Pharmacogenetics and Oxcarbazepine in Children and Adolescents: Beyond HLA-B*15:02.

Background: Oxcarbazepine is thought to be better-tolerated and less susceptible to drug-drug interactions than its predecessor, carbamazepine. Genetic testing for HLA-B*15:02 is recommended in specific populations to identify those at high risk of severe hypersensitivity reactions; however, other pharmacologic and pharmacogenetic factors that can impact drug disposition may be involved. Methods: We present a case of an 8-year-old boy treated with oxcarbazepine who developed drug reaction with eosinophilia and systemic symptoms (DRESS) with Stevens-Johnsons syndrome overlap and was negative for HLA-B*15:02. We review the extant literature related to oxcarbazepine disposition, and potential pharmacogenetic variants in aldoketoreductase 1C (AKR1C)2-4 that may contribute to this risk. Results: Genetic variability in oxcarbazepine disposition pathways may contribute to tolerability and toxicity, including the development of hypersensitivity reactions. Conclusions: While preemptive genetic testing for HLA-B*15:02 in individuals of Asian ancestry is recommended to prevent severe hypersensitivity reactions to oxcarbazepine, oxcarbazepine concentrations and AKR1C variation may contribute to the risk of severe adverse reactions. We provide recommendations for future study to elucidate whether these individual factors are important for reducing the risk of severe adverse events.

Pharmacogenetic Testing in Patients with Autism Spectrum Disorder Evaluated in a Precision Medicine Clinic.

OBJECTIVE: This study investigated outcomes of pharmacogenetic testing of youth with autism spectrum disorder (ASD) referred to a precision medicine clinic and explored associations between patient characteristics and pharmacogenomic testing results. METHODS: Records for patients diagnosed with ASD and subsequently referred to a pediatric hospital's precision medicine clinic between July 1, 2010, and June 30, 2020, were reviewed. Pharmacogenetic testing results were abstracted focusing on CYP2D6 and CYP2C19. In addition, we compiled counts of patients' co-occurring diagnoses, histories of adverse drug reactions (ADRs), previously trialed ineffective medications, and previous psychiatric medication changes. Logistic regression models were fit to examine CYP2C19 and CYP2D6 metabolizer status as functions of patient demographics and prereferral medication histories. RESULTS: Of 202 patients (mean age = 12.18 yrs), 66% were referred to precision medicine because of poor medication response. Among patients with pharmacogenomic testing results for CYP2D6, 9% were classified as poor metabolizers; among patients with results for CYP2C19, 10% were classified as rapid/ultrarapid metabolizers. Patient demographics and medication response history did not predict pharmacogenomic results. However, the number of co-occurring diagnoses positively predicted the number of nonpsychiatric ADRs and a higher probability of CYP2D6 poor metabolizer status; moreover, nonpsychiatric ADRs positively predicted CYP2C19 rapid/ultrarapid metabolizer status. CONCLUSION: In one of the largest reported samples of youth with ASD clinically referred for pharmacogenetic testing, we observed high variability in medication response and yield for actionable results. Our findings suggest potential clinical utility for pharmacogenetic testing and introduce possible clinical profiles associated with metabolizer status.

Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia.

Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates <2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control.

Pharmacogenetic Testing for the Pediatric Gastroenterologist: Actionable Drug-Gene Pairs to Know.

Gastroenterologists represent some of the earlier adopters of precision medicine through pharmacogenetic testing by embracing upfront genotyping for thiopurine S-methyltransferase nucleotide diphosphatase (TPMT) before prescribing 6-mercaptopurine or azathioprine for the treatment of inflammatory bowel disease. Over the last two decades, pharmacogenetic testing has become more readily available for other genes relevant to drug dose individualization. Common medications prescribed by gastroenterologists for conditions other than inflammatory bowel disease now have actionable guidelines, which can improve medication efficacy and safety; however, a clear understanding of how to interpret the results remains a challenge for many clinicians, precluding wide implementation of genotype-guided dosing for drugs other than 6-mercaptopurine and azathioprine. Our goal is to provide a practical tutorial on the currently available pharmacogenetic testing options and a results interpretation for drug-gene pairs important to medications commonly used in pediatric gastroenterology. We focus on evidence-based clinical guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC®) to highlight relevant drug-gene pairs, including proton pump inhibitors and selective serotonin reuptake inhibitors and cytochrome P450 (CYP) 2C19, ondansetron and CYP2D6, 6-mercaptopurine and TMPT and Nudix hydrolase 15 (NUDT15), and budesonide and tacrolimus and CYP3A5.

