Theophylline toxicokinetics in premature newborns.

BACKGROUND: While cytochrome P4501A2 is the primary pathway for theophylline (aminophylline ethylenediamine) metabolism in adults, it is developmentally immature in the newborn. OBJECTIVE: To report the developmental differences in theophylline toxicokinetics of neonates. DESIGN: Case series. Three premature neonates received inadvertent intravenous overdoses of theophylline for apnea of prematurity while in newborn intensive care. Maximum serum concentrations ranged from 55 to 123 mg/L. Theophylline-derived caffeine levels plateaued at 8.4 to 13 mg/L and did not decline during the sampling period. All newborns experienced sinus tachycardia and agitation. Sequential theophylline and caffeine serum levels were obtained periodically for 62 to 100 hours. In contrast to older children and adults, in whom theophylline disposition follows zero-order kinetics at high concentrations, a monoexponential function best described theophylline elimination in the premature newborn, with half-lives ranging from 24.7 to 36.5 hours and estimated clearance from 0.02 to 0.05 L/kg per hour. These values are consistent with those previously reported in neonates. All patients were treated with supportive care without invasive procedures. No seizures or apparent sequelae occurred. CONCLUSION: Developmental differences in the balance between nonrenal (ie, metabolic) and renal elimination pathways produce the unique toxicokinetics of theophylline in the neonate.

Clinical trials in children: problems and pitfalls.

Recent initiatives by the US Congress and the Food and Drug Administration have provided effective incentives to develop new drugs for children leading to a dramatic increase in the number of paediatric clinical trials being done in the US. There also is increased international interest in development of pharmaceuticals for children as reflected in the draft International Conference on Harmonisation guidelines. The demands created by these initiatives are challenging the industry, regulators, and clinical investigator community. As the infrastructure for paediatric clinical research evolves, it is paramount that the ethical issues unique to children are not forgotten and that children do not become a commodity in the clinical trial economy. Furthermore, it is important to recognise that the adult paradigm for clinical research cannot simply be imposed on paediatric studies and that protocols must be appropriately designed for different age groups. Clinical studies can be, are being, and will continue to be successfully carried out in children on behalf of children so that ultimately children can benefit from therapeutic advances to the same extent enjoyed by their parents and grandparents.

Rifapentine pharmacokinetics in adolescents.

OBJECTIVE: Determination of rifapentine pharmacokinetics in healthy adolescent children. DESIGN: Prospective Phase II clinical trial. SETTING: Clinical research center within a university children's hospital. PATIENTS: Twelve subjects ranging in age from 12 to 15 years, male and female. INTERVENTIONS: A single oral dose of rifapentine was administered to healthy adolescent volunteers, 450 mg if <45 kg or 600 mg if > or =45 kg. Blood was collected at serial intervals (0, 2, 3, 4, 5, 6, 8, 12, 18, 24, 48 and 72 h postdose). Subjects were observed for adverse effects during the period of study. MEASUREMENTS: High pressure liquid chromatography was used to measure the plasma concentration of rifapentine and 25-desacetyl rifapentine in each blood sample. For each subject a plot of mean plasma concentration vs. time data for rifapentine and its metabolite (i.e. 25-desacetyl rifapentine) were created. Subsequently model-independent methods were used to determine the pharmacokinetic profiles for each subject. RESULTS: All subjects tolerated rifapentine without adverse effects. The 2-h postdose plasma concentrations of rifapentine (6.59 to 9.05 microg/ml) and 25-desacetyl rifapentine (0.57 to 2.64 microg/ml) far exceeded the MIC of Mycobacterium tuberculosis to rifapentine (approximately 0.12 microg/ml). The combination of a high Cmax (rifapentine, 9.95 to 18.63 microg/ml; 25-desacetyl rifapentine, 3.73 to 7.46 microg/ml) and lengthy terminal elimination phase t1/2 (rifapentine, 10 to 23 h; 25-desacetyl rifapentine, 14 to 35 h) resulted in potentially effective plasma concentrations of both compounds that persisted for at least 48 h in most subjects. CONCLUSIONS: A well-tolerated oral rifapentine dose produced rapid and sustained plasma drug concentrations in adolescents that should effectively treat infections caused by M. tuberculosis. Rifapentine pharmacokinetics appears to be similar in adolescent and adult populations.

Flumazenil in children after esophagogastroduodenoscopy.

