Publications by authors named "Kristine R Crews"

67 Publications

Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies.

Cancer 2021 Feb 17. Epub 2021 Feb 17.

Children's Hospital Los Angeles, Los Angeles, California.

Background: A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies.

Methods: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m /d) in combination with clofarabine (40 mg/m ), etoposide (100 mg/m ), and dexamethasone (8 mg/m ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5.

Results: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m /d, 6 were treated at the dose level of 40 mg/m /d, and 4 were treated at the dose level of 60 mg/m /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years.

Conclusions: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509).

Lay Summary: Improvements to the existing chemotherapy regimen are still needed for patients who relapse after targeted therapies and immunotherapies and for those who are not eligible for or have no access to such therapies. A regimen combining cyclophosphamide, clofarabine, and etoposide has been used in relapsed and refractory pediatric patients with hematologic malignancies. This study shows that substituting bendamustine for cyclophosphamide in combination with clofarabine and etoposide is safe and effective.
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http://dx.doi.org/10.1002/cncr.33465DOI Listing
February 2021

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy.

Clin Pharmacol Ther 2021 Jan 2. Epub 2021 Jan 2.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

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.
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http://dx.doi.org/10.1002/cpt.2149DOI Listing
January 2021

Pharmacogenomics of intracellular methotrexate polyglutamates in patients' leukemia cells in vivo.

J Clin Invest 2020 12;130(12):6600-6615

Hematological Malignancies Program, and.

BACKGROUNDInterpatient differences in the accumulation of methotrexate's active polyglutamylated metabolites (MTXPGs) in leukemia cells influence its antileukemic effects.METHODSTo identify genomic and epigenomic and patient variables determining the intracellular accumulation of MTXPGs, we measured intracellular MTXPG levels in acute lymphoblastic leukemia (ALL) cells from 388 newly diagnosed patients after in vivo high-dose methotrexate (HDMTX) (1 g/m2) treatment, defined ALL subtypes, and assessed genomic and epigenomic variants influencing folate pathway genes (mRNA, miRNA, copy number alterations [CNAs], SNPs, single nucleotide variants [SNVs], CpG methylation).RESULTSWe documented greater than 100-fold differences in MTXPG levels, which influenced its antileukemic effects (P = 4 × 10-5). Three ALL subtypes had lower MTXPG levels (T cell ALL [T-ALL] and B cell ALL [B-ALL] with the TCF3-PBX1 or ETV6-RUNX1 fusions), and 2 subtypes had higher MTXPG levels (hyperdiploid and BCR-ABL like). The folate pathway genes SLC19A1, ABCC1, ABCC4, FPGS, and MTHFD1 significantly influenced intracellular MTXPG levels (P = 2.9 × 10-3 to 3.7 × 10-8). A multivariable model including the ALL subtype (P = 1.1 × 10-14), the SLC19A1/(ABCC1 + ABCC4) transporter ratio (P = 3.6 × 10-4), the MTX infusion time (P = 1.5 × 10-3), FPGS mRNA expression (P = 2.1 × 10-3), and MTX systemic clearance (P = 4.4 × 10-2) explained 42% of the variation in MTXPG accumulation (P = 1.1 × 10-38). Model simulations indicated that a longer infusion time (24 h vs. 4 h) was superior in achieving higher intracellular MTXPG levels across all subtypes if ALL.CONCLUSIONSThese findings provide insights into mechanisms underlying interpatient differences in intracellular accumulation of MTXPG in leukemia cells and its antileukemic effectsFUNDINGTHE National Cancer Institute (NCI) and the Institute of General Medical Sciences of the NIH, the Basque Government Programa Posdoctoral de Perfeccionamiento de Personal Investigador doctor, and the American Lebanese Syrian Associated Charities (ALSAC).
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http://dx.doi.org/10.1172/JCI140797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685728PMC
December 2020

Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia.