Parental understanding and attitudes following pharmacogenomic testing for pediatric neuropsychiatric patients.

Aim: This study explores parental understanding and attitudes around pharmacogenomic results in their child(ren). Patients and methods: In-depth interviews with parents whose child(ren) had received a pharmacogenomic testing panel for management of neuropsychiatric medications were completed. Interviews were analyzed for themes and accuracy of understanding of results. Results: In 18 parents interviewed, 49/63 (78%) of statements made regarding results were accurate. Differences in understanding were seen by clinic, number of medications and result type. Parents expected results to guide prescribing and perceived the greatest utility in results that could impact current care. Results predicting normal drug metabolism may create mixed feelings. Conclusion: Parents perceive utility in pharmacogenomic testing for their children. Challenges exist in understanding probabilistic and multifactorial information about pharmacogenomic results.

Retrospective Review of Pharmacogenetic Testing at an Academic Children's Hospital.

There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessive-compulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population.

An electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children.

Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States and the most common cause of drug recall. As opposed to the recognized direct toxicity of super-therapeutic acetaminophen or chemotherapeutic agents in children, limited data exists for pediatric populations on the incidence of idiosyncratic DILI (iDILI) that may develop independently of drug dose or duration of administration. To improve the detection of adverse drug reactions at our hospital, we utilized electronic medical records-based automated trigger tools to alert providers of potential iDILI. Clinical criteria concerning for iDILI were defined as serum ALT > 5x or serum bilirubin > 1.5x upper limit of normal in the setting of medication exposure. Over a two year period, 12 patients were identified as having possible or probable iDILI. Out of the identified patients, three were males, and the mean age was 10.8 years. Implicated agents included eight antibiotics, two anti-epileptics, one anti-psychotic, and one anti-inflammatory medication. Roussel-Uclaf Causality Assessment Methods identified one "possible" case, 11 "probable" cases, and one "highly probable" case of iDILI. Improved awareness and more vigilant programming can generate better data on iDILI and improve our understanding of the condition and its incidence in children.

Description of an Innovative Pediatric Individualized Therapeutics Clinic: Working toward Precision Drug Therapy.

The GOLDILOKs® (Genomic and Ontogeny-Linked Dose Individualization and cLinical Optimization for KidS) Clinic aims to provide families and physicians with data to make more informed decisions with regard to pharmacological therapy by using innovative therapy and genomic technologies. The objectives are two-fold: (1) To describe the utility of the GOLDILOKs® Clinic to referring prescribers by evaluating the type of referrals made to the GOLDILOKs® Clinic and (2) to assess the most often utilized technologies (e.g., genotyping) completed to formulate therapy recommendations. Patient data from July 2010 to June 2016 was retrospectively reviewed following Institutional Review Board (IRB) approval. The GOLDILOKs® Clinic evaluated 306 patients and had increases in annual referrals from 14 in 2010⁻2011 to 84 in 2016⁻2017. The children that were referred were predominately Caucasian (82%) and male (59%) with an average age of 12.4 ± 5.9 years. Subspecialty versus primary care referrals accounted for 82% and 18% of referrals, respectively. Adverse drug reactions (n = 166) and poor medication response (n = 179) were the major reasons for referral. However, it must be noted that patients could have multiple reasons for referral. Pharmacogenetic results were extensively used to provide guidance for future therapy in patients with medication-related problems. Genotyping of drug metabolizing enzymes and drug target receptors was performed in 221 patients (72.2%). Recommendations were fully accepted by 63% and partially accepted by 22% of internal provider referrals.

Variability of surgical prophylaxis in penicillin-allergic children.

We retrospectively evaluated the effect of penicillin adverse drug reaction (ADR) labeling on surgical antibiotic prophylaxis. Cefazolin was administered in 86% of penicillin ADR-negative (-) and 28% penicillin ADR-positive (+) cases. Broad-spectrum antibiotic use was more common in ADR(+) cases and was more commonly associated with perioperative adverse drug events.

