, from one of the largest Arab cohorts studied to date, provides the most comprehensive overview of SLCO1B1 variants, and the subsequent OATP1B1 activity of this ethnic group, which thus far remains relatively underrepresented in available international genomic databases. We believe that the presented data provides a basis for further clinical investigations and the application of personalized statin drug therapy guidance in Arabs.

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion.

Bupropion is used for treating depression, obesity, and seasonal affective disorder, and for smoking cessation. Bupropion is commonly prescribed, but has complex pharmacokinetics and interindividual variability in metabolism and bioactivation may influence therapeutic response, tolerability, and safety. Bupropion is extensively and stereoselectively metabolized, the metabolites are pharmacologically active, and allelic variation in cytochrome P450 (CYP) 2B6 affects clinical hydroxylation of single-dose bupropion. Genetic effects on stereoselective disposition of steady-state bupropion are not known. In this preplanned secondary analysis of a prospective, randomized, double-blinded, crossover study which compared brand and generic bupropion XL 300 mg drug products, we measured steady-state enantiomeric plasma and urine parent bupropion and primary and secondary metabolite concentrations. This investigation evaluated the influence of genetic polymorphisms in CYP2B6, CYP2C19, and P450 oxidoreductase on the disposition of Valeant Pharmaceuticals Wellbutrin brand bupropion in 67 participants with major depressive disorder. We found that hydroxylation of both bupropion enantiomers was lower in carriers of the CYP2B6*6 allele and in carriers of the CYP2B6 516G>T variant, with correspondingly greater bupropion and lesser hydroxybupropion plasma concentrations. Hydroxylation was 25-50% lower in CYP2B6*6 carriers and one-third to one-half less in 516T carriers. Hydroxylation of the bupropion enantiomers was comparably affected by CYP2B6 variants. CYP2C19 polymorphisms did not influence bupropion plasma concentrations or hydroxybupropion formation but did influence the minor pathway of 4'-hydroxylation of bupropion and primary metabolites. P450 oxidoreductase variants did not influence bupropion disposition. Results show that CYP2B6 genetic variants affect steady-state metabolism and bioactivation of Valeant brand bupropion, which may influence therapeutic outcomes. SIGNIFICANCE STATEMENT: Bupropion, used for depression, obesity, and smoking cessation, undergoes metabolic bioactivation, with incompletely elucidated interindividual variability. We evaluated cytochrome P450 (CYP) 2B6, CYP2C19 and P450 oxidoreductase genetic variants and steady-state bupropion and metabolite enantiomers disposition. Both enantiomers hydroxylation was lower in CYP2B6*6 and CYP2B6 516G>T carriers, with greater bupropion and lesser hydroxybupropion plasma concentrations. CYP2C19 polymorphisms did not affect bupropion or hydroxybupropion but did influence minor 4'-hydroxylation of bupropion and primary metabolites. CYP2B6 variants affect steady-state bupropion bioactivation, which may influence therapeutic outcomes.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.