Bioavailability testing of a newly developed clindamycin oral suspension in a pediatric porcine model.

Background: Clindamycin's bitter taste and odor is known to affect treatment adherence in children. Recently, a formulation of clindamycin HCl complexed with ion exchange resin IRP 69 was shown to mask the bitter taste. Because of the potential benefit of this formulation for children, a pilot study using a porcine model was conducted to evaluate its relative bioavailability. Methods: A randomized two-way crossover study design using six (n = 6) healthy male piglets 10-12 kg was used to evaluate the absorption profiles and pharmacokinetic parameters of clindamycin from the resinate complex formulation (Test) compared to a commercialized reference suspension. A dose of 15 mg/kg was administered orally by gastric gavage to each piglet followed by repeated blood sampling over 12 h. A wash-out period of 48 h occurred between treatments. Plasma concentration vs. time data was analyzed by non-compartmental analysis. Results: The mean relative bioavailability of clindamycin from the resinate formulation was 78.8%. A two-tailed, paired Student t test yielded a p < 0.05 for AUC∞ and Tmax parameters. A two one-sided test (TOST) suggested a difference in AUC∞ and Cmax for the Test formulation compared to the reference formulation according to the FDA's criteria for bioequivalence. Conclusion: The bioavailability of clindamycin from this novel oral formulation supports continued evaluation of the drug in humans for potential pediatric applications.

Blood Viral Load in Symptomatic Congenital Cytomegalovirus Infection.

BACKGROUND: Viral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear. METHODS: Post hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy. RESULTS: Higher baseline VL was associated with central nervous system involvement (3.82 log, range 1-5.65 vs 3.32 log, range 1-5.36; P = .001), thrombocytopenia (3.68 log, range 1-5.65 vs 3.43 log, range 1-5.36; P = .03), and transaminitis at presentation (3.73 log, range 1-5.60 vs 3.39 log, range 1-5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing. CONCLUSIONS: In infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes.

An Adaptable Pediatrics Faculty Mentoring Model.

An effective faculty mentoring program (FMP) is 1 approach that academic departments can use to promote professional fulfillment, faculty retention, and mitigate the risks of faculty burnout. Mentoring has both direct benefits for junior faculty mentees as they navigate the academic promotion process with their mentors, in addition to broader departmental and institutional benefits, with regard to recruitment, retention, and academic productivity. We describe a successful FMP model that has been adapted for use in 6 other pediatrics departments, summarizing the key personnel, mentoring process, and program evaluation methods. Important lessons learned and a generalizable mentoring "model" are provided. Program evaluation indicates a positive effect for the FMP on enhanced faculty self-efficacy, job satisfaction, and career development. The importance of communication, oversight, feedback, accountability, and valuing all faculty members is emphasized. Strategies to promote faculty engagement and the critical role of departmental leadership in prioritizing mentorship are discussed. The success of academic medical departments is inextricably linked to its commitment to the career development of individual faculty members at all levels and in all academic pathways. With our findings, we support the positive impact of a formal FMP in promoting enhanced self-efficacy and career satisfaction, which directly benefits the department and institution through enhanced productivity, retention, successful promotion, and overall professional fulfillment.

Variation in Tularemia Clinical Manifestations-Arkansas, 2009-2013.

BACKGROUND: Francisella tularensis, although naturally occurring in Arkansas, is also a Tier 1 select agent and potential bioterrorism threat. As such, tularemia is nationally notifiable and mandatorily reported to the Arkansas Department of Health. We examined demographic and clinical characteristics among reported cases and outcomes to improve understanding of the epidemiology of tularemia in Arkansas. METHODS: Surveillance records on all tularemia cases investigated during 2009-2013 were reviewed. RESULTS: The analytic dataset was assembled from 284 tularemia reports, yielding 138 probable and confirmed tularemia cases during 2009-2013. Arthropod bite was identified in 77% of cases. Of 7 recognized tularemia manifestations, the typhoidal form was reported in 47% of cases, approximately double the proportion of the more classic manifestation, lymphadenopathy. Overall, 41% of patients were hospitalized; 3% died. The typhoidal form appeared to be more severe, accounting for the majority of sepsis and meningitis cases, hospitalizations, and deaths. Among patients with available antibiotic data, 88% received doxycycline and 12% received gentamicin. CONCLUSIONS: Contrary to expectation, lymphadenopathy was not the most common manifestation observed in our registry. Instead, our patients were more likely to report only generalized typhoidal symptoms. Using lymphadenopathy as a primary symptom to initiate tularemia testing may be an insensitive diagnostic strategy and result in unrecognized cases. In endemic areas such as Arkansas, suspicion of tularemia should be high, especially during tick season. Outreach to clinicians describing the full range of presenting symptoms may help address misperceptions about tularemia.