Comparison of Arginine Hydrochloride and Acetazolamide for the Correction of Metabolic Alkalosis in Pediatric Patients.

Metabolic alkalosis is a common acid-base disturbance occurring in critically ill pediatric patients. Acetazolamide and arginine hydrochloride are pharmacologic agents used at our institution for patients refractory to first-line therapy or those unable to tolerate fluid replacement. The objective of this retrospective review was to determine if a course of arginine hydrochloride or acetazolamide was more effective at correcting metabolic alkalosis within a 24-hour period. Patients included received a course of acetazolamide or arginine hydrochloride for metabolic alkalosis with a repeat metabolic panel 18-30 hours after treatment initiation. Exclusion criteria consisted of previous treatment with either drug within 24 hours or a documented metabolic disorder. Efficacy was determined by proportion of patients achieving resolution of metabolic alkalosis (treatment success: serum CO2 <30 mmol/L and Cl >96 mmol/L). Additionally, mean change in serum bicarbonate and chloride concentrations was assessed. Thirty-four patients met inclusion criteria, 19 patients received acetazolamide and 15 patients received arginine hydrochloride. Treatment success was similar in patients receiving acetazolamide and arginine hydrochloride (37% vs. 7%, P = 0.053). Correction of serum bicarbonate was observed in more patients treated with acetazolamide (42% vs. 7%, P = 0.047). Both groups had a similar increase in mean serum chloride concentration (5.7 ± 5.3 vs. 4.4 ± 4.4 mmol/L, P = 0.458). Mean decrease in serum bicarbonate concentration was equivalent between groups (5.6 ± 5.2 vs. 2.8 ± 4.7, mmol/L, P = 0.110). Acetazolamide and arginine hydrochloride appear to be equally effective in correcting metabolic alkalosis in critically ill pediatric patients.

Evaluation of an Alternative Intravenous N-Acetylcysteine Regimen in Pediatric Patients.

OBJECTIVE: Conventionally, intravenous N-acetylcysteine (IV-NAC) administration is a 3-bag regimen administered over the course of 21 hours, which increases the risk of reconstitution and administration errors. To minimize errors, an alternative IV-NAC regimen consists of a loading dose (150 mg/kg) followed by a maintenance infusion (15 mg/kg/hr) until termination criteria are met. The aim was to determine the clinical outcomes of an alternative IV-NAC regimen in pediatric patients. METHODS: A retrospective review of pharmacy dispensing records and diagnostic codes at a pediatric hospital identified patients who received alternative IV-NAC dosing from March 1, 2008, to September 10, 2012, for acetaminophen overdoses. Exclusion criteria included chronic liver disease, initiation of oral or other IV-NAC regimens, and initiation of standard IV-NAC infusion prior to facility transfer. Clinical and laboratory data were abstracted from the electronic medical record. Descriptive statistics were utilized. Clinical outcomes and adverse drug reaction incidences were compared between the alternative and Food and Drug Administration (FDA)-approved IV-NAC regimens. RESULTS: Fifty-nine patients (mean age 13.4 ± 4.3 years; range: 2 months-18 years) with acetaminophen overdoses were identified. Upon IV-NAC discontinuation, 45 patients had normal alanine transaminase (ALT) concentrations, while 14 patients' ALT concentrations remained elevated (median 140 units/L) but were trending downward. Two patients (3.4%) developed hepatotoxicity (aspartate transaminase/ALT > 1000 units/L). No patients developed hepatic failure, were listed for a liver transplant, were intubated, underwent hemodialysis, or died. Two patients (3.4%) developed anaphylactoid reactions. No known medication or administration errors occurred. Clinical outcome incidences of the studied endpoints with the alternative IV-NAC regimen are at the lower end of published incidence ranges compared to the FDA IV-NAC regimen for acetaminophen overdoses. CONCLUSIONS: This alternative IV-NAC regimen appears to be effective and well tolerated among pediatric patients when compared to the FDA-approved regimen. It may also result in fewer reconstitution and administration errors, leading to improved patient safety.

Improving pain assessment in the NICU: a quality improvement project.

