The challenges of delivering pharmacogenomics into clinical pediatrics.
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Adolescent↗
Biomedical subjects
G L Kearns
Publications and source records attributed to G L Kearns.
Pharmacokinetics and metabolism of oral midazolam in preterm infants.
AIMS: To characterize the pharmacokinetics and metabolism of oral midazolam in 15 preterm infants. METHODS: After an oral dose (0.1 mg kg(-1)), blood was drawn up to 24 h after administration. Midazolam and 1-OH-midazolam concentrations were determined with GC-MS. In 8 out of these 15 patients the pharmacokinetics of intravenous midazolam was also studied. RESULTS: Apparent oral clearance, apparent volume of distribution, plasma half-life and 1-OH-Midazolam/Midazolam AUC ratio were [median (range)]: 2.7 [0.67-15.5] ml kg(-1) min(-1), 1.4 [0.3-12.1] l kg(-1), 7.6 [1.2-15.1], h and 0.03 [0.01-0.96], respectively. Absolute bioavailability was 0.49 [0.12-1.0]. CONCLUSIONS: Midazolam oral clearance is markedly decreased in preterm infants as compared with older children, probably because of immature CYP3A4 activity.
Administration, Oral↗
Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation.
Cytochrome P4502D6 (CYP2D6) activity has been shown to be a determinant of both the pharmacokinetics and pharmacodynamics of tramadol in adults. This study evaluated the association between CYP2D6 activity, as determined by dextromethorphan (DM) urinary metabolite ratio, and tramadol biotransformation in 13 children (7-16 years). CYP2D6 genotype was determined by XL-PCR and PCR/RFLP. Phenotype was assessed by HPLC quantitation of DM and its metabolites from a 12- to 24-hour urine collection following a single oral dose of DM. There was only a modest correlation between tramadol/M1 (metabolite 1) plasma concentration or AUC and the DM/dextrorphan (DX) urinary molar ratio in the study cohort; however, when subjects were segregated based on the number of functional CYP2D6 alleles, a much stronger relationship was observed for subjects with two functional alleles, with essentially no relationship evident in those individuals with one functional allele. Further evaluation of these data suggested that the CYP2D6-mediated metabolite (M1) is formed to a lesser extent, and the formation of the non-CYP2D6 product (M2) is more pronounced in subjects with one versus two functional alleles. Thus, the number of functional CYP2D6 alleles and the availability of alternative cytochromes P450 capable of metabolizing tramadol may explain the poor association between DM, a well-characterized CYP2D6 probe, and tramadol in a population of CYP2D6 extensive metabolizers.
Adolescent↗
Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents.
BACKGROUND: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.
Acetaminophen↗
Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.
BACKGROUND: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. METHODS: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. RESULTS: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (C(max)), time to reach C(max) (T(max)), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC(0-t)) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. DISCUSSION: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.
Anti-Anxiety Agents↗
The clearance and metabolism of biotin administered intravenously to pigs in tracer and physiologic amounts is much more rapid than previously appreciated.
Understanding of biotin pharmacokinetics and regulation of metabolism is essential for the determination of the biotin requirement for humans. Using Landrace-Cambrough pigs as a model, we initially demonstrated that biotin binding to protein accounts for only a small percentage of the total biotin in plasma. A physiologic amount of [14C]biotin was administered intravenously to three pigs; nine blood samples were collected over 48 h. Plasma concentrations of 14C-labeled metabolites were negligible for the first 2 h after biotin infusion. Disappearance curves of total 14C and of [14C]biotin were similar; both fit a triexponential function consistent with a three-compartment, open model. To characterize the rapid early phase of disappearance more precisely, a physiologic amount of [14C]biotin was administered intravenously to five pigs; eight blood samples were collected over the first hour and 16 total samples over 48 h. Again a triexponential function provided an excellent fit. The mean half-life values (+/- 1 SD) for the three phases were 0.11 +/- 0.07, 1.43 +/- 0.42 and 22 +/- 4 h. The [14C]biotin accumulated primarily in the liver, kidney and muscle. When administered intravenously at tracer doses to three pigs, [3H]biotin exhibited similar early pharmacokinetics; however, substantial quantities of a 3H-labeled metabolite appeared after 1 h. These studies provide evidence that egress of biotin from plasma is more rapid than previously appreciated. The slower second and third phases may represent transport into the cytosol, biotransformation into intermediates and covalent binding to intracellular proteins. Similar pharmacokinetics are likely to be seen in humans.