Association of Medical School Pediatric Department Chairs Principles of Lifelong Learning in Pediatric Medicine.

Pediatric general and subspecialty care requires continuous effort to maintain knowledge and competencies in clinical practice. Equally important are efforts by investigators and educators to maintain knowledge and competencies in the conduct of research and training. The Association of Medical School Pediatric Department Chairs initiated a survey in July 2015 to define principles of lifelong learning in pediatric medicine and determine the approaches and strategies used by chairs to assess knowledge and competence across the care, research, and teaching missions. A total of 101 of 142 chairs (71%) completed the survey. Six of 7 proposed principles were endorsed by 84% to 96% of Association of Medical School Pediatric Department Chairs members. The focus areas included individual accountability, individually relevant activities, use of evidence-based guidelines/national standards, gaining cognitive expertise, learning as a continuous effort, affordability, and focus on individual understanding. The chairs endorsed a requirement for evidence of lifelong learning, competence, and compliance by all faculty members in clinical (n = 89 [88%]), research (n = 63 [62%]), and educational (n = 85 [84%]) practice. The survey identified the strategies to assess lifelong learning and faculty competence and compliance in clinical, research, and educational roles. Across missions, chairs endorsed an expectation for individual responsibility supplemented by formal evaluation practices and institutional and regulatory office oversight. While chairs endorsed an important role for the American Board of Pediatrics in assessing and verifying lifelong learning, knowledge, and competence in general and specialty certification, most (n = 91 [90%]) endorsed a need to revise current board requirements to better emphasize closing gaps in knowledge and using approaches that are evidence-based. This study provides the perspectives of pediatric department chairs on principles for lifelong learning and strategies and approaches used to assess faculty competence and commitment to lifelong learning across missions.

A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis.

BACKGROUND: Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. METHODS: Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. RESULTS: Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. CONCLUSIONS: Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Vaccine policy and Arkansas childhood immunization exemptions: a multi-year review.

BACKGROUND: An increase in total vaccine exemptions (medical, philosophic, and religious) occurred in Arkansas after a 2003 legislation added a philosophic category and used a new process for vaccine exemptions. By legislative requirement, the Arkansas Department of Health monitored exemptions through the 2009-2010 school year. PURPOSE: The goal of the study was to determine the prevalence of vaccine exemption in 2003-2010 compared to the number of requests prior to the legislation enacted in 2003. METHODS: Exemptions were calculated by school-age category using raw numbers of exemptions, total estimates of the population by age level, enrollment numbers for students in public and private schools, and in enrolled college students born after 1957. Exemptions also were analyzed by school district, grade level, type of exemption, and particular vaccine exemption requested. RESULTS: Overall exemptions continued to rise each year, with an average increase of 23.1% annually. Medical exemptions declined from an average of 21.3% of all exemptions before to an average of 4.8% thereafter. The greatest increase in number of exemptions was observed among college students. The highest total rate of exemptions per precollegiate student population was <1.3%. When exemption requests were categorized, most (79%) were for exemptions from "all vaccines." The most common single exempted vaccine was MMR (measles, mumps, rubella). CONCLUSIONS: Since philosophic exemptions were codified in 2003 in Arkansas, the number and rate of vaccine exemptions continue to progressively increase. However, vaccine-preventable disease clusters have not yet been linked to or identified in any population with a high rate of vaccine exemptions.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Single-dose pharmacokinetics and tolerability of daptomycin 8 to 10 mg/kg in children aged 2 to 6 years with suspected or proved Gram-positive infections.

