Plasma protein distribution and its impact on pharmacokinetics of liposomal amphotericin B in paediatric patients with malignant diseases.
OBJECTIVE
This study investigates the association of liposomal amphotericin B (L-AmB) with plasma proteins and its impact on the pharmacokinetics of L-AmB in paediatric patients with malignant diseases.


METHODS
Paediatric oncology patients (n = 39) who received multiple-doses of L-AmB were recruited into this study. The association of the drug with plasma lipoprotein was investigated using single vertical spin density gradient ultracentrifugation and quantitated with a validated HPLC assay. The unbound amphotericin B (AmB) in the plasma was separated by ultrafiltration and determined with a validated LC/MS/MS assay.


RESULTS
The ex vivo lipoprotein distribution of L-AmB found that 68.3 +/- 11.8% of the drug was associated with the high density lipoprotein (HDL) fraction, which demonstrated a significant inverse correlation with posterior Bayesian estimates of L-AmB clearance (r = -0.690, p < 0.01). The average of unbound fraction of AmB in plasma of patients administered with L-AmB was 0.005, but its relationship with L-AmB clearance did not reach a statistical significance.


CONCLUSIONS
L-AmB displays different