Animals↗
Coadministration of mefloquine and chloroqine: use of a pharmacokinetic-based approach to reduce toxicity.
A child with malaria from a chloroquine-resistant area received an accidental overdose of chloroquine administered by a parent. Application of pharmacokinetics permitted definitive treatment with mefloquine in a safe and effective manner.
Antimalarials↗
Evaluation of occult acetaminophen hepatotoxicity in hospitalized children receiving acetaminophen. Pediatric Pharmacology Research Unit Network.
The safety of repeated doses of acetaminophen in ill children with the potential of reduced glutathione stores has been questioned. This study measured hepatic transaminases in children and adolescents (n=100) who received > or = 6 therapeutic doses of acetaminophen over a 48-hour period of hospitalization. Acetaminophen-protein adducts were measured in a cohort of subjects with hepatic transaminase elevation (n=8) and in those (n=10) receiving concurrent drug therapy with agents that induce the cytochrome P450 enzymes involved in acetaminophen metabolism. Acetaminophen-protein adducts were not detected in this cohort of 18 subjects. Based on this pilot study, the routine use of acetaminophen at therapeutic doses in ill, hospitalized children and adolescents appears safe.
Acetaminophen↗
Montelukast dose selection in children ages 2 to 5 years: comparison of population pharmacokinetics between children and adults.
Montelukast, a leukotriene receptor antagonist, has demonstrated efficacy and tolerability in the treatment of asthma in patients age 6 years and older. The purpose of this open, one-period, multicenter population pharmacokinetic study was to identify a chewable tablet (CT) dose of montelukast for administration to children ages 2 to 5 years with asthma, yielding a single-dose pharmacokinetic profile (area under the plasma concentration-time curve [AUC]) comparable to that of the 10 mg film-coated tablet (FCT) dose in adults. Because patient numbers were small and the volume of blood that could be collected from individual 2- to 5-year-old patients was limited, a population pharmacokinetic approach was used to estimate population AUC (AUCpop). The 4 mg CT dose of montelukast was well tolerated and yielded an AUCpop (2721 ng.h/mL) similar to that of the adult AUCpop (2595 ng.h/mL) observed after a 10 mg FCT dose. These results support the selection of a 4 mg once-daily CT dose of montelukast for future efficacy and safety studies in children ages 2 to 5 years with asthma.
Acetates↗
Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .
Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.
Acetaminophen↗
The single-dose pharmacokinetics of midazolam and its primary metabolite in pediatric patients after oral and intravenous administration.
The first-dose pharmacokinetics of midazolam and its primary alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of alpha-hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.
Administration, Oral↗
Treatment of pain with gabapentin in a neonate.
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Acetates↗
Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus.
OBJECTIVE: Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. METHODS: Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC. RESULTS: A total of 27 premature infants were included (gestational age, 28.6 +/- 1.9 weeks; birth weight, 1250 +/- 460 g; values are mean +/- standard deviation). Ibuprofen pharmacokinetics followed a 2-compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vd(c)) (0.244 versus 0.171 L/kg; P =.03) and area under the plasma concentration-time curve (524 versus 447 mg. h/L; P =.01). The decrease in Vd(c) was most pronounced in patients with a closing ductus. Total body clearance and plasma half-life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment. CONCLUSION: Ibuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus.
Anti-Inflammatory Agents, Non-Steroidal↗
Cytochrome P450 Involvement in the biotransformation of cisapride and racemic norcisapride in vitro: differential activity of individual human CYP3A isoforms.
