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Pharmacokinetics and adverse effects of amphotericin B in infants and children
1Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
Insights
This study on amphotericin B in children found significant pharmacokinetic variability and adverse effects. Individualized dosing based on therapeutic drug monitoring is recommended for safer and more effective treatment of fungal infections.
Area of Science:
- Pediatric pharmacology
- Infectious diseases
- Clinical pharmacokinetics
Background:
- Amphotericin B is a critical antifungal agent used in pediatric patients.
- Understanding its pharmacokinetics and safety profile in children is essential for effective treatment.
- Previous studies have indicated variability in amphotericin B dosing and response.
Purpose of the Study:
- To evaluate the pharmacokinetics and safety of amphotericin B infusion in pediatric patients.
- To determine the optimal dosing strategy for amphotericin B in infants and children.
- To assess the relationship between amphotericin B serum concentrations and clinical outcomes.
Main Methods:
- A cohort of 13 infants and children received amphotericin B for fungal infections.
- Dosing started at 0.5 mg/kg on day 1, followed by 1 mg/kg daily, infused over 4-6 hours.
- Serum concentrations were monitored at various time points, alongside safety assessments (hemoglobin, platelets, creatinine, etc.).
Main Results:
- Serum concentrations exceeded the target therapeutic level (0.3 microgram/ml) within 6 hours on day 1, but decreased by 24 hours.
- By day 3 and days 7-10, concentrations remained above 0.3 microgram/ml throughout the 24-hour period, with a tendency to increase.
- Significant decreases in hemoglobin and platelets, and increases in serum creatinine and liver enzymes were observed, indicating potential toxicity.
Conclusions:
- Amphotericin B exhibits significant pharmacokinetic variability in pediatric patients, influenced by age.
- The observed toxicity necessitates careful monitoring and consideration of individualized dosing.
- Therapeutic drug monitoring is recommended to optimize amphotericin B therapy and minimize adverse events in children.
Abstract:
The pharmacokinetics and safety of amphotericin B infusion were studied in 13 infants and children (age range 3 weeks to 18 years; median age 11 years) treated with the drug for proved (n = 11) or suspected (n = 2) fungal infections. The dose during the first day was 0.5 mg/kg, followed by a daily dose of 1 mg/kg for the rest of the treatment period in most patients. The drug was infused over 4 to 6 hours. During the first day, serum concentrations were above the target therapeutic level of 0.3 microgram/ml in all patients at 2 and 6 hours from the start of the infusion, in 12 of 13 patients at 12 hours, but in only 6 of 13 patients at 24 hours. On the third day, all concentrations were greater than 0.3 microgram/ml throughout the 24-hour period, and in 12 of 13 patients were greater than 0.5 microgram/ml. The same kinetic profile prevailed on days 7 to 10 of therapy, with a tendency for increasing concentrations. Elimination half-life was 9.93 +/- 1.5 hours (mean +/- SEM), clearance rate 26 +/- 5 ml/kg.hr, and distribution volume 378 +/- 25 ml/kg. The half-life inversely correlated with patient's age. Pharmacokinetic values calculated during the first day were not different from those calculated on day 3. Significant decreases in hemoglobin, platelets, and serum potassium concentration were recorded along with significant increases in serum creatinine, urea, and aspartate transaminase values. Because of the large pharmacokinetic variability and the high rate of serious adverse effects, individualized dosing of amphotericin B based on therapeutic drug monitoring should be considered.