Search tips
Search criteria

Results 1-6 (6)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
author:("Pinto, cavin")
1.  Case report: inability to achieve a therapeutic dose of tacrolimus in a pediatric allogeneic stem cell transplant patient after generic substitution 
Tacrolimus is an immunosuppressive drug that is used to lower the activity of the patient’s immune system to prevent organ rejection. Unfortunately, there is limited data regarding the therapeutic equivalency of generic tacrolimus formulations especially in children. We report the case of a pediatric patient having an inability to achieve a therapeutic trough level for tacrolimus after conversion from brand name to the generic formulation.
Case presentation
A 17-month-old male patient diagnosed with T-cell acute lymphoblastic leukemia underwent allogeneic stem cell transplantation. The patient initially received intravenous (IV) tacrolimus for graft-versus-host disease (GVHD) prophylaxis and achieved therapeutic levels. The patient was then switched to an oral brand formulation of tacrolimus, and was able to maintain trough levels within the therapeutic range. After being discharged, the patient received the generic formulation of tacrolimus from an outside pharmacy and the care team was unable to reach therapeutic levels despite multiple dose escalations. Returning to brand name tacrolimus resulted in prompt achievement of therapeutic levels.
A likely etiology for the inability to achieve therapeutic trough levels in this patient is the change in formulation from brand formulation to generic version. Other factors including drug-drug interaction, preparation of the medication by a different pharmacy, drug-food interaction and genetic factors were also considered. Physicians and pharmacists must be aware of the inability to achieve targeted therapeutic concentrations of tacrolimus resulting from the conversion of brand name to the generic formulation until these generic formulations are tested in clinical trials in a pediatric population.
PMCID: PMC4287354  PMID: 25472557
Tacrolimus; Generic; Children
2.  Trans-population Analysis of Genetic Mechanisms of Ethnic Disparities in Neuroblastoma Survival 
Black patients with neuroblastoma have a higher prevalence of high-risk disease and worse outcome than white patients. We sought to investigate the relationship between genetic variation and the disparities in survival observed in neuroblastoma.
The analytic cohort was composed of 2709 patients. Principal components were used to assign patients to genomic ethnic clusters for survival analyses. Locus-specific ancestry was calculated for use in association analysis. The shorter spans of linkage disequilibrium in African populations may facilitate the fine mapping of causal variants in regions previously implicated by genome-wide association studies conducted primarily in patients of European descent. Thus, we evaluated 13 single nucleotide polymorphisms known to be associated with susceptibility to high-risk neuroblastoma from genome-wide association studies and all variants with highly divergent allele frequencies in reference African and European populations near the known susceptibility loci. All statistical tests were two-sided.
African genomic ancestry was associated with high-risk neuroblastoma (P = .007) and lower event-free survival (P = .04, hazard ratio = 1.4, 95% confidence interval = 1.05 to 1.80). rs1033069 within SPAG16 (sperm associated antigen 16) was determined to have higher risk allele frequency in the African reference population and statistically significant association with high-risk disease in patients of European and African ancestry (P = 6.42×10−5, false discovery rate < 0.0015) in the overall cohort. Multivariable analysis using an additive model demonstrated that the SPAG16 single nucleotide polymorphism contributes to the observed ethnic disparities in high-risk disease and survival.
Our study demonstrates that common genetic variation influences neuroblastoma phenotype and contributes to the ethnic disparities in survival observed and illustrates the value of trans-population mapping.
PMCID: PMC3691940  PMID: 23243203
3.  Using Germline Genomics to Individualize Pediatric Cancer Treatments 
Clinical Cancer Research  2012;18(10):2791-2800.
The amazing successes in cure rates for children with cancer over the last century have come in large part from identifying clinical, genetic and molecular variables associated with response to therapy in large cooperative clinical trials and stratifying therapies according to the predicted risk of relapse. There is an expanding interest in identifying germline genomic variants, as opposed to genetic variants within the tumor, that are associated with susceptibility to toxicity and for risk of relapse. This review highlights the most important germline pharmacogenetic and pharmacogenomic studies in pediatric oncology. Incorporation of germline genomics into risk-adapted therapies will likely lead to safer and more effective treatments for children with cancer.
PMCID: PMC3354919  PMID: 22589487
Pediatric Oncology; Pharmacogenetics; Pharmacogenomics; Genome-wide Association Studies; Single Nucleotide Polymorphisms
4.  Clinically Relevant Genetic Variations in Drug Metabolizing Enzymes 
Current drug metabolism  2011;12(5):487-497.
In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed.
PMCID: PMC3110519  PMID: 21453273
Adverse drug reactions; Cytochrome P450; drug metabolizing enzymes; pharmacogenetics; pharmacogenomics; single nucleotide polymorphisms
5.  Racial and Ethnic Disparities in Risk and Survival in Children With Neuroblastoma: A Children's Oncology Group Study 
Journal of Clinical Oncology  2010;29(1):76-82.
Although health disparities are well-described for many cancers, little is known about racial and ethnic disparities in neuroblastoma. To evaluate differences in disease presentation and survival by race and ethnicity, data from the Children's Oncology Group (COG) were analyzed.
Patients and Methods
The racial/ethnic differences in clinical and biologic risk factors, and outcome of patients with neuroblastoma enrolled on COG ANBL00B1 between 2001 and 2009 were investigated.
A total of 3,539 patients (white, 72%; black, 12%; Hispanic, 12%; Asian, 4%; and Native American, < 1%) with neuroblastoma were included. The 5-year event-free survival (EFS) rates were 67% for whites (95% CI, 65% to 69%), 69% for Hispanics (95% CI, 63% to 74%), 62% for Asians (95% CI, 51% to 71%), 56% for blacks (95% CI, 50% to 62%), and 37% for Native American (95% CI, 17% to 58%). Blacks (P < .001) and Native Americans (P = .04) had a higher prevalence of high-risk disease than whites, and significantly worse EFS (P = .01 and P = .002, respectively). Adjustment for risk group abrogated these differences. However, closer examination of the EFS among high-risk patients who remained event free for 2 years or longer, revealed a higher prevalence of late-occurring events among blacks compared with whites (hazard ratio, 1.5; 95% CI, 1.0 to 2.3; P = .04).
Black and Native American patients with neuroblastoma have a higher prevalence of high-risk disease, accounting for their worse EFS when compared with whites. The higher prevalence of late-occurring events among blacks with high-risk disease suggests that this population may be more resistant to chemotherapy. Studies focused on delineating the genetic basis for the racial disparities observed in this study are planned.
PMCID: PMC3055862  PMID: 21098321
6.  Pharmacogenetic studies related to cyclophosphamide-based therapy 
Pharmacogenomics  2009;10(12):1897.
Cyclophosphamide is a cornerstone in the treatment of many pediatric and adult malignancies, as well as in the treatment of refractory autoimmune conditions. Genetic factors are thought to play a role in the interindividual variation in both response and toxicities associated with cyclophosphamide-based therapies. This drug focus reviews the most compelling studies conducted on the pharmacogenetics of cyclophosphamide-based therapies. Broader pharmacogenomic studies are needed and may reveal additional factors important in susceptibility to toxicity and/or response to therapy.
PMCID: PMC2820268  PMID: 19958089

Results 1-6 (6)