Identification of the human cytochrome P450 (P450) enzymes involved in the metabolism of cisapride and racemic norcisapride [(+/-)-norcisapride] was investigated at 0.1 and 1 microM, concentrations that span the mean plasma C(max) for cisapride. Formation of norcisapride (Nor), 3-fluoro-4-hydroxycisapride (3F), and 4-fluoro-2-hydroxycisapride (4F) from cisapride and an uncharacterized metabolite (UNK) from (+/-)-norcisapride in human liver microsomes (HLMs) were consistent with Michaelis-Menten kinetics for a single enzyme (K(m), 6.0, 14.3, 13.9, and 107 microM; V(max), 1350, 696, 568, and 25 pmol/mg of protein, respectively). HLMs converted cisapride to Nor at rates that were at least 3 orders of magnitude greater than those observed for (+/-)-norcisapride conversion to UNK. The sample-to-sample variation in the rates of Nor, 3F, 4F, and UNK formation correlated strongly (r(2) > 0.796) with CYP3A4/5 activity in a panel of HLMs (n = 7) and was markedly reduced by ketoconazole, a potent CYP3A inhibitor. Ketoconazole virtually eliminated (+/-)-norcisapride conversion to UNK (94 +/- 0.5%). Studies with 10 cDNA-expressed enzymes revealed that CYP3A4 catalyzed the formation of Nor and 4F at rates >100 times those of non-CYP3A enzymes and >100- and 50-fold higher than CYP3A5 and CYP3A7, respectively. CYP3A4 was the only P450 capable of UNK formation. Therefore, CYP3A4 is the principal P450 enzyme responsible for the conversion of cisapride to Nor, 3F, and 4F and of (+/-)-norcisapride to UNK. Compared with cisapride, factors related to CYP3A4-mediated (+/-)-norcisapride metabolism (e.g., ontogeny of drug-metabolizing enzymes, inhibition, and induction) should be clinically unimportant due to the apparent lack of dependence on cytochromes P450 for elimination.
Anti-Ulcer Agents↗
Pediatric acetaminophen overdose: risk factors associated with hepatocellular injury.
OBJECTIVES: To characterize demographic and clinical factors associated with pediatric acetaminophen overdose and identify risk factors for hepatocellular injury. DESIGN: Retrospective 10-year chart review. SETTING: Two regional children's hospitals. MATERIALS AND METHODS: Records of patients examined because of acetaminophen ingestion from January 1, 1988, through December 31, 1997, were reviewed. Hepatocellular injury was defined as elevation of serum aminotransferase levels greater than 2 times the reference values. Severe hepatotoxic effect was defined as hepatotoxic effect with evidence of encephalopathy and/or coagulopathy. RESULTS: Data from 322 patients (208 girls and 114 boys, aged 1-17 years) were obtained. Ingestions were intentional in 140 patients (median age, 14 years) and unintentional in 172 (median age, 2 years). Another 10 cases represented dosing errors with therapeutic intent (median age, 3.5 years). Twenty-seven patients had hepatocellular injury; of these, 4 had severe hepatotoxic effects and 1 died. Hepatocellular injury occurred in 10.0% of the dosing error group, 17.9% of the intentional group, and 0.6% of the unintentional group. No patients underwent liver transplantation. Hepatocellular injury was associated with presentation longer than 24 hours after ingestion (odds ratio [OR], 335.0; 95% confidence interval [CI], 40.8-275.0), age 10 to 17 years (OR, 36.9; 95% CI, 4.9-275.4), intentional overdose (OR, 37.2; 95% CI, 5.0-278.2), dose greater than 150 mg/kg (OR, 17.9; 95% CI, 2.3-139.2), and white race (OR, 2.8; 95% CI, 1.1-7.2). CONCLUSIONS: Intentional and unintentional acetaminophen overdoses occurred with similar frequency. Therapeutic misadventure was relatively uncommon, as was hepatocellular injury. Practitioners should have greater suspicion of acetaminophen-associated hepatocellular injury in patients who present more than 24 hours after ingestion, older children, and those who have intentional ingestion.
Acetaminophen↗
Impact of developmental pharmacology on pediatric study design: overcoming the challenges.