Clin Pharmacol Ther 2020 Oct 29. Epub 2020 Oct 29.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

6-mercaptopurine (6-MP) is widely used in the treatment of acute lymphoblastic leukemia (ALL), and its cytotoxicity is primarily mediated by thioguanine nucleotide (TGN) metabolites. A recent genomewide association study has identified germline polymorphisms (e.g., rs72846714) in the NT5C2 gene associated with 6-MP metabolism in patients with ALL. However, the full spectrum of genetic variation in NT5C2 is unclear and its impact on 6-MP drug activation has not been comprehensively examined. To this end, we performed targeted sequencing of NT5C2 in 588 children with ALL and identified 121 single nucleotide polymorphisms nominally associated with erythrocyte TGN during 6-MP treatment (P < 0.05). Of these, 61 variants were validated in a replication cohort of 372 children with ALL. After considering linkage disequilibrium and multivariate analysis, we confirmed two clusters of variants, represented by rs72846714 and rs58700372, that independently affected 6-MP metabolism. Functional studies showed that rs58700372 directly altered the activity of an intronic enhancer, with the variant allele linked to higher transcription activity and reduced 6-MP metabolism (lower TGN). By contrast, rs72846714 was not located in a regulatory element and instead its association signal was explained by linkage disequilibrium with a proximal functional variant rs12256506 that activated NT5C2 transcription in-cis. Our results indicated that NT5C2 germline variation significantly contributes to interpatient variability in thiopurine drug disposition.
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http://dx.doi.org/10.1002/cpt.2095DOI Listing
October 2020

Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia.

Nat Cancer 2020 Mar 9;1(3):329-344. Epub 2020 Mar 9.

Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of mRNA and miRNA expression, DNA methylation, SNPs, CNAs and SNVs/Indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid-resistance. Single cell RNAseq and network-based transcriptomic modelling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells.
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http://dx.doi.org/10.1038/s43018-020-0037-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467080PMC
March 2020

Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia.

Cancer 2020 Nov 18;126(21):4800-4805. Epub 2020 Aug 18.

St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).

Methods: To determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m ) before and in combination with fludarabine and cytarabine.

Results: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.

Conclusions: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.
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http://dx.doi.org/10.1002/cncr.33156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722063PMC
November 2020

Fluoroquinolone prophylaxis does not increase risk of neuropathy in children with acute lymphoblastic leukemia.

Cancer Med 2020 09 25;9(18):6550-6555. Epub 2020 Jul 25.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.

Background: Fluoroquinolone antibiotics are frequently utilized in pediatric oncology patients as prophylaxis or step-down therapy following broad spectrum beta-lactam therapy for febrile neutropenia. Concerns regarding neurotoxicity limit the use of these agents. No studies have evaluated the association between fluoroquinolone use and neurotoxicity in pediatric oncology patients receiving other neurotoxic agents such as vincristine.

Methods: An observational cohort study comprising patients aged 0-18 at diagnosis enrolled on a prospective study for treatment of acute lymphoblastic leukemia (ALL) at a pediatric comprehensive cancer center between October 2007 and November 2018. Data for neuropathic pain and sensory or motor neuropathy were collected prospectively, and a Cox proportional hazards regression model was used to evaluate associations between administration of fluoroquinolone antibiotics during induction therapy and subsequent development of vincristine-induced peripheral neurotoxicity (VIPN).

Results: A total of 598 participants were enrolled, including 338 (57%) who received fluoroquinolones during induction therapy; of these 470 (79%) were diagnosed with VIPN and 139 (23%) were diagnosed with high-grade (Grade 3+) VIPN. On unadjusted analyses, and analyses adjusted for age and race, there was no evidence of an association between fluoroquinolone exposure and subsequent VIPN (hazard ratio [HR] 0.8, 95% CI 0.5-1.04, P = .08) or high-grade VIPN (HR 1.1, 95% CI 0.4-2.2, P = .87).

Conclusions: The results of this observational study do not show an association between exposure to fluoroquinolone antibiotics during induction therapy for ALL and subsequent development of vincristine-induced peripheral neuropathies, and suggest that a large increase in VIPN is unlikely.
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http://dx.doi.org/10.1002/cam4.3249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520302PMC
September 2020

and Liver Iron Content in Children with Sickle Cell Anemia and Iron Overload.