Pain assessment documentation was inadequate because of the use of a subjective pain assessment strategy in a tertiary level IV neonatal intensive care unit (NICU). The aim of this study was to improve consistency of pain assessment documentation through implementation of a multidimensional neonatal pain and sedation assessment tool. The study was set in a 60-bed level IV NICU within an urban children's hospital. Participants included NICU staff, including registered nurses, neonatal nurse practitioners, clinical nurse specialists, pharmacists, neonatal fellows, and neonatologists. The Plan Do Study Act method of quality improvement was used for this project. Baseline assessment included review of patient medical records 6 months before the intervention. Documentation of pain assessment on admission, routine pain assessment, reassessment of pain after an elevated pain score, discussion of pain in multidisciplinary rounds, and documentation of pain assessment were reviewed. Literature review and listserv query were conducted to identify neonatal pain tools. Survey of staff was conducted to evaluate knowledge of neonatal pain and also to determine current healthcare providers' practice as related to identification and treatment of neonatal pain. A multidimensional neonatal pain tool, the Neonatal Pain, Agitation, and Sedation Scale (N-PASS), was chosen by the staff for implementation. Six months and 2 years following education on the use of the N-PASS and implementation in the NICU, a chart review of all hospitalized patients was conducted to evaluate documentation of pain assessment on admission, routine pain assessment, reassessment of pain after an elevated pain score, discussion of pain in multidisciplinary rounds, and documentation of pain assessment in the medical progress note. Documentation of pain scores improved from 60% to 100% at 6 months and remained at 99% 2 years following implementation of the N-PASS. Pain score documentation with ongoing nursing assessment improved from 55% to greater than 90% at 6 months and 2 years following the intervention. Pain assessment documentation following intervention of an elevated pain score was 0% before implementation of the N-PASS and improved slightly to 30% 6 months and 47% 2 years following implementation. Identification and implementation of a multidimensional neonatal pain assessment tool, the N-PASS, improved documentation of pain in our unit. Although improvement in all quality improvement monitors was noted, additional work is needed in several key areas, specifically documentation of reassessment of pain following an intervention for an elevated pain score.

Pediatric Pharmacovigilance: Enhancing Adverse Drug Reaction Reporting in a Tertiary Care Children's Hospital.

BACKGROUND: Adverse drug reactions (ADRs) are notoriously underreported within health care facilities. In 2009-2010, ADRs were detected in only 0.5% of patients at the authors' institution, a pediatric hospital in the Midwestern United States. Additionally, historical ADRs were often inaccurately or incompletely documented in the medical record. An integrative Drug Safety Service (DSS) was implemented to improve the detection and accurate documentation of ADRs. METHODS: The DSS incorporated standardized ADR terminology, computerized triggers to identify ADRs, and a simplified voluntary reporting system within the facility. The DSS staff provided extensive hospital staff education on ADR reporting and the role of the DSS. The primary aim of this report was to assess the impact of the DSS on the number of ADRs reported at the authors' institution. The secondary aims were to evaluate the mechanisms by which patients with ADRs were identified and to assess the accuracy of ADR documentation after implementation of the DSS. RESULTS: A significant increase was observed (slope, 6.01; P < .001) in ADR detection after implementation of the DSS, with a greater than 4-fold increase from 10 cases per 10,000 admissions before initiation to 41 cases per 10,000 admissions after DSS implementation. Computerized triggers, International Classification of Diseases, 9th Edition (ICD-9) codes associated with ADRs, and the DSS identified 33%, 33%, and 24% of ADRs, respectively, while voluntary reporting only detected 9% of ADRs. CONCLUSIONS: Implementation of a multifaceted, interdisciplinary DSS was more effective in detecting ADRs than voluntary reporting alone. A proactive approach to ADR detection resulted in a significant increase in the identification and evaluation of ADRs.

Development of criteria for gentamicin monitoring in a neonatal intensive care unit.