The need to establish drug-dosing guidelines in children highlights the challenges associated with the development of phases I and II pediatric clinical trials. These challenges are the consequence of significant developmental changes that characterize childhood and adolescence and can affect drug absorption, binding, renal elimination, and, especially, metabolism. In addition, genetic polymorphism can contribute to the variations in the expression of activity for specific drug-metabolizing enzymes. These developmental and genetic variations in pharmacokinetics are the major determinants of drug exposure over time and are thus directly related to the safety, efficacy, and toxicity of a drug dose. Therefore, in the development of pediatric protocols and appropriate dosing in children, it is essential to develop a strategy for addressing the developmental variables that affect drug exposure and to incorporate them into study design.
Adolescent↗
Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail".
BACKGROUND: Simultaneous administration of several probes enhances the utility of phenotyping, but poor specificity, side effects, and use of drugs not approved by the Food and Drug Administration limit the usefulness of prior phenotyping cocktails. OBJECTIVES: To evaluate potential drug-drug interactions associated with use of a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam for simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase. METHODS: Twelve subjects received caffeine + dextromethorphan, omeprazole, and midazolam (each alone), and a cocktail of caffeine + dextromethorphan + omeprazole + midazolam. Blood samples were collected at 120 minutes for omeprazole and 5/-hydroxyomeprazole, and at 0, 5, 30, 60, 120, 240, 300, and 360 minutes for midazolam. Twelve-hour urine samples were collected for analysis of dextromethorphan, caffeine, and metabolites. RESULTS: The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84). Likewise, the median N-acetyltransferase-2, xanthine oxidase, and CYP2D6 metabolic ratios were not significantly different after cocktail administration (P = .977 for each N-acetyltransferase-2; P = .795 for xanthine oxidase; P = .75 for CYP2D6). The median CYP2C19 metabolic ratio after cocktail administration was not significantly different from that obtained after omeprazole administered alone (P = 1.000). Also, midazolam plasma clearance was not significantly different after cocktail administration compared with that after administration of midazolam alone (P = .708). The only side effect was sedation, which was associated with intravenous midazolam and occurred to a similar extent after both individual and cocktail phenotyping. CONCLUSIONS: These results indicate no pharmacokinetic or pharmacodynamic interactions that would limit the utility of this phenotyping cocktail for simultaneous measurement of the activity of multiple drug-metabolizing enzymes.
Administration, Oral↗
The use of nuclear magnetic resonance spectroscopy in the detection of drug intoxication.
The use of nuclear magnetic resonance (NMR) spectroscopy as a method for drug analysis has the advantages of reduced pre-analytical preparation time and the potential to detect and quantitate drug conjugates and metabolites simultaneously. NMR was investigated as a method to screen for organic substances (and metabolites) in 25 patients who presented to the Emergency Department with clinical indications of a drug overdose. Urine specimens were examined by 1H NMR spectroscopy at 300 MHz and the results compared with gas chromatography-mass spectrometry (GC-MS) results. There was a 56% concordance (14 of 25 samples) between NMR and GC-MS. NMR identified acetaminophen, ibuprofen, aspirin, valproate, carbamazepine, and pseudoephedrine as parent compounds or metabolites. For a patient for whom GC-MS results were negative, NMR strongly suggested the presence of erythromycin. NMR was most successful in identifying analgesics and antiepileptic drugs (sensitivity 83-100%). In 10 patients, signals from 1,2-propanediol, a common vehicle for some pediatric medications, were observed by NMR spectroscopy. NMR had 0% sensitivity in identifying tricyclic antidepressants and antipsychotic drugs. In these samples, GC-MS detected a variety of compounds, including tricyclic antidepressants and their metabolites and chlorpromazine. In addition, other substances that had not been disclosed as having been ingested, such as caffeine, diphenhydramine, and nicotine, were detected by GC-MS. NMR spectroscopy represents an emerging supplementary analytical technique that is applicable to a wide range of possible intoxicants and to the evaluation of the intoxicated patient, particularly when larger amounts of the intoxicant (> 200 mg) are ingested.
Adolescent↗