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Browsing by Author "Callaghan, John T."
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Item Association of QT interval-prolonging drugs with clinical trial eligibility in patients with advanced cancer(Frontiers Media, 2022-12-15) Rowe, Elizabeth J.; Shugg, Tyler; Ly, Reynold C.; Philips, Santosh; Rosenman, Marc B.; Callaghan, John T.; Radovich, Milan; Overholser, Brian R.; Schneider, Bryan P.; Tisdale, James E.; Skaar, Todd C.; Medicine, School of MedicineIntroduction: Drug-induced prolongation of the heart rate-corrected QT interval (QTc) is associated with increased risk for the potentially fatal arrhythmia torsades de pointes. Due to arrhythmia risk, clinical trials with cancer therapeutics often exclude patients based on thresholds for QTc prolongation. Our objective was to assess associations between prescriptions for QT-prolonging drugs and the odds of meeting cancer trial exclusionary QTc thresholds in a cohort of adults with advanced cancer. Methods: Electronic health records were retrospectively reviewed for 271 patients seen at our institutional molecular solid tumor clinic. Collected data included demographics, QTc measurements, ventricular arrhythmia-related diagnoses, and all inpatient and outpatient prescriptions. Potential associations were assessed between demographic and clinical variables, including prescriptions for QT-prolonging drugs, and QTc measurements. Results: Women had longer median QTc measurements than men (p = 0.030) and were prescribed more QT-prolonging drugs during the study (p = 0.010). In all patients, prescriptions for QT-prolonging drugs were associated with longer median and maximum QTc measurements at multiple assessed time points (i.e., for QT-prolonging drugs prescribed within 10, 30, 60, and 90 days of QTc measurements). Similarly, the number of QT-prolonging drugs prescribed was correlated with longer median and maximum QTc measurements at multiple time points. Common QTc-related exclusionary criteria were collected from a review of ClinicalTrials.gov for recent cancer clinical trials. Based on common exclusion criteria, prescriptions for QT-prolonging drugs increased the odds of trial exclusion. Conclusion: This study demonstrates that prescriptions for QT-prolonging drugs were associated with longer QTc measurements and increased odds of being excluded from cancer clinical trials.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers(American Society of Clinical Oncology, 2022) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.; Medicine, School of MedicinePurpose: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. Methods: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. Results: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. Conclusion: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers(ASCO, 2022) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.; Medicine, School of MedicinePURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.(American Society of Clinical Oncology, 2022-02) Shugg, Tyler; Ly, Reynold C.; Rowe, Elizabeth J.; Philips, Santosh; Hyder, Mustafa A.; Radovich, Milan; Rosenman, Marc B.; Pratt, Victoria M.; Callaghan, John T.; Desta, Zeruesenay; Schneider, Bryan P.; Skaar, Todd C.PURPOSE: Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. METHODS: Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. RESULTS: Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. CONCLUSION: Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update(Wiley, 2021) Karnes, Jason H.; Rettie, Allan E.; Somogyi, Andrew A.; Huddart, Rachel; Fohner, Alison E.; Formea, Christine M.; Lee, Ming Ta Michael; Llerena, Adrian; Whirl-Carrillo, Michelle; Klein, Teri E.; Phillips, Elizabeth J.; Mintzer, Scott; Gaedigk, Andrea; Caudle, Kelly E.; Callaghan, John T.; Medicine, School of MedicinePhenytoin is an antiepileptic drug with a narrow therapeutic index and large interpatient pharmacokinetic variability, partly due to genetic variation in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotypes (updates on cpicpgx.org).Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update(Wiley, 2016-01) Saito, Yoshiro; Stamp, Lisa K.; Caudle, Kelly E.; Hershfield, Michael; McDonagh, Ellen M.; Callaghan, John T.; Tassaneeyakul, Wichittra; Mushiroda, Taisei; Kamatani, Naoyuki; Goldspiel, Barry R.; Phillips, Elizabeth J.; Klein, Teri E.; Lee, Ming Ta Michael; Department of Pharmacology and Toxicology, IU School of MedicineThe Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up-to-date information can be found at PharmGKB (http://www.pharmgkb.org).Item Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy(Wiley, 2021) Crews, Kristine R.; Monte, Andrew A.; Huddart, Rachel; Caudle, Kelly E.; Kharasch, Evan D.; Gaedigk, Andrea; Dunnenberger, Henry M.; Leeder, J. Steven; Callaghan, John T.; Samer, Caroline Flora; Klein, Teri E.; Haidar, Cyrine E.; Van Driest, Sara L.; Ruano, Gualberto; Sangkuhl, Katrin; Cavallari, Larisa H.; Müller, Daniel J.; Prows, Cynthia A.; Nagy, Mohamed; Somogyi, Andrew A.; Skaar, Todd C.; Medicine, School of MedicineOpioids 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 which 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.Item Drug–gene and drug–drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial(Future Medicine, 2019-04) Fulton, Cathy R.; Zang, Yong; Desta, Zeruesenay; Rosenman, Marc B.; Holmes, Ann M.; Decker, Brian S.; Zhang, Yifei; Callaghan, John T.; Pratt, Victoria M.; Levy, Kenneth D.; Gufford, Brandon T.; Dexter, Paul R.; Skaar, Todd C.; Eadon, Michael T.; Medicine, School of MedicineBackground: Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. Methods: This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). Results: Within 60 days of receiving tramadol or codeine, clinicians more frequently prescribed an alternative opioid in ultrarapid and poor metabolizers (odds ratio: 19.0; 95% CI: 2.8-160.4) as compared with normal or indeterminate metabolizers (p = 0.01). After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Conclusion: Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.Item Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers(American Society for Microbiology, 2016-11) Desta, Zeruesenay; Metzger, Ingrid F.; Thong, Nancy; Lu, Jessica B. L.; Callaghan, John T.; Skaar, Todd C.; Flockhart, David A.; Galinsky, Raymond E.; Medicine, School of MedicineCytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t1/2) and increased both the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve from 0 h to t (AUC0-t) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P < 0.0001) with marked intersubject variability (e.g., the percent change in efavirenz AUC0-t ranged from 0.4% to ∼224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P < 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC0-t (Pearson r = >0.8; P < 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selective in vivo probe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability. (This study is registered at ClinicalTrials.gov under identifier NCT01104376.).Item Substantial effect of efavirenz monotherapy on bilirubin levels in healthy volunteers(Elsevier, 2014-09-27) Metzger, Ingrid F.; Quigg, Troy C.; Epstein, Noam; Aregbe, Abdulateef O.; Thong, Nancy; Callaghan, John T.; Flockhart, David A.; Nguyen, Anne T.; Stevens, Colleen K.; Gupta, Samir K.; Desta, Zeruesenay; Department of Medicine, School of MedicineBACKGROUND: Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. OBJECTIVES: To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. METHODS: Men and women (aged 18-49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. RESULTS: Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its effects on hemoglobin. CONCLUSIONS: Efavirenz monotherapy significantly lowers plasma total bilirubin concentration in healthy volunteers independent of its effect on hemoglobin, probably through its effects on bilirubin metabolism and transport (uptake and efflux). These findings help explain reversal by efavirenz of hyperbilirubinemia induction observed by some protease inhibitor antiretroviral drugs (eg, atazanavir). Besides its well-documented role on drug interactions, efavirenz may alter the disposition of endogenous compounds relevant in physiologic homeostasis through its interaction with drug metabolizing enzymes and/or drug transporters. ClinicalTrials.gov identifier: NCT00668395.