J Clin Med 2019 Nov 5;8(11). Epub 2019 Nov 5.

Department of Hematology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Chronic blood transfusions in patients with sickle cell anemia (SCA) cause iron overload, which occurs with a degree of interpatient variability in serum ferritin and liver iron content (LIC). Reasons for this variability are unclear and may be influenced by genes that regulate iron metabolism. We evaluated the association of the copy number of the glutathione S-transferase M1 () gene and degree of iron overload among patients with SCA. We compared LIC in 38 children with SCA and ≥12 lifetime erythrocyte transfusions stratified by genotype. Baseline LIC was measured using magnetic resonance imaging (MRI), R2*MRI within 3 months prior to, and again after, starting iron unloading therapy. After controlling for weight-corrected transfusion burden (mL/kg) and splenectomy, mean pre-chelation LIC (mg/g dry liver dry weight) was similar in all groups: wild-type (WT) (11.45, SD±6.8), heterozygous (8.2, SD±4.52), and homozygous deletion (-null; 7.8, SD±6.9, = 0.09). However, after >12 months of chelation, -null genotype subjects had the least decrease in LIC compared to non-null genotype subjects (mean LIC change for -null = 0.1 (SD±3.3); versus -0.3 (SD±3.0) and -1.9 (SD±4.9) mg/g liver dry weight for heterozygous and WT, respectively, = 0.047). homozygous deletion may prevent effective chelation in children with SCA and iron overload.
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http://dx.doi.org/10.3390/jcm8111878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912836PMC
November 2019

Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 01 14;67(1):e28040. Epub 2019 Oct 14.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Glucocorticoids and asparaginase, used to treat acute lymphoblastic leukemia (ALL), can cause hypertriglyceridemia. We compared triglyceride levels, risk factors, and associated toxicities in two ALL trials at St. Jude Children's Research Hospital with identical glucocorticoid regimens, but different asparaginase formulations. In Total XV (TXV), native Escherichia coli l-asparaginase was front-line therapy versus the pegylated formulation (PEG-asparaginase) in Total XVI (TXVI).

Procedure: Patients enrolled on TXV (n = 498) and TXVI (n = 598) were assigned to low-risk (LR) or standard/high-risk (SHR) treatment arms (ClinicalTrials.gov identifiers: NCT00137111 and NCT00549848). Triglycerides were measured four times and were evaluable in 925 patients (TXV: n = 362; TXVI: n = 563). The genetic contribution was assessed using a triglyceride polygenic risk score (triglyceride-PRS). Osteonecrosis, thrombosis, and pancreatitis were prospectively graded.

Results: The largest increase in triglycerides occurred in TXVI SHR patients treated with dexamethasone and PEG-asparaginase (4.5-fold increase; P <1 × 10 ). SHR patients treated with PEG-asparaginase (TXVI) had more severe hypertriglyceridemia (>1000 mg/dL) compared to native l-asparaginase (TXV): 10.5% versus 5.5%, respectively (P = .007). At week 7, triglycerides did not increase with dexamethasone treatment alone (LR patients) but did increase with dexamethasone plus asparaginase (SHR patients). The variability in triglycerides explained by the triglyceride-PRS was highest at baseline and declined with therapy. Hypertriglyceridemia was associated with osteonecrosis (P = .0006) and thrombosis (P = .005), but not pancreatitis (P = .4).

Conclusion: Triglycerides were affected more by PEG-asparaginase than native l-asparaginase, by asparaginase more than dexamethasone, and by drug effects more than genetics. It is not clear whether triglycerides contribute to thrombosis and osteonecrosis or are biomarkers of the toxicities.
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http://dx.doi.org/10.1002/pbc.28040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868303PMC
January 2020

Challenges in clinical implementation of CYP2D6 genotyping: choice of variants to test affects phenotype determination.

Genet Med 2020 01 25;22(1):232-233. Epub 2019 Jul 25.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

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http://dx.doi.org/10.1038/s41436-019-0614-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702299PMC
January 2020

Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge.

J Clin Oncol 2019 08 12;37(23):2051-2061. Epub 2019 Jun 12.

