The advent of digital, electronic, and molecular technologies has allowed the study of complete genomes. Integrating this information into drug development has opened the door for pharmacogenomic (PGx) interventions in direct patient care. PGx allows clinicians to better identify drug of choice and optimize dosing regimens based on an individual's genetic characteristics. Integrating PGx into pediatric care is a priority for the Sanford Children's Genomic Medicine Consortium, a partnership of ten children's hospitals across the US committed to the innovation and advancement of genomics in pediatric care. In this white paper, we review the current state of PGx research and its clinical utility in pediatrics, a largely understudied population, and make recommendations for advancing cutting-edge practice in pediatrics.
We prospectively evaluated tumour response and renal function in 12 newly-diagnosed children with high-risk Wilms tumour receiving ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. Two cycles of ICE were followed by 5 weeks of vincristine, dactinomycin, and doxorubicin (Adriamycin) (VDA), and nephrectomy, radiotherapy, additional VDA, and a third ICE cycle. Carboplatin dosage was based on glomerular filtration rate (GFR) to achieve targeted systemic exposure (6 mg/ml × min). Mean GFR (measured by technetium 99m-DTPA clearance) declined by 7% after 2 cycles of ICE and by 38% after nephrectomy; the mean carboplatin dose was reduced 32% after nephrectomy. Mean GFR remained stable after the third ICE cycle. Although urinary β 2 -microglobulin excretion increased during therapy, no patient had clinically significant renal tubular dysfunction at the end of treatment.Treatment with ICE, nephrectomy, and radiotherapy significantly reduces GFR, largely as the result of nephrectomy. Adjustment of carboplatin dosage on the basis of GFR and careful monitoring of renal function may alleviate nephrotoxicity.
Background and Objective Monitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients, and developed new equations for estimated glomerular filtration rate (GFR) in these patients. Methods A retrospective analysis was conducted on patients comparing the estimated GFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from 99mTechnetium-DPTA (99mTc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from 99mTc-DTPA were compared to doses calculated by GFR estimating equations. Results Overall, the bedside Schwartz and Brandt equations did not precisely or accurately predict mGFR in our pediatric oncology patient population. Using a subset of the data, we developed a 5-covariate equation, which included the covariates of height, serum creatinine, age, BUN, and gender, and a simplified version (2-covariates), which only contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of the mGFR values. The equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation. Conclusions Two new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations.
The level of systemic exposure in our anephric patient was comparable to or lower than that achieved in patients with normal renal function at similar dosages. The patient tolerated therapy without problems. It appears that pediatric patients in renal failure can be treated with paclitaxel as a 24-h continuous infusion at doses similar to those used in patients with normal renal function.
Several healthcare organizations across Minnesota have developed formal pharmacogenomic (PGx) clinical programs to increase drug safety and effectiveness. Healthcare professional and student education is strong and there are multiple opportunities in the state for learners to gain workforce skills and develop advanced competency in PGx. Implementation planning is occurring at several organizations and others have incorporated structured utilization of PGx into routine workflows. Laboratory-based and translational PGx research in Minnesota has driven important discoveries in several therapeutic areas. This article reviews the state of PGx activities in Minnesota including educational programs, research, national consortia involvement, technology, clinical implementation and utilization and reimbursement, and outlines the challenges and opportunities in equitable implementation of these advances.
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.
Purpose of review Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future. Recent findings The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while ‘poor metabolizer’ haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform. Summary The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future.
With the initiatives by the National Institutes of Health and the US Food and Drug Administration, pharmacogenomics is transitioning from the laboratory to patient care. Nearly 200 drug products now contain pharmacogenomic information as part of their labeling; many of these products are commonly used in the pediatric population. Because pharmacogenomic testing can provide patient-specific predictors for drug response, pharmacists are positioned to assume a leadership role in pharmacogenomic testing, clinical interpretation of results, and recommendations for individualization of drug therapy. Opportunities for pharmacists exist in both inpatient and outpatient settings, such as pharmacist-managed clinical pharmacogenomics consultation services and educating patients and families about pharmacogenomic testing. Given the potential for genetic and age-dependent factors to influence drug selection and dosing, pediatric pharmacists should be involved in the development of dosing recommendations and interprofessional practice guidelines regarding pharmacogenomic testing in pediatric patients. Opportunities to become knowledgeable and competent in pharmacogenomics extend from coursework as part of the pharmacy curriculum to postgraduate education (e.g., residencies, fellowship, continuing education). The Pediatric Pharmacy Advocacy Group acknowledges a need for increased education of both students and practicing pharmacists with consideration for infants and children.
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