OBJECTIVE: Our aim was to evaluate if the routine use of the benzodiazepine antagonist flumazenil would shorten postprocedure recovery times after esophagogastroduodenoscopy in pediatric patients receiving standard intravenous conscious sedation with the benzodiazepine diazepam in combination with meperidine. METHODS: Upper endoscopy was performed using intravenous conscious sedation with standardized doses of diazepam and meperidine on 29 children, age range 6-18 yr. Patients were randomized in a double-blind fashion to receive either intravenous normal saline (placebo) or 0.01 mg/kg (maximum, 1.0 mg) flumazenil within 5 min of procedure completion. Evaluation of the degree of sedation using a modified Observer' s Assessment of Alertness/Sedation Scale was performed presedation, immediately before reversal solution administration, and serially over 60 min after reversal solution injection. RESULTS: Fifteen patients received flumazenil and 14 received placebo; patient group composition did not vary significantly in age and weight. Fifty-four percent of flumazenil patients and 30% of control patients achieved full alertness within 10 min of reversal solution injection. However, this difference between groups was not significant (p > 0.45). Resedation or side effects directly attributable to flumazenil were not observed. CONCLUSIONS: A single postsedation dose of flumazenil is well-tolerated in children >6 yr old. However, its routine use after esophagogastroduodenoscopy is of questionable benefit in shortening recovery time in this age group.

Investigation of terbinafine as a CYP2D6 inhibitor in vivo.

BACKGROUND: Terbinafine is an orally active antifungal used in the treatment of dermatophytoses. To date, studies evaluating the effect of terbinafine on the cytochromes P450 have failed to show any significant interactions. This prospective open-label study was designed to confirm our previous finding that terbinafine may inhibit CYP2D6. METHODS: Nine healthy volunteers were enrolled in this study-6 genotypically consistent with an extensive metabolizer phenotype and 3 genotypic poor metabolizers for CYP2D6. The change in CYP2D6 enzyme activity before (x 3) and after (monthly x 6 months) administration of terbinafine (250 mg once daily x 14 days) was evaluated with the dextromethorphan to dextrorphan urinary metabolite ratios. On each study day a predose urine sample was collected, 0.3 mg/kg dextromethorphan was administered, and urine was collected for 24 hours. Dextromethorphan and its metabolites were quantified from urine by HPLC. RESULTS: Baseline phenotype values were concordant with individual genotype. In all extensive metabolizers, the administration of terbinafine resulted in a dramatic increase in the dextromethorphan/dextrorphan ratio, converting 4 of the 6 extensive metabolizers into phenotypic poor metabolizers. On average, a 97-fold increase in ratio (range, 35 to 265) was observed for extensive metabolizers after the administration of terbinafine. No significant change was observed in the metabolite ratios of poor metabolizers during the course of the study. CONCLUSIONS: Terbinafine inhibits CYP2D6 sufficiently to produce a discordance between genotype and phenotype for the enzyme. The dextromethorphan/dextrorphan metabolite ratios increased in all individuals, with otherwise functional CYP2D6 activity. The disposition of CYP2D6 substrates coadministered with terbinafine may be significantly altered in extensive metabolizers for this cytochrome P450 isoform, who comprise approximately 93% of the population.

Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children.

OBJECTIVE: To compare the pharmacokinetics and metabolism of R(+)- and S(-)- ketorolac in children. METHODS: Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S(-)- and R(+)-ketorolac were measured in plasma; S(-)- and R(+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient. RESULTS: Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S(-) enantiomer was 4 times that of the R(+) enantiomer. Terminal half-life of S(-)-ketorolac was 40% that of the R(+) enantiomer, and the apparent volume of distribution of the S(-) enantiomer was greater than that of the R(+) form. Recovery of S(-)-ketorolac glucuronide was 2.3 times that of the R(+) enantiomer. CONCLUSION: The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S(-)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S(-) enantiomer suggests that stereoselective metabolism may also be a contributing factor.

A randomized comparison of ketorolac tromethamine and morphine for postoperative analgesia in critically ill children.

OBJECTIVES: To evaluate the efficacy of a single dose of ketorolac compared with morphine for the relief of pain in children, and to determine the safety of ketorolac. SETTING: Tertiary pediatric intensive care unit in a university-affiliated hospital. DESIGN: Prospective, randomized, double-blind, parallel, single-dose, positive control study. PATIENTS: Children admitted to the intensive care unit with postoperative pain. INTERVENTIONS: Patients received a single dose of either morphine or ketorolac as the first postoperative analgesic when the pain score indicated significant pain. Blood pressure, heart rate, and urine output were recorded, as well as blood urea nitrogen, creatinine, bleeding time, hematuria or proteinuria, and aspartate aminotransferase. Side effects such as nausea and vomiting were noted. Morphine was used for rescue treatment if the patient continued to have significant pain > or =30 mins after study drug administration. MEASUREMENTS AND MAIN RESULTS: Of the 102 children studied, 48 received morphine and 54 received ketorolac. The percentage of patients reporting pain relief in the first and second hours after drug administration was not different between groups. Likewise, the proportion of patients who met the criteria for pain relief during the entire evaluation period was not different between groups. There was a trend toward fewer patients who received ketorolac requiring remedication in the first 4 hrs compared with those who received morphine, but this trend did not reach statistical significance. More patients in the morphine group failed to achieve pain relief at any time after the dose compared with those who received ketorolac. There were no differences between the two groups in physiologic or laboratory variables. Vomiting was more common in patients who received ketorolac. CONCLUSION: Ketorolac is comparable to morphine in relief of postoperative pain in children. A single dose of ketorolac does not result in abnormal postoperative bleeding or alter renal function. However, ketorolac may cause nausea and vomiting in some patients.

