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.

Pediatric Pharmaceutical Ingestions.

Pharmaceutical ingestions comprise an important part of pediatric toxicology. Based on the 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System, coupled with recent epidemiology articles on the topic of pediatric toxicology, it is apparent that poison prevention education has not been completely successful in decreasing exposures to toxic drugs. From the unintentional ingestion in a toddler due to unsafe storage to the intentional adolescent ingestion for misuse and abuse, pharmaceutical medications continue to cause harm. Access to adult prescription drugs in the home accounted for most of the exposures in children age ≤5 years as well as adolescents age 13 to 19 years. Ingestions resulting from more common pharmaceutical exposures are discussed with the hope of increasing awareness about the need for added vigilance. [Pediatr Ann. 2017;46(12):e459-e465.].

Do rapid comprehensive urine drug screens change clinical management in children?

CONTEXT: Multiple studies have concluded that urine drug screens rarely change clinical management. The rapid comprehensive urine drug screen (RCUDS) at our institution detects over 300 substances using a combination of EIA and GC/MS and typically takes 2-5 h for completion. OBJECTIVE: We sought to determine whether this RCUDS altered management in the pediatric population. METHODS: All patients >1 month and <18 years of age in which a RCUDS was completed from 1 January 2012 to 31 December 2012 were eligible for the study. Assuming that clinical management would not be altered in at least 90% of cases with a confidence interval of 95%, an alpha error of 5%, we calculated a sample size of 122 cases to ensure adequate study power. Four board-certified medical toxicologists reviewed 160 cases. Cases were assigned to the toxicologists based on a random-number generator. In addition, each toxicologist reviewed 12 random cases from the other three toxicologist's cases to determine inter-rater reliability. All four toxicologists reviewed any case in which a RCUDS was believed to have changed management. RESULTS: A total of 908 RCUDS were performed during the study period, and 160 were selected for study. Mean age was 10.5 years; male = 83, female = 77. Most were ordered from the ED (101/160 = 63%), followed by the inpatient unit (36/160 = 23%), outpatient (14/160 = 9%), and ICU (9/160 = 6%). 111/160 (69%) had a history of ingestion. Of the 160 randomly chosen cases, only three cases were found in which overall clinical management was altered based on the results of the RCUDS. All three cases were children <3 years old with a RCUDS positive for amfetamines. In all the three cases, police, Division of Family Services (DFS), and social work were involved. In no case did the acute clinical management change occurred due to the results of the RCUDS. CONCLUSIONS: The RCUDS rarely changed management in patients at our institution. Further study is warranted.

In vivo characterization of CYP2D6*12, *29 and *84 using dextromethorphan as a probe drug: a case report.

CYP2D6*84 was first described in a Black South African subject, however, its function remains unknown. Astrolabe, a probabilistic scoring tool developed in our laboratory to call genotypes from whole genome sequence, identified CYP2D6*84 in a trio. The father presented with intermediate metabolism when challenged with the CYP2D6 probe drug dextromethorphan (DM/dextrorphan [DX] = 0.0839). Since his second allele, CYP2D6*12, is nonfunctional, the observed activity is derived by CYP2D6*84. This finding suggests that the allele's hallmark P267H causes decreased activity toward DM and that this allele should receive a value of 0.5 for Activity Score calculations. The mother's DM/DX of 0.0543 was consistent with the decreased activity classification of CYP2D6*29. The child, a critically ill neonate, was not phenotyped, but predicted to be a normal metabolizer.

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.

Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem.

Many women of reproductive age in the United States are marginally iodine deficient, perhaps because the salt in processed foods is not iodized. Iodine deficiency, per se, can interfere with normal brain development in their offspring; in addition, it increases vulnerability to the effects of certain environmental pollutants, such as nitrate, thiocyanate, and perchlorate. Although pregnant and lactating women should take a supplement containing adequate iodide, only about 15% do so. Such supplements, however, may not contain enough iodide and may not be labeled accurately. The American Thyroid Association recommends that pregnant and lactating women take a supplement with adequate iodide. The American Academy of Pediatrics recommends that pregnant and lactating women also avoid exposure to excess nitrate, which would usually occur from contaminated well water, and thiocyanate, which is in cigarette smoke. Perchlorate is currently a candidate for regulation as a water pollutant. The Environmental Protection Agency should proceed with appropriate regulation, and the Food and Drug Administration should address the mislabeling of the iodine content of prenatal/lactation supplements.

Chronic amitriptyline overdose in a child.