1St Jude Children's Research Hospital, Memphis, TN.

Purpose: Pegaspargase (PEG-ASP) has largely replaced native asparaginase (L-ASP) in the treatment of acute lymphoblastic leukemia because of its longer half-life and lower immunogenicity. Risk factors for allergic reactions to PEG-ASP remain unclear. Here, we identify risk factors for reactions in a front-line acute lymphoblastic leukemia trial and assess the usefulness of serum antibodies for diagnosing allergy and predicting rechallenge outcome.

Patients And Methods: PEG-ASP was administered to 598 patients in St Jude's Total XVI study. Results were compared with Total XV study (ClinicalTrials.gov identifiers: NCT00549848 and NCT00137111), which used native L-ASP. Serum samples (n = 5,369) were analyzed for anti-PEG-ASP immunoglobulin G by enzyme-linked immunosorbent assay. Positive samples were tested for anti-polyethylene glycol (PEG) and anti-L-ASP. We analyzed potential risk factors for reactions and associations between antibodies and reactions, rechallenge outcomes, and PEG-ASP pharmacokinetics.

Results: Grade 2 to 4 reactions were less common in the Total XVI study with PEG-ASP (81 [13.5%] of 598) than in the Total XV study with L-ASP (169 [41.2%] of 410; = 1.4 × 10). For Total XVI, anti-PEG, not anti-L-ASP, was the predominant component of anti-PEG-ASP antibodies (96%). In a multivariable analysis, more intrathecal therapy (IT) predicted fewer reactions ( = 2.4 × 10), which is consistent with an immunosuppressant contribution of IT. Anti-PEG-ASP was associated with accelerated drug clearance ( = 5.0 × 10). Failure of rechallenge after initial reactions was associated with anti-PEG-ASP ( = .0078) and was predicted by the occurrence of angioedema with first reaction ( = .01).

Conclusion: Less IT therapy was the only independent clinical risk factor for reactions to PEG-ASP. PEG, and not L-ASP, is the major antigen that causes allergic reactions. Anti-PEG-ASP has utility in predicting and confirming clinical reactions to PEG-ASP as well as in identifying patients who are most likely to experience failure with rechallenge.
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http://dx.doi.org/10.1200/JCO.18.02439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804844PMC
August 2019

The Case for Pharmacogenetics-Guided Prescribing of Codeine in Children.

Clin Pharmacol Ther 2019 06 22;105(6):1300-1302. Epub 2018 Nov 22.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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http://dx.doi.org/10.1002/cpt.1260DOI Listing
June 2019

Genome-wide association analysis identifies SNPs predictive of leukemic cell sensitivity to cytarabine in pediatric AML.

Oncotarget 2018 Oct 9;9(79):34859-34875. Epub 2018 Oct 9.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Cytarabine has been an integral part of acute myeloid leukemia (AML) chemotherapy for over four decades. However, development of resistance and high rates of relapse is a significant impediment in successfully treating AML. We performed a genome-wide association analysis (GWAS) and identified 113 (83 after adjusting for Linkage Disequilibrium) SNPs associated with cytarabine chemosensitivity of diagnostic leukemic cells from a cohort of 50 pediatric AML patients (p<10). Further evaluation of diagnostic leukemic cell gene-expression identified 19 SNP-gene pairs with a concordant triad of associations: i)SNP genotype with cytarabine sensitivity (p<0.0001), ii) gene-expression with cytarabine sensitivity (p<0.05), and iii) genotype with gene-expression (p<0.1). Two genes from SNP-gene pairs, rs1376041- and rs75400242-, were functionally validated by siRNA knockdown in AML cell lines. Consistent with association of rs1376041 and gene-expression in AML patients siRNA mediated knock-down of GPR56 increased cytarabine sensitivity of AML cell lines. Similarly for , knockdown increased the cytarabine sensitivity of AML cell lines consistent with results in AML patients. Given both and are promising drug-targets in AML, our results on SNPs driving the expression/function of these genes will not only enhance our understanding of cytarabine resistance but also hold promise in personalizing AML for targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.26163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201857PMC
October 2018

Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients.

