Pharmacokinetics of Oral Vitamin D in Children with Obesity and Asthma.

BACKGROUND AND OBJECTIVE: Vitamin D insufficiency is common in several pediatric diseases including obesity and asthma. Little data exist describing the pharmacokinetics of oral vitamin D in children or the optimal dosing to achieve therapeutic 25(OH)D targets. Describe the pharmacokinetics of oral Vitamin D in children with asthma. METHODS: This was a multi-center, randomized, open-label, oral supplementation study to describe the pharmacokinetics of vitamin D in children aged 6-17 years who have asthma and were overweight/obese. Participants had a serum 25(OH)D concentration between 10 and < 30 ng/mL at baseline. In Part 1 of the study, we assessed four 16-week dosing regimens for their ability to achieve 25(OH)D concentrations ≥ 40 ng/mL. Using serial serum 25(OH)D sampling over 28 weeks, we created a population pharmacokinetic model and performed dosing simulations to achieve 25(OH)D concentrations ≥ 40 ng/mL. In Part 2, the optimal regimen chosen from Part 1 was compared (2:1) to a standard-of-care control dose (600 international units [IU] daily) over 16 weeks. A final population pharmacokinetic model using both parts was developed to perform dosing simulations and determine important co-variates in the pharmacokinetics of vitamin D. RESULTS: Based on empiric and simulation data, the daily dose of 8000 IU and a loading dose of 50,000 IU were chosen; this regimen raised 25(OH)D concentrations above 40 ng/mL in the majority of participants while avoiding concentrations > 100 ng/mL. A 50,000-IU loading dose led to faster achievement of 25(OH)D therapeutic concentrations (≥ 40 ng/mL). The estimated median (5th-95th percentiles) apparent clearance of vitamin D from the final population pharmacokinetic model was 0.181 (0.155-0.206) L/h. The body mass index z-score was a significant covariate on apparent clearance and was associated with a significantly decreased median half-life in 25(OH)D (body mass index z-score 1.00-1.99: 97.7 days, body mass index z-score 2.00-2.99: 65.9 days, body mass index z-score ≥ 3.00: 39.1 days, p < 0.001). CONCLUSIONS: Obesity impacts vitamin D clearance and the half-life, but serum concentrations > 40 ng/mL can be reached in most children using a loading dose of 50,000 IU followed by a daily dose of 8000 IU. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT03686150.

Paradoxical Antibiotic Effect of Ampicillin: Use of a Population Pharmacokinetic Model to Evaluate a Clinical Correlate of the Eagle Effect in Infants With Bacteremia.

BACKGROUND: High doses of ampicillin are often used to achieve therapeutic drug concentrations in infants. A paradoxical antibiotic effect, often called the Eagle effect, occurs when increasing concentrations of antibiotic above a threshold results in decreased efficacy. It is unknown if infants treated with ampicillin are at risk for this paradoxical effect. METHODS: We identified infants <28 days of age with Escherichia coli, Enterococcus or Streptococcus agalactiae (group B streptococcus) bloodstream infections from 1997 to 2012 and previously included in an ampicillin pharmacokinetic (PK) modeling study. We compared the odds of death for ampicillin dose, estimated time above the minimum inhibitory concentration (T > MIC) and PK parameters using separate logistic regression models. Adjusted logistic regression and Poisson models were used to calculate the odds of prolonged bacteremia ≥3 days and the duration of bacteremia, respectively, for dose, T > MIC and multiple PK parameters. RESULTS: Among 1272 infants meeting inclusion criteria, odds of death 7 or 30 days after the positive blood culture were not consistent with a paradoxical effect across any of the dosing regimens or PK parameters evaluated. The odds of prolonged bacteremia was lowest at the lowest dose category and the lowest daily dose category but not associated with the area-under-the-concentration time curve from 0 to 24 hours, or the maximum or minimum concentrations at steady state. T > MIC of ≥50% of the dosing interval was associated with decreased duration of bacteremia and odds of prolonged bacteremia. CONCLUSIONS: It is unlikely that a paradoxical antibiotic effect will have a clinical correlate when ampicillin is used for neonatal bacteremia. A T > MIC ≥50% decreased both duration of bacteremia and odds of prolonged bacteremia.