Kinetics of primidone metabolism and excretion in children.

The metabolism and excretion of orally administered primidone was studied in 12 children, aged 7 to 14 yr during long-term dosing. Plasma concentrations of primidone (Pr) peaked at 4 to 6 hr and declined exponentially from 6 to 24 hr, with half-life (t1/2) values ranging from 4.5 to 11 hr. A mean of 92% (72% to 123%) of the administered dose was recovered within 24 hr from the urine as Pr and its metabolites. Of the total Pr daily dose, 42.3% (15.2% to 65.9%) was recovered as unchanged drug, 45.2% (16.3% to 65.3%) as phenylethylmalonamide (PEMA), and 4.9% (1.1% to 8.0%) as phenobarbital (Pb). The mean rate constant for conversion of Pr to PEMA (K1) was 0.0424 hr-1, for conversion of Pr to Pb (K2) was 0.0045 hr-1, and for excretion of unchanged Pr (K3) was 0.0389 hr-1. Of Pb excreted, 43% (13% to 100%) was unchanged, 15% (0% to 27%) was unconjugated p-OH Pb, 20% (0% to 44%) was conjugated p-OH Pb, and 22% (0% to 33%) was conjugated 3,4-OH Pb. KE appears to be important determinant of the steady-state plasma concentration of Pb, but interindividual differences in K2 have little influence on the overall rate constant for elimination of Pr.

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.

Adverse drug reactions in children leading to hospital admission.

To provide information regarding pediatric hospital admissions prompted by adverse drug reactions, data were reviewed from an intensive drug surveillance program in which 10,297 patients admitted to diverse pediatric wards at four teaching and three community hospitals were systematically monitored. Among 3,026 neonatal intensive care unit admissions, 0.2% were prompted by adverse drug reactions; among 725 children with cancer, 22% of admissions were prompted by adverse drug reactions. Among 6,546 children with other conditions monitored on general medical and specialty wards at two teaching hospitals and on general pediatric wards at three community hospitals, 2% (131) of admissions were prompted by adverse drug reactions. Two patients (0.03%) died because of their reactions. The proportion of admissions prompted by drug reactions increased between infancy and 5 years of age and tended to be relatively stable thereafter. The drugs most commonly implicated in the admissions were phenobarbital, aspirin, phenytoin, ampicillin/amoxicillin, theophylline/aminophylline, trimethoprim-sulfamethoxazole, and diphtheria-pertussis-tetanus vaccine. Similar proportions of admissions were prompted by adverse drug reactions in teaching hospitals (2.1%) and in community hospitals (1.8%), and the drug groups implicated in these admissions were generally similar in the two settings. In contrast to adult populations, children with adverse drug reactions account for a small proportion of hospital admissions. Findings from this large, systematic study of pediatric admissions to teaching and community hospitals may serve as a baseline to which other pediatric facilities can compare their experience.

Pharmacokinetic studies in paediatric patients. Clinical and ethical considerations.

Important advances in paediatric clinical pharmacology have been made over the past 2 decades. However, there remains a reluctance to pursue pharmacodynamic and pharmacokinetic studies in children and, consequently, many important therapeutic agents have not been adequately studied in this population. Age-related pharmacokinetic/pharmacodynamic studies are not only essential to provide optimal drug therapy for children, but are quite feasible. Usually, paediatric pharmacokinetic studies are conducted in children receiving treatment for a specific medical condition. The approach to soliciting participation of paediatric subjects requires special sensitivity to the fears and anxieties of the child and the parents. Factors influencing subject enrollment and suggestions to enhance enrollment into study protocols are discussed. Pharmacokinetic/pharmacodynamic studies require repeated measurements over time and often entail obtaining multiple blood and urine samples. Techniques for reducing sample volume and number of necessary samples while minimising the discomfort and fear associated with obtaining multiple samples include the development of highly sensitive analytical methods to measure drug concentrations in small volume samples. The number of samples obtained from individual subjects can be minimised by using pharmacokinetic analytical approaches such as the nonlinear mixed effect model (NONMEM) which allows estimation of pharmacokinetic characteristics of a population using limited data from each subject. In addition, less invasive methods to measure drug metabolism/elimination such as salivary sampling, transcutaneous collection and breath analysis have been applied to the study of certain drugs. Children are a particularly vulnerable population because of their limited cognitive abilities and dependence on adults. Thus, they must be afforded greater protection from exploitation as research subjects than that provided to adults.

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.

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.

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.

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.

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.

Therapeutic challenges. Prenatal and paediatric safety considerations.

Developmental changes make the fetus and child uniquely susceptible to drug toxicities which do not occur in mature individuals. Passive exposure to maternally administered drugs during fetal life introduces the potential risk of morphological or behavioural teratogenesis. Although animal studies are useful in identifying potential teratogens, they are poor predictors of human teratogenesis. Most drugs are excreted into breast milk in insufficient quantity to cause adverse effects in the nursing infant. However, there are several exceptions. Therefore, it is important to document the extent to which a drug appears in breast milk and is absorbed by the nursing infant prior to its use by the mother. Plasticity of growing tissues and changes in body composition, the rate of drug metabolism, drug metabolic pathways and elimination rates during growth and development may alter susceptibility to unique drug toxicities. This requires that drug safety and efficacy be established in children at different ages. Ethical and technical constraints inherent in drug studies in children introduce increased effort and cost. However, there is a moral imperative for academicians, government agencies and the pharmaceutical industry to work together to ensure that drugs intended for use in children are adequately tested in children.

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.

Effective and efficient use of drug level measurements to guide medication dosing.

Proper administration of dose (particularly in the case of IV medications), proper timing of samples, knowledge of pharmacokinetics of the drug, and knowledge of the patient's condition, are as important to clinical application of drug levels as is accurate laboratory analysis, and are frequently the difference between a drug level being clinically useful or irrelevant.