Amitriptyline, a tricyclic antidepressant, has a well-described toxicity profile, and acute ingestions are common in the pediatric toxicology world. However, little can be found in the literature regarding chronic overdose. We describe a case of a 6-year-old girl who was prescribed amitriptyline 30 mg nightly for sleep problems, but was mistakenly given 300 mg (15 mg/kg) nightly for over a month. She was noted to have mental status changes and difficulty reading several days after starting the medication. She presented to the local children's hospital in status epilepticus with significant cardiac conduction abnormalities on ECG. Her total amitriptyline/nortriptyline level was found to be 1676 ng/mL (normal therapeutic level 50-300 ng/mL). She was treated for several days with sodium bicarbonate. Within 24 h, her neurologic status improved and had returned to baseline within several days. Her ECG normalized, and she was discharged home, without apparent sequelae. A brief discussion of possible protective mechanisms (including pharmacogenomic) is presented.

Serum concentrations in three children with unintentional tetrahydrozoline overdose.

BACKGROUND: Major symptoms can occur from tetrahydrozoline (THZ) overdoses in young children, requiring intensive care management. We report three cases that presented with CNS depression and cardiovascular effects where serum concentrations were performed. CASE REPORT: Case 1 ingested an unknown amount of eye drops containing THZ, resulting in altered mental status, bradycardia, hypothermia, and hypotension. Cases 2 and 3 ingested 7.5 mL of eye drops containing THZ. Case 2 presented to the emergency department (ED) without symptoms but became lethargic and bradycardic 90 min after ingestion. By contrast, Case 3 became lethargic 15 min after ingestion and required intubation on arrival to the ED. All children were admitted to ICU for observation and improved within 24 h of ingestion. Urine obtained for drug screening was positive for THZ. Blood was obtained to assess level using gas-chromatography mass-spectrometry (GC-MS). CASE DISCUSSION: Case 1 had plasma levels of 51.4 and 23.6 ng/mL at 7 and 12 h, respectively, after ingestion, revealing a half-life of 4.4 h. Numerous case reports have been published documenting the dangers of ingesting these topical over-the-counter (OTC) products. However, human PK data are not available to help in our understanding of THZ toxicokinetics and disposition in humans after ingestion. CONCLUSION: We report three pediatric cases after ingestion of THZ where plasma concentrations were obtained with a calculated half-life of 4.4 h in one case.

24-hour provoked urine excretion test for heavy metals in children with autism and typically developing controls, a pilot study.

INTRODUCTION: The complementary and alternative medicine practice of prescribing chelators to children with autism is based on the premise that the chronic symptoms of autism can be ameliorated by reducing heavy metal body burden. However, there has not been definitive evidence, published to date, to support the assertion that children with autism are at increased risk of an excess chelatable body burden of heavy metals. The oral chelator meso-2,3-dimercaptosuccinic acid (DMSA) can be used diagnostically to mobilize heavy metals from extravascular pools, enhancing the identification of individuals who have a chelatable body burden. METHODS: Seventeen children with autism and five typically developing children were enrolled in a pilot study to test for chelatable body burden of Arsenic (As), Cadmium (Cd), Lead (Pb), and Mercury (Hg). Evaluation included a questionnaire regarding potential exposure to heavy metals, diet restrictions, a baseline 24-hour urine collection, and a DMSA-provoked urine collection. Urine collections were sent for As, Cd, Pb, and Hg quantification by Inductively Coupled Plasma-Mass Spectrometry. Unprovoked reference ranges were used in the interpretation of all collections. RESULTS: Fifteen autistic children and four typically developing children completed the study. Three autistic subjects excreted one metal in greater quantity during the provoked excretion than baseline. Two of these were very close to the limit of detection. In the third case, the provoked excretion of mercury was between the upper limit of normal and lower limit of the potentially toxic reference range. Fish was removed from this child's diet for greater than one month, and the provoked excretion test repeated. The repeat excretion of mercury was within the normal range. CONCLUSION: In the absence a proven novel mode of heavy metal toxicity, the proportion of autistic participants in this study whose DMSA provoked excretion results demonstrate an excess chelatable body burden of As, Cd, Pb, or Hg is zero. The confidence interval for this proportion is 0-22%.

The epidemiology of pediatric environmental exposures.

Currently, the only national databases that are available to aid in a search to assess the effect of environmental exposures on children's health are those provided by the Pediatric Environmental Health Specialty Units and poison control centers. Both have limitations and are largely deficient in accurate, helpful numbers. Both, however, offer insight into factors that are important to the public and health care professionals and provide some outcome data to measure morbidity and mortality. This article presents an analysis of the information in these databases about children's exposure to toxic environmental substances.

