Ralph E. Kauffman

Single-Dose Pharmacokinetics of Intravenous Itraconazole and Hydroxypropyl-β-Cyclodextrin in Infants, Children, and Adolescents

ABSTRACT This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-β-cyclodextrin (HP-β-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-β-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (Cmax) for itraconazole, hydroxyitraconazole, and HP-β-CD averaged 1,015 ± 692 ng/ml, 293 ± 133 ng/ml, and 329 ± 200 μg/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-β-CD averaged 4,922 ± 6,784 ng·h/ml, 3,811 ± 2,794 ng·h/ml, and 641.5 ± 265.0 μg·h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 ± 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r2 = 0.18, P = 0.02), Cmax (r2 = 0.14, P = 0.045), and terminal elimination rate (r2 = 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.

A study of adverse reaction algorithms in a drug surveillance program

To improve agreement among observers, several investigators have recently proposed methods (algorithms) to standardize assessments of causality for presumed adverse drug reactions. We evaluated one such method in the context of an intensive pediatric drug surveillance program. Four observers rated 50 randomly selected case reports drawn from the program, first using only general guidelines and then, several months later, using the strict criteria of the algorithm. Agreement among observers was poor in both study phases. The presence of selected characteristics of adverse events (e.g., major severity) did not improve agreement in either phase of the study. We conclude that routine use of such algorithms in drug surveillance programs is not likely to be of benefit.

The Creating Hope Act: what is old is new again

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Pediatric Health, Medicine and Therapeutics 2014:5 49–57 Pediatric Health, Medicine and Therapeutics Dovepress

340 BIOAVAILABILITY OF ORAL CHLORAMPHENICOL PALMITATE COMPARED TO INTRAVENOUS CHLORAMPHENICOL SUCCINATE

The relative bioavailability of intravenous (I.V.) chloramphenicol succinate (CAP-S) and oral chloramphenicol palmitate (CAP-P) was compared in 14 children ages 2 months to 8 years. Chloramphenicol and CAP-S were measured in serum and urine by HPLC. The area under the serum concentration vs time curve (AUC) of chloramphenicol and urinary excretion of CAP-S were determined in each child under steady-state conditions while receiving CAP-S and again while receiving CAP-P. In 12 of the 14 children AUC was greater during oral CAP-P therapy, in 1 patient AUC was unchanged, and in 1 patient AUC was slightly decreased during oral compared to I.V. therapy. The mean AUC was significantly greater during oral therapy compared to I.V. therapy (116.3±6.8 mg.hrs/L vs 77.7±9.1 mg.hrs/L, p<.005). The relative bioavailability of I.V. CAP-S was 67% compared to oral CAP-P. This was explained by a loss of 39% of the I.V. dose in the urine as unhydrolyzed CAP-S. The dose of I.V. CAP-S did not correlate with AUC (r=.247). However, there was a significant correlation between dose of oral CAP-P and AUC (r=.733, p<.005). The bioavailability of oral CAP-P is superior to I.V. CAP-S. Furthermore, there is a greater correlation between dose and amount of active drug in the body when the oral preparation is used. Oral CAP-P appears to offer significant therapeutic advantages in patients who can tolerate oral medication.

Access to information at the point of service. Effect on patient care and resource consumption in hospitals. 1777

Access to information at the point of service. Effect on patient care and resource consumption in hospitals. 1777

KETOROLAC PHARMACOKINETICS AND METABOLISM IN CHILDREN. |[bull]| 433

Pharmacokinetics (PK) and metabolism of ketorolac (KT) were studied in 50 children ages 3-18 yrs (median 11.6 yrs) following a single IV 0.6 mg/kg infusion of KT over 10 min for postoperative pain. Serial plasma samples were collected at 10, 15, 30, 60, 120, 180, 240, 300, 360, 480, and 720 minutes and urine was collected for 24 hours following KT infusion. Urine was kept at 3 degrees C during collection and stored frozen to minimize spontaneous hydrolysis of KT-glucuronide. Racemic KT was measured in plasma; KT, KT-OH, and KT-glucuronide were measured in urine. Mean ± SEM PK values were: Cmax=4.698±232 ng/ml; dist t1/2=29±3 min; elim t1/2=243±19 min; Vd=0.35±0.03 L/kg; Cl=1.1±0.07 ml/min/kg. Plasma kinetics of KT were best described in most patients by a model incorporating zero order infusion and biexponential decay. There was no correlation between age and Vd, elim t1/2, or Cl. A median of 40.6% (range 14.5-92.8%) of the dose was recovered in the urine: 22.8% (7.3-44%) as parent drug; 9.3% (0.8-54.6%) as KT-OH; and 8.7% (1.8-33.2%) as KT-glucuronide. A comparison of our data with KT kinetics reported in adults is shown in thetable.

KETOROLAC (+)R AND (-)S STEREOISOMER PHARMACOKINETICS FOLLOWING IV ADMINISTRATION OF RS KETOROLAC TO CHILDREN. • 432

Ketorolac (KT) is administered as a racemic mixture although cyclooxygenase inhibitory activity resides with the (-S) stereoisomer. Little is known about KT stereo-specific pharmacokinetics. We studied plasma pharmacokinetics of(+R) and (-S) KT in 8 children (median age 11.8 yrs) following a 0.6 mg/kg IV dose of racemic KT. Twelve timed plasma samples were collected over 720 minutes after the dose. (+R)-KT and (-S)-KT were measured by HPLC using a CHIRACEL OJ-R column. Kinetic values were estimated from non-linear iterative fit of the the plasma concentrations to a bi-exponential or tri-exponential equation with 10 minutes infusion function. Significant differences were observed between the two enantiomers: Cmax was higher, AUC greater, t1/2elim longer, and Cl less for (+R)-KT. There was no difference between the enatiomers in Vd or t1/2dist. Table

Ketorolac for the Treatment of Severe Pain in Critically-Ill Children. |[bull]| 286

Ketorolac (KT) is a parenteral nonsteroidal anti-inflammatory analgesic used for the treatment of moderate to severe pain. We studied the efficacy and safety of intravenous (IV) KT, compared to IV morphine (MS) in critically-ill children.

1083 DIFFUSION OF MOXALACTAM INTO CSF OF CHILDREN WITH BACTERIAL MENINGITIS

Moxalactam (MOX), a new oxa-β-lactam antibiotic,is active against an expanded spectrum of gram negative organisms including Haemophilus influenzae. It has also been reported to diffuse into cerebrospinal fluid. We administered IV MOX to children (6 wks-4½ yrs) receiving conventional antimicrobial therapy for bacterial meningitis. Plasma and CSF specimens were collected 2 to 3 hours after a dose and assayed for MOX concentration by HPLC (capable of detecting 1 μg/ml of MOX). Eight patients received single doses of 15 or 25 mg/kg. In 11 determinations the plasma levels ranged between 4.7 and 29.4 μg/ml but MOX was detected in the CSF in only one instance. Eight patients received 50 mg/kg of MOX every 8 hours for 3 doses, and in 5 patients the drug diffused into CSF. MOX was detectable in 3/5 of CSF specimens early in the course of illness (2nd or 3rd day) and averaged 20% (range 2.5 to 30%) of plasma concentration. It was detectable in 5/11 of CSF specimens obtained later in the illness (13th to 22nd day) and averaged 15.7% (6 to 36%) of plasma concentration. There was no correlation between the diffusion of MOX into CSF and the CSF white cell count, however MOX diffused to a greater extent in patients with higher CSF protein content. In summary, MOX diffuses into CSF but such diffusion is unpredictable. Caution must be exercised in using MOX alone in the treatment of meningitis.