Amphotericin B dose optimization in children with malignant diseases.
In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (C(ss,trough)) and plasma creatinine concentrations (C(creat)) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB C(ss,trough) were identified by determining the probability of large (>24%, 75th percentile) increases in C(creat) after 6 days of AmB for a series of C(ss,trough) ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76-1.05 mg/l C(ss,trough) range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces C(ss,trough) within this range for children weighing 25-45 kg. Lighter children (10-25 kg) require higher AmB doses (1.25-1.5 mg/kg/day) to achieve target C(ss,trough), while heavier children (45-55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.
Nath
Christa E
CE
Department of Biochemistry, The Children's Hospital at Westmead, Westmead, Australia. Christan@chw.edu.au
McLachlan
Andrew J
AJ
Shaw
Peter J
PJ
Coakley
John C
JC
Earl
John W
JW
D000293:Adolescent; D000666:Amphotericin B / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004338:Drug Combinations; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009181:Mycoses / Q000517:prevention & control; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D012307:Risk Factors; D014508:Urea / Q000097:blood; D005723:gamma-Glutamyltransferase / Q000097:blood
D000935:Antifungal Agents; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D003840:Deoxycholic Acid; D000666:Amphotericin B; D016572:Cyclosporine; C059765:amphotericin B, deoxycholate drug combination; D014508:Urea; D003404:Creatinine; D005723:gamma-Glutamyltransferase