A pharmacokinetic analysis was performed for single intravenous doses of daptomycin 8 or 10 mg/kg in subjects aged 2 to 6 years. Proportional increases in maximum plasma concentration (68.4 µg/mL, 79.2 µg/mL) and area under the curve (429.1 µg · h/mL, 549.7 µg · h/mL) were observed for each dose cohort, respectively. Half-life, clearance, and distribution volume were similar between groups. Both doses were well tolerated.

Pharmacokinetics and tolerability of single-dose intravenous ertapenem in infants, children, and adolescents.

BACKGROUND: Ertapenem is a carbapenem antibiotic with broad spectrum activity and a pharmacokinetic profile that favors once-daily administration in adults. OBJECTIVES: This investigation was designed to evaluate the dose-exposure profile of ertapenem in children from infancy through adolescence. METHODS: Eighty-four children (3 months-16 years) requiring antibiotic therapy were enrolled in this multicenter trial. Children received a single intravenous dose of ertapenem at 15, 20, or 40 mg/kg followed by repeated blood sampling for 24 hours. Free and total plasma ertapenem concentrations were quantitated by high-performance liquid chromatography, and the pharmacokinetics were determined using a model-independent approach. RESULTS: Ertapenem exposure increased proportionally with increasing dose; however, achievable concentrations were influenced by age. Children older than 12 years attained higher dose-normalized concentrations at the end of the infusion (concentration at the end of the infusion [Ceoi]: 8.7 ± 1.9 mg/L per mg/kg dose) and total body exposure (area under the curve area under the plasma concentration-time curve [AUC]0-∞: 34.7 ± 14.7 mg hr/L per mg/kg dose) as compared with children 2 to 12 years (Ceoi: 6.9 ± 2.4 mg/L per mg/kg dose, AUC0-∞: 18.4 ± 8.0 mg hr/L per mg/kg dose) and children younger than 2 years (Ceoi: 6.1 ± 2.2 mg/L per mg/kg dose, AUC0-∞: 17.0 ± 5.4 mg hr/L per mg/kg dose). These findings were accounted for by age-dependent changes in ertapenem clearance and distribution volume. In 3 children adverse events (nausea, n = 2; injection site reaction, n = 1) were considered related to study drug administration. CONCLUSIONS: Children younger than 12 years require dosing more frequently than once daily to achieve optimal efficacy when treating organisms with a minimum inhibitory concentration near the susceptibility breakpoint.

Safety of oseltamivir compared with the adamantanes in children less than 12 months of age.

BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.

Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month through 11 years of age.

BACKGROUND: Valacyclovir provides enhanced acyclovir bioavailability in adults, but limited data are available in children. METHODS: Children 1 month through 5 years of age with or at risk for herpesvirus infection received a single 25 mg/kg dose of extemporaneously compounded valacyclovir oral suspension (n = 57), whereas children 1 through 11 years of age received 10 mg/kg valacyclovir oral suspension twice daily for 3-5 days (herpes simplex virus infection) (n = 28) or 20 mg/kg 3 times daily for 5 days (varicella-zoster virus infection) (n = 27). Blood samples for pharmacokinetic analysis were collected during the 6 h after the first dose. Safety was monitored throughout the studies. RESULTS: Dose proportionality in the maximum observed concentration (C(max)) of acyclovir and the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) existed across the 10 to 20 mg/kg valacyclovir dose range. For children 2 through 5 years of age, an increase in dose from 20 to 25 mg/kg resulted in near doubling of the C(max) and AUC(0-infinity). Among infants 1 through 2 months of age receiving 25 mg/kg, the mean AUC(0-infinity) and C(max) were higher ( approximately 60% and 30%, respectively) than those among older infants and children receiving the same dose. Valacyclovir oral suspension was well tolerated. No clinically significant trends were noted in clinical chemical, hematologic, or urinalysis values from screening to follow-up. CONCLUSIONS: Among children 3 months through 11 years of age, the 20 mg/kg dose of this formulation of valacyclovir oral suspension produces favorable acyclovir blood concentrations and is well tolerated. A dosing recommendation cannot be made for infants <3 months of age because of decreased clearance in this age group. Trial registration. ClinicalTrials.gov identifier: NCT00297206 .

Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system.