Pharmacogenomics 2018 09 8;19(14):1101-1110. Epub 2018 Aug 8.

Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.

Aim: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP.

Method: We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68).

Results: Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: high-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs.

Conclusion: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.
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http://dx.doi.org/10.2217/pgs-2018-0086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219441PMC
September 2018

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.

Antimicrob Agents Chemother 2018 08 27;62(8). Epub 2018 Jul 27.

Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven pneumonia, and 4 cases (0.5%) of possible pneumonia. The incidence of possible breakthrough pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1128/AAC.00173-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105857PMC
August 2018

Development of a postgraduate year 2 pharmacy residency in clinical pharmacogenetics.

Am J Health Syst Pharm 2017 Mar;74(6):409-415

Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, TN.

Purpose: The structure and development of an innovative, ASHP-accredited postgraduate year 2 (PGY2) clinical pharmacogenetics residency program are described.

Summary: A 12-month PGY2 clinical pharmacogenetics residency was created at St. Jude Children's Research Hospital in accordance with the ASHP standards for advanced practice residencies. The purpose of this 12-month residency program is to prepare pharmacy residents to implement pharmacogenetics in clinical practice. The program helps residents develop expertise in the science of pharmacogenetics as well as an understanding of translational research, innovative pharmacy practice model development, and clinical informatics. The resident learns to optimize patient outcomes through the expert provision of evidence-based, patient-centered precision medicine as an integral part of an interprofessional team. After completing the program, residents are expected to have the clinical skills necessary to practice in the field of clinical pharmacogenetics and independently implement pharmacogenetic testing in other health-system settings. Because implementation of pharmacogenetics requires collaboration across many disciplines, residents works within an interprofessional team of physicians, nurses, informatics specialists, pharmacists, and clinical laboratory personnel to achieve program goals. Since the first resident graduated in 2012, the program has graduated 1 resident each year. Graduated residents have accepted pharmacogenetics positions at major academic medical centers and community hospitals, as well as academic and research positions with a pharmacogenetics emphasis.

Conclusion: A PGY2 clinical pharmacogenetics residency was successfully developed at St. Jude in 2013. After completion of the program, residents are equipped with the clinical skills and necessary experience to drive precision medicine forward and lead the implementation of pharmacogenetic testing in other healthcare settings.
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http://dx.doi.org/10.2146/ajhp160174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499519PMC
March 2017

The impact of the UGT1A1*60 allele on bilirubin serum concentrations.

Pharmacogenomics 2017 Jan 14;18(1):5-16. Epub 2016 Dec 14.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.

Aim: Identify the functional status of the uridine-diphosphate glucuronyl transferase 1A1 (UGT1A1) -3279T>G (*60) variant.

Materials & Methods: Retrospective review of clinically obtained serum bilirubin concentrations in pediatric patients to evaluate the association of the UGT1A1 -3279T>G (*60) variant with bilirubin concentrations and assessed linkage disequilibrium of the UGT1A1 -3279T>G (*60) and A(TA)7TAA (*28) variants.

Results: Total bilirubin concentration did not differ between patients who had a UGT1A1*1/*1 diplotype and patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant. Total bilirubin concentration was lower in patients homozygous for the UGT1A1 -3279T>G (*60/*60) variant than in patients homozygous for the UGT1A1 A(TA)7TAA (*28/*28) variant (p < 0.01). The -3279T>G (*60) and A(TA)7TAA (*28) variants were in strong incomplete linkage disequilibrium in both black and white patients.

Conclusion: The presence of the UGT1A1 -3279T>G (*60) variant is not associated with increased bilirubin concentrations.
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http://dx.doi.org/10.2217/pgs-2016-0135DOI Listing
January 2017

CC-PROMISE effectively integrates two forms of molecular data with multiple biologically related endpoints.

BMC Bioinformatics 2016 Oct 6;17(Suppl 13):382. Epub 2016 Oct 6.

Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, 38105, USA.

Background: As new technologies allow investigators to collect multiple forms of molecular data (genomic, epigenomic, transcriptomic, etc) and multiple endpoints on a clinical trial cohort, it will become necessary to effectively integrate all these data in a way that reliably identifies biologically important genes.