Unusual presentation of iatrogenic phenytoin toxicity in a newborn.

BACKGROUND: Medication errors may produce severe toxicity resulting in hospitalization. This can be compounded if the physician obtains the wrong concentration from a reference manual and a pharmacy miscalculates the conversion. We report a child presenting with ileus, hypothermia and lethargy after receiving supratherapeutic dosing of phenytoin after a concentration miscalculation. CASE REPORT: A one-month-old infant presented to the Emergency Department with progressive worsening of abdominal distension, diminished activity, and a one day history of difficulty feeding secondary to a decreased level of consciousness. The past medical history was significant for neonatal Group B Strep meningitis with seizures. Among the child's discharge medications was a prescription for phenytoin (30 mg/5 mL) 2.5 cc by mouth three times daily. On exam, the child was hypothermic with pink mottled skin, poor responsiveness, prolonged capillary refill, abdominal distension with hypoactive bowel sounds, and a dysconjugate gaze. The Initial phenytoin serum concentration was 91.8 mcg/mL. She was admitted to the PICU and was started on ampicillin and cefotaxime for R/O sepsis. Phenytoin was withheld and subsequent serum concentrations revealed an extremely slow elimination (mcg/mL vs. time pair coordinates were 78.2/13.3h; 74.3/62.3h; 43.7/109.6h; 10.8/160.9h) reflecting zero-order kinetics. Post discontinuing antibiotics, phenytoin levels decreased at rates expected. She was discharged after resolution of symptoms. The MD who had written the phenytoin prescription had based it on the Harriet Lane Handbook, 2000 Ed. The 30 mg/5 mL formulation has been unavailable in the US for several years. A community pharmacy substituted the 125 mg/5 mL formulation, but miscalculated the dosage to be 1.6 cc (40 mg) tid. CONCLUSIONS: Abdominal distension and ileus may be presenting symptoms in children at toxic phenytoin levels. Ampicillin and cefotaxime may effect the elimination rate of phenytoin at such levels. We report one of the highest phenytoin levels recorded after therapeutic misadventure. Physicians must be aware of inaccuracies in reference manuals that may result in dosing errors.

Cisapride: a potential model substrate to assess cytochrome P4503A4 activity in vivo.

OBJECTIVES: Cisapride was compared with midazolam in vivo to determine its potential applicability as a cytochrome P450 (CYP) 3A4 "probe." As well, we evaluated whether cisapride was transported by P-glycoprotein. METHODS: Bidirectional transport assays were conducted in LLC-PK1 cells and the derivative cell line L-MDR1 to determine whether cisapride was a substrate for P-glycoprotein. A pharmacokinetic study was also conducted in 17 healthy adults (n = 8 women) who received intravenous midazolam (0.025 mg/kg), oral midazolam (0.15 mg/kg), and oral cisapride (0.07 mg/kg) in a randomized crossover design. Plasma concentrations were quantitated from repeated after-dosing blood samples by HPLC with ultraviolet detection for midazolam and HPLC with tandem mass spectrometry detection for cisapride and norcisapride. Pharmacokinetic parameters were determined by noncompartmental methods. Both linear and nonlinear regression analyses were used to examine the association between the apparent plasma clearance of midazolam and cisapride and the cisapride/norcisapride plasma concentration ratios. RESULTS: Although not a substrate for P-glycoprotein, cisapride inhibited P-glycoprotein with an apparent inhibition constant (K(i)) of 16.1 micromol/L. Linear correlations between cisapride clearance and both intravenous and oral midazolam clearance (P =.01, r(2) = 0.43 and P =.001, r(2) = 0.46, respectively) were found. Cisapride/norcisapride plasma concentration ratios at 8 hours (P =.001, r(2) = 0.90) and 12 hours (P =.001, r(2) = 0.96), as well as cisapride plasma concentrations at these time points, were shown to accurately predict the area under the plasma concentration versus time curve for cisapride. CONCLUSIONS: CYP3A4 activity reflected by the total body clearance after oral administration of cisapride should be independent of transport by P-glycoprotein. Concordance between the pharmacokinetics for cisapride and midazolam support the applicability of oral cisapride as a pharmacologic substrate to assess total CYP3A4 activity in vivo. Cisapride plasma concentration ratios at 8 or 12 hours after a single oral cisapride dose may prove useful as a single-point determination to reflect the area under the plasma concentration versus time curve and the plasma clearance of cisapride and, as well, total CYP3A4 activity in vivo.