BACKGROUND: Ganciclovir protects against hearing deterioration in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system (CNS). OBJECTIVES: To assess the neurodevelopmental impact of ganciclovir therapy in this population. STUDY DESIGN: 100 neonates were enrolled into a controlled Phase III study of symptomatic congenital CMV involving the CNS, and were randomized to either 6 weeks of intravenous ganciclovir or no treatment. Denver developmental tests were performed at 6 weeks, 6 months, and 12 months. For each age, developmental milestones that > or =90% of normal children would be expected to have achieved were identified. The numbers of milestones not met ("delays") were determined for each subject. The average number of delays per subject was compared for each treatment group. RESULTS: At 6 months, the average number of delays was 4.46 and 7.51, respectively, for ganciclovir recipients and "no treatment" subjects (p=0.02). At 12 months, the average number of delays was 10.06 and 17.14, respectively (p=0.007). In a multivariate regression model, the effect of ganciclovir therapy remained statistically significant at 12 months (p=0.007). CONCLUSIONS: Infants with symptomatic congenital CMV involving the CNS receiving intravenous ganciclovir therapy have fewer developmental delays at 6 and 12 months compared with untreated infants. Based on these data as well as the previously published data regarding ganciclovir treatment and hearing outcomes, 6 weeks of intravenous ganciclovir therapy can be considered in the management of babies with symptomatic congenital CMV disease involving the CNS. If treatment is initiated, it should be started within the first month of life and patients should be monitored closely for toxicity, especially neutropenia. Since existing data only address the treatment of symptomatic congenital CMV disease involving the CNS, these data cannot be extrapolated to neonates with other manifestations of CMV disease, including asymptomatic babies and symptomatic babies who do not have CNS involvement.

Single-dose pharmacokinetics of daptomycin in children with suspected or proved gram-positive infections.

BACKGROUND: New antimicrobials such as daptomycin fill a void in the growing need for antibiotics effective against resistant Gram-positive pathogens. Although the pharmacokinetics of daptomycin have been well characterized in adults, no studies have evaluated the pharmacokinetics and tolerability in a pediatric population. METHODS: Twenty-five children (12-17 years, n = 8; 7-11 years, n = 8; 2-6 years, n = 9) were enrolled in this multicenter, open-label study. Daptomycin was administered as a single 4-mg/kg intravenous dose followed by repeated blood sampling for 24 hours. Daptomycin was quantitated from plasma using a validated high performance liquid chromatography method and pharmacokinetic variables determined using a model-dependent approach. RESULTS: Daptomycin systemic exposure decreased with decreasing age, reflecting more rapid rates of clearance in younger children. Total body exposure estimates in adolescents were approximately 1.7x those observed in children <6 years of age (374.4 versus 215.3 microg*h/L), they were comparable to those observed in adult historic controls. Estimates of apparent elimination half-life averaged 6.7 hours in adolescents, 5.6 hours in children 7-11 years of age, and 5.3 hours in children <6 years of age. One child had an adverse event (infusion site reaction) considered to be related to study drug. CONCLUSIONS: Systemic drug exposure after a single weight-adjusted daptomycin dose is reduced in younger children compared with adolescents and adults consequent to an apparent age-associated change in total plasma clearance.

Pharmacokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease.

BACKGROUND: Intravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system. METHODS: Twenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration of valganciclovir oral solution and of intravenous ganciclovir. RESULTS: On the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC12 (area under the concentration-time curve over a 12-h period) of 27 mg x h/L was defined. The median dose of oral valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC12 of 27.4 mg x h/L. The bioavailability of valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had > or =4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects. CONCLUSIONS: In neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganciclovir.

Single-dose pharmacokinetics of intravenous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents.

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-beta-cyclodextrin (HP-beta-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-beta-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 (C(max)) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 1,015 +/- 692 ng/ml, 293 +/- 133 ng/ml, and 329 +/- 200 mug/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 4,922 +/- 6,784 ng.h/ml, 3,811 +/- 2,794 ng.h/ml, and 641.5 +/- 265.0 mug.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 (r(2) = 0.18, P = 0.02), C(max) (r(2) = 0.14, P = 0.045), and terminal elimination rate (r(2) = 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.