Methods: We introduce CC-PROMISE as an integrated data analysis method that combines components of canonical correlation (CC) and projection onto the most interesting evidence (PROMISE). For each gene, CC-PROMISE first uses CC to compute scores that represent the association of two forms of molecular data with each other. Next, these scores are substituted into PROMISE to evaluate the statistical evidence that the molecular data show a biologically meaningful relationship with the endpoints.

Results: CC-PROMISE shows outstanding performance in simulation studies and an example application involving pediatric leukemia. In simulation studies, CC-PROMISE controls the type I error (misleading significance) rate very near the nominal level across 100 distinct null settings in which no molecular-endpoint association exists. Also, CC-PROMISE has better statistical power than three other methods that control type I error in 396 of 400 (99 %) alternative settings for which a molecular-endpoint association is present; the power advantage of CC-PROMISE exceeds 30 % in 127 of the 400 (32 %) alternative settings. These advantages of CC-PROMISE are also observed in an example application.

Conclusion: CC-PROMISE very effectively identifies genes for which some form of molecular data shows a biologically meaningful association with multiple related endpoints.

Availability: The R package CCPROMISE is currently available from www.stjuderesearch.org/site/depts/biostats/software .
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http://dx.doi.org/10.1186/s12859-016-1217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073973PMC
October 2016

Pharmacogenetics for Safe Codeine Use in Sickle Cell Disease.

Pediatrics 2016 07;138(1)

Hematology, and.

After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations.
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http://dx.doi.org/10.1542/peds.2015-3479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925073PMC
July 2016

Vincristine pharmacogenomics: 'winner's curse' or a different phenotype?

Pharmacogenet Genomics 2016 Feb;26(2):51-2

St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

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http://dx.doi.org/10.1097/FPC.0000000000000192DOI Listing
February 2016

Reply to: Glucarpidase for the Treatment of Methotrexate-Induced Renal Dysfunction and Delayed Methotrexate Excretion.

Pediatr Blood Cancer 2016 Feb 21;63(2):365. Epub 2015 Oct 21.

Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee.

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http://dx.doi.org/10.1002/pbc.25800DOI Listing
February 2016

Clinical significance of in vivo cytarabine-induced gene expression signature in AML.

Leuk Lymphoma 2016 16;57(4):909-20. Epub 2015 Oct 16.

f Oncology, St Jude Children's Research Hospital , Memphis , TN , USA.

Despite initial remission, ∼60-70% of adult and 30% of pediatric patients experience relapse or refractory AML. Studies so far have identified base line gene expression profiles of pathogenic and prognostic significance in AML; however, the extent of change in gene expression post-initiation of treatment has not been investigated. Exposure of leukemic cells to chemotherapeutic agents such as cytarabine, a mainstay of AML chemotherapy, can trigger adaptive response by influencing leukemic cell transcriptome and, hence, development of resistance or refractory disease. It is, however, challenging to perform such a study due to lack of availability of specimens post-drug treatment. The primary objective of this study was to identify in vivo cytarabine-induced changes in leukemia cell transcriptome and to evaluate their impact on clinical outcome. The results highlight genes relevant to cytarabine resistance and support the concept of targeting cytarabine-induced genes as a means of improving response.
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http://dx.doi.org/10.3109/10428194.2015.1086918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794368PMC
December 2016

NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.

Nat Genet 2015 Jun 4;47(6):607-14. Epub 2015 May 4.

1] Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases.
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http://dx.doi.org/10.1038/ng.3283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449308PMC
June 2015

Considerations for the Utility of the CPIC Guideline for CYP2D6 Genotype and Codeine Therapy.

Clin Chem 2015 May 13;61(5):775-6. Epub 2015 Mar 13.

Division of Clinical Pharmacology Department of Medicine Indiana University School of Medicine Indianapolis, IN.

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http://dx.doi.org/10.1373/clinchem.2014.237412DOI Listing
May 2015

Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.

JAMA 2015 Feb;313(8):815-23

Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.