PURPOSE: The results of a study to identify factors associated with serum gentamicin levels outside the therapeutic range in a neonatal population are reported. METHODS: A single-center retrospective chart review was conducted to identify cases involving gentamicin use in the neonatal intensive care unit; a sample of cases sufficient for risk-factor analysis (n = 225) was selected for evaluation. In all evaluated cases, gentamicin was administered according to a standardized dosing protocol based on gestational age and weight. Selected clinical factors and laboratory values potentially associated with undesirably high or low serum drug levels were analyzed. RESULTS: Of the 225 patient cases included in the analysis, 184 (82%) involved appropriate (i.e., per protocol) gentamicin dosing. Of the 41 doses classified as inappropriate, 33 were higher and 8 were lower than those recommended by the protocol. Six (18%) of the newborns who received doses classified as inappropriately high had supratherapeutic serum trough concentrations, and 3 (9%) had subtherapeutic trough values. Among the neonates with supratherapeutic peak values, none had an elevated trough value and only 1 received a gentamicin dose deemed to be inappropriately high. Factors associated with an increased relative risk (RR) of a supratherapeutic trough included inappropriate dosing (RR, 2.9; 95% confidence interval [CI], 1.18-6.9), an elevated serum creatinine (SCr) concentration (>0.8 mg/dL) on the day of blood sampling for drug level assessment (RR, 25.6; 95% CI, 9.1-71.4), low urine output (<1 mL/kg/hr) on the day of blood sampling (RR, 7.8; 95% CI, 3.0-15.4), and shock (RR, 3.16; 95% CI, 1.32-7.57). CONCLUSION: When adhering to a weight-based gentamicin dosing protocol, the SCr level and urine output are the best indicators for identifying neonatal patients at risk for supratherapeutic gentamicin trough levels. Shock and inappropriate dosing strategies also put patients at increased risk for supratherapeutic troughs.

Safety and efficacy of two potassium cocktail formulations for treatment of neonatal hyperkalemia.

BACKGROUND: A consensus has not been established for the standard treatment of hyperkalemia in the neonatal population. Most treatment regimens include a dextrose/insulin infusion. Additional agents used include calcium, sodium bicarbonate, polystyrene sulfonate, and albuterol. This study assessed the safety and efficacy of a potassium cocktail (k-cocktail) containing dextrose, insulin, calcium gluconate, and sodium lactate for treatment of neonatal hyperkalemia. OBJECTIVE: To determine whether modifications to a potassium cocktail formulation, based on a prior quality improvement project, resulted in a decrease in the incidence of hyperglycemia and acidosis associated with its use, and to evaluate the effectiveness of the k-cocktail in lowering serum potassium levels and the incidence of adverse effects. METHODS: We conducted a retrospective cohort study of neonates with hyper-kalemia who received 2 k-cocktail formulations (group 1 [n = 13], original formulation, dextrose:insulin 5:1; group 2 [n = 26], modified formulation, dextrose: insulin 3.3:1). Group 2 subjects were matched 2:1 by gestational age and birth weight with those in group 1. Variables related to safety and effectiveness of therapy were assessed by medical record review. The following tests were used to assess group differences: χ(2), Fisher exact, 2-tailed t-tests, and mixed linear models. RESULTS: The incidence of hyperglycemia during the modified k-cocktail infusion in group 2 decreased from 76.9% to 21.7% (p = 0.001). Serum blood glucose concentrations increased during the infusion, on average, for group 1 infants and were unchanged during the infusion for those in group 2. The incidence of acidosis during the infusion was similar between groups (group 1 [76.9%] vs group 2 [68.2%]; p = 0.58). No significant adverse events were observed. Serum potassium concentrations decreased similarly in both groups. CONCLUSIONS: An intravenous infusion including a dextrose:insulin ratio of 3.3:1, compared with a higher ratio, results in less hyperglycemia and appears to be as effective in decreasing potassium concentrations in newborns.

Magnetic resonance imaging studies without sedation in the neonatal intensive care unit: safe and efficient.

Use of magnetic resonance imaging (MRI) in the neonatal intensive care unit has been increasing over the past several years because of improved MRI technology and increased clinical awareness of the prognostic and diagnostic information available. Historically, the use of sedation has been the standard for achieving quality imaging without motion artifact, but it exposed the patient to risks associated with sedation medications. In an effort to obtain MRI studies with elimination of risks associated with sedation, a quality improvement project was initiated. Implementing a standardized approach utilizing a vacuum immobilizer has led to successful neonatal MRI completion without the need for sedation in 94% of study attempts. Acceptable or excellent image quality was achieved in more than 97% of attempts. Time away from the neonatal intensive care unit significantly decreased with this approach, with the mean duration of time away decreasing from 60 to 48 minutes (P < .0001). Obtaining MRI studies without sedation can be successfully implemented in a neonatal intensive care unit, nearly eliminating patient risks associated with sedation while improving utilization of hospital resources and maintaining adequate quality imaging.