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Decreased chloramphenicol clearance in malnourished Ethiopian children
M Ashton1, P Bolme, E Alemayehu
1Department of Biopharmaceutics and Pharmacokinetics, Uppsala University, Sweden.
Insights
Severe malnutrition, particularly kwashiorkor, significantly impacts chloramphenicol clearance in Ethiopian children. This affects drug bioavailability and increases exposure, necessitating careful dosage adjustments for these vulnerable populations.
Area of Science:
- Pharmacokinetics
- Pediatric Infectious Diseases
- Nutritional Science
Background:
- Chloramphenicol is a critical antibiotic, but its use can be limited by variable pharmacokinetics.
- Nutritional status significantly influences drug metabolism and clearance in children.
- Understanding chloramphenicol disposition in malnourished children is crucial for effective treatment.
Purpose of the Study:
- To investigate the pharmacokinetic profile of chloramphenicol and its prodrug, chloramphenicol monosuccinate, in Ethiopian children with varying nutritional statuses.
- To determine the impact of malnutrition, specifically kwashiorkor and marasmus, on chloramphenicol plasma clearance and bioavailability.
- To explore the potential for using single plasma chloramphenicol measurements for individualized dosing.
Main Methods:
- Studied the disposition of chloramphenicol and chloramphenicol monosuccinate in 34 Ethiopian children.
- Administered a single intravenous dose of chloramphenicol (25 mg/kg).
- Analyzed plasma clearance, AUC, urinary excretion of the prodrug, and unbound drug fractions.
Main Results:
- Plasma clearance of chloramphenicol monosuccinate was reduced in severely malnourished children with kwashiorkor.
- Urinary recovery of intact prodrug was variable (0-51%), indicating incomplete bioavailability.
- Marasmic and kwashiorkor subjects showed 2- and 3-fold increases in chloramphenicol AUC, respectively, due to reduced hepatic clearance.
- Unbound fractions of chloramphenicol and its prodrug were slightly elevated in kwashiorkor patients.
Conclusions:
- Severe malnutrition, especially kwashiorkor, significantly impairs chloramphenicol clearance in children.
- Reduced hepatic clearance and altered protein binding contribute to increased drug exposure in malnourished states.
- Individualized dosing strategies, potentially guided by single plasma chloramphenicol measurements, are warranted for malnourished children.
Abstract:
The disposition of chloramphenicol and chloramphenicol monosuccinate has been studied in thirty-four Ethiopian children of varying nutritional status. After a single intravenous dose corresponding to chloramphenicol 25 mg per kg bodyweight, the plasma clearance of chloramphenicol monosuccinate was decreased only in severely malnourished children with kwashiorkor. Seventeen % of the dose (range 0-51%) was recovered in urine as intact prodrug, indicating incomplete and variable bioavailability of chloramphenicol. Compared to underweight children, on average marasmic and kwashiorkor subjects exhibited a 2- and 3-fold increase, respectively, in the AUC of chloramphenicol. Elevated AUCs could be traced to reduced hepatic clearance of the drug. The unbound fraction both of chloramphenicol and its prodrug were slightly elevated in serum from kwashiorkor subjects. The possibility of using a single point measurement of plasma chloramphenicol as a guide to individualized dosage are discussed.