Importance: With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment.

Objective: To identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL.

Design, Setting, And Participants: Genome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children's Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children's Oncology Group (COG) protocol AALL0433 with toxic effects follow-up 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.

Exposure: Treatment with vincristine at a dose of 1.5 or 2.0 mg/m2.

Main Outcomes And Measures: Vincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4).

Results: Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) 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-analysis 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 (56%; 95% CI, 41.2%-70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4×10(-6)). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.

Conclusions And Relevance: In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.
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http://dx.doi.org/10.1001/jama.2015.0894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377066PMC
February 2015

Comparable efficacy with varying dosages of glucarpidase in pediatric oncology patients.

Pediatr Blood Cancer 2015 Sep 28;62(9):1518-22. Epub 2015 Jan 28.

Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Glucarpidase rapidly reduces methotrexate plasma concentrations in patients experiencing methotrexate-induced renal dysfunction. Debate exists regarding the role of glucarpidase in therapy given its high cost. The use of reduced-dose glucarpidase has been reported, and may allow more institutions to supply this drug to their patients. This report explores the relationship between glucarpidase dosage and patient outcomes in pediatric oncology patients.

Methods: The authors evaluated data from 26 patients who received glucarpidase after high-dose methotrexate. Decrease in plasma methotrexate concentrations and time to renal recovery were evaluated for an association with glucarpidase dosage, which ranged from 13 to 90 units/kg.

Results: No significant relationship was found between glucarpidase dosage (units/kg) and percent decrease in methotrexate plasma concentrations measured by TDx (P > 0.1) or HPLC (P > 0.5). Patients who received glucarpidase dosages <50 units/kg had a median percent reduction in methotrexate plasma concentration of 99.4% (range, 98-100) measured by HPLC compared to a median percent reduction of 99.4% (range, 77.2-100) in patients who received ≥50 units/kg. Time to SCr recovery was not related to glucarpidase dosage (P > 0.8).

Conclusions: The efficacy of glucarpidase in the treatment of HDMTX-induced kidney injury was not dosage-dependent in this retrospective analysis of pediatric oncology patients.
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http://dx.doi.org/10.1002/pbc.25395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770903PMC
September 2015

Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.

J Clin Oncol 2015 Apr 26;33(11):1235-42. Epub 2015 Jan 26.

Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.

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.
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http://dx.doi.org/10.1200/JCO.2014.59.4671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375304PMC
April 2015

Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers.

Annu Rev Pharmacol Toxicol 2015 2;55:89-106. Epub 2014 Oct 2.

Department of Pharmaceutical Sciences and.

Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe 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.
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http://dx.doi.org/10.1146/annurev-pharmtox-010814-124835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607278PMC
September 2015

Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes.

Pharmacogenomics 2014 Jun;15(8):1065-78

Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.

Aim: Our objective was to describe the association between voriconazole concentrations and CYP2C19 diplotypes in pediatric cancer patients, including children homozygous for the CYP2C19*17 gain-of-function allele.

Materials & Methods: A linear mixed effect model compared voriconazole dose-corrected trough concentrations (n = 142) among CYP2C19 diplotypes in 33 patients (aged 1-19 years). Voriconazole pharmacokinetics was described by a two-compartment model with Michaelis-Menten elimination.

Results: Age (p = 0.05) and CYP2C19 diplotype (p = 0.002) were associated with voriconazole concentrations. CYP2C19*17 homozygotes never attained therapeutic concentrations, and had lower dose-corrected voriconazole concentrations (median 0.01 μg/ml/mg/kg; p = 0.02) than CYP2C19*1 homozygotes (median 0.07 μg/ml/mg/kg). Modeling indicates that higher doses may produce therapeutic concentrations in younger children and in those with a CYP2C19*17/*17 diplotype.

Conclusion: Younger age and the presence of CYP2C19 gain-of-function alleles were associated with subtherapeutic voriconazole concentrations. Starting doses based on age and CYP2C19 status could increase the number of patients achieving therapeutic voriconazole exposure.
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http://dx.doi.org/10.2217/pgs.14.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155516PMC
June 2014