A community outreach lead screening program using capillary blood collected on filter paper.

OBJECTIVE: To test whether a method of fingerstick blood sample collection onto filter paper could be used as an alternative screening method in the field in settings where environmental lead contamination is a high risk. METHOD: Members of the Pediatric Mobile Team of Children's Hospital of Michigan, Detroit, collected paired venous and capillary blood samples from 120 children, aged 6 months to 6 years, who presented for services at any of 7 sites located in decaying neighborhoods of older sections of Detroit. All samples were analyzed for lead content by graphite furnace atomic absorption spectrometry. RESULTS: When filter paper samples with blood lead levels of 0.48 micromol/L (10 microg/dL) or higher were compared with matched venous samples, the concordance coefficient was 0.96. The sensitivity and specificity of the filter paper samples relative to the venous samples for a cutoff of 0.48 micromol/L (10 microg/dL) or higher were 94% and 99%, respectively, with a positive predictive value of 97%. However, at a cutoff of 0.72 micromol/L (15 microg/dL), the sensitivity and specificity dropped to 75% and 98%, respectively, with filter paper samples underreporting blood lead values. At any cutoff point (0.48, 0.72, or 0.96 micromol/L [10, 15, or 20 microg/dL]), the filter paper method was highly specific for lead. CONCLUSIONS: Capillary filter paper sampling is an accurate and practical alternative to venous sampling for blood lead screening using 0.48 micromol/L (10 microg/dL) as the cutoff. The filter paper method predicts levels of 0.72 micromol/L (15 microg/dL) or higher less well. The cause of divergent values above 0.72 micromol/L (15 microg/dL) is not clear. Environmental contamination of capillary filter paper, however, does not seem to be an explanation.

A new filter paper method to measure capillary blood lead level in children.

OBJECTIVE: To develop and evaluate a new filter paper method to determine capillary blood lead levels accurately in children. DESIGN: Paired comparison of lead levels determined in capillary whole blood dried on filter paper with lead levels in venous whole blood samples determined by a reference method. SETTING: Children's Hospital of Michigan clinics, Detroit. PATIENTS: One hundred children aged 9 months to 6 years. INTERVENTIONS: Lead concentrations determined in capillary whole blood samples dried on filter paper were compared with concentrations measured in paired venous whole blood samples by a reference method. MAIN OUTCOME MEASURES: Comparability of the two lead assay methods was assessed with the concordance coefficient. The sensitivity, specificity, and positive predictivity of the capillary filter paper method relative to the reference method were determined at three intervention decision concentrations of blood lead defined by the Centers for Disease Control and Prevention. RESULTS: There was high agreement between the two assay methods, with a concordance coefficient of O.96. The capillary filter paper assay had a sensitivity of 90% and specificity of 90% for differentiating blood lead levels of 0.48 mumol/L (10 micrograms/dL) or more. Blood lead levels of 0.72 mumol/L (15 micrograms/dL) or more and 0.96 mumol/L (20 micrograms/dL) or more were identified with 98% and 94% sensitivity and 98% and 99% specificity, respectively. Positive predictivity was 93%, 98%, and 97%, respectively, at the three blood lead concentration decision points. CONCLUSION: The capillary filter paper method for blood lead analysis described herein provides a convenient, sensitive, accurate, and inexpensive method to examine children for elevated blood lead levels.

Pharmacokinetics of erythropoietin following single-dose subcutaneous administration in preterm infants.

The pharmacokinetics of recombinant human erythropoietin was studied in 12 very low birth weight preterm infants < 32 weeks of gestation after subcutaneous administration of 300 IU/kg at a postconceptional age of 34 (32-37) weeks and a weight of 1,505 (1330-1,740)g (median and range). The administration of recombinant human erythropoietin produced a rapid increase in serum erythropoietin levels with a peak level of 362.8 mIU/ml at 8.9 h. The area under the curve was 8,177.5 (4,597.1-15,453.0) mIU/ml/h, the absorption half-life was 5.5 (1.6-6.6) h, the elimination half-life was 7.9 (5.6-19.4) h, and the residence time was 19.6 (5.1-32.6) h (all values reflect median and range). There was no significant correlation between absorption and elimination half-life of erythropoietin and birth weight, gestational age, sex, and age and weight of the infants at the time of administration of erythropoietin. Based on absorption and elimination kinetics, the dosing interval for subcutaneous administration must not be < 48 h.

Occult cocaine and opiate exposure in children and associated physical findings.

We determined the prevalence of cocaine and opiate exposure and the association of exposure with objective physical findings in children presenting to an urban pediatric emergency department. The study included 942 children between one and 60 months of age who required urinalysis for investigation of their chief complaint. Anonymously and without informed consent, urine was screened for benzoylecgonine (BE) and opiates, using an enzyme multiplied immunoassay technique (EMIT) with sensitivity of 50 ng/ml. EMIT-positive samples were rescreened using a fluorescence polarization immunoassay (FPIA). Specimens positive by both EMIT and FPIA were confirmed by gas chromatography/mass spectrometry (GC/MS) if sufficient quantity of urine was available. BE was identified in 41 (4.4%) and opiates in 46 (4.9%) patients by both EMIT and FPIA. The presence of BE or opiate was confirmed by GC/MS in all 34 cases where sufficient urine was available. The age- and sex-adjusted systolic and diastolic blood pressure percentiles were greater, and head circumference and weight percentiles were lower in BE-positive patients compared to those with negative drug screens. There were no associations between opiate exposure and any of these variables. We conclude that occult postnatal cocaine exposure is associated with measurable physical and physiologic differences.

Status of drug approval processes and regulation of medications for children.

The term therapeutic orphan was coined in 1968 to describe the exclusion of infants and children from approved indications for use of the majority of drugs approved by the US Food and Drug Administration (FDA). Although the 1962 Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act were designed to insure the efficacy and safety of drugs approved for human use, infants and children have largely been excluded from the protection of the law. Approximately 80% of the drugs approved by the FDA during the past 30 years have been approved with a labeling disclaimer for use by children. This high percentage is due largely to the lack of studies in children to document safety and efficacy or a failure to use available data to amend labeling to include pediatric indications. Recently, several initiatives by the FDA and the National Institute of Child Health and Human Development have been implemented that promise to increase the number of drugs studied and labeled for children. These initiatives may introduce a new era of drug development for children in which pediatric investigators, the FDA, the National Institutes of Health, and the pharmaceutical industry join together to bring the same level of pharmacotherapeutic safety and efficacy to children that adult patients enjoy.

Drug trials in children: ethical, legal, and practical issues.

Technical limitations, logistic challenges, and ethical constraints no longer provide excuses for not conducting well-designed studies of therapeutic agents in children. In fact, to not do so is difficult to defend ethically. Clinical trials in children are feasible and essential for safe and effective use of medications in children. The time is long past when drugs with therapeutic potential in children should be marketed with labeling for use only in adults.

Comparison of simultaneous esophageal pH monitoring and scintigraphy in infants with gastroesophageal reflux.

Twenty-nine infants under 1 yr of age were studied by simultaneous esophageal pH monitoring and scintigraphy for evaluation of gastroesophageal reflux (GER). Scintigraphy and pH monitoring were performed for 120 min after infants ingested their usual volume of formula. The number of reflux episodes during six 20-min intervals, as determined by both tests, were recorded. Esophageal pH monitoring was continued for 18-24 h. Sixteen of 29 patients exhibited GER by pH monitoring during the 2-h study. Gastroesophageal reflux occurred in seven of 29 during the first hour and 13 of 29 during the second hour. The mean time of first reflux episode detected by pH monitoring following the feeding was 82.4 +/- 49.3 min. In comparison, 28 of 29 patients had GER by scintigraphy during the 2 h. All 28 exhibited GER during the first hour, whereas only 22 of 29 patients exhibited GER during the second hour. The mean time of first episode of reflux by scintigraphy was 3.1 +/- 2.7 min. Forty-five percent of all reflux episodes detected by scintigraphy occurred during the first 20 min and 80% were detected during the first hour. In contrast, only 17% of reflux episodes were seen by pH monitoring during the first 20 min and 35% during the first hour; 65% of reflux episodes detected by pH monitoring were during the second hour. There was no correlation between the total number of reflux episodes detected by scintigraphy and 2-h esophageal pH monitoring during the 2-h study period (r = 0.326; p > 0.1). Overall, to detect reflux, scintigraphy was a more sensitive method than esophageal pH monitoring under the conditions of this study. Scintigraphy selectively detected reflux during the first 60 min post-prandially whereas pH monitoring was more likely to detect reflux beyond the first postprandial hour. These observations help to explain the lack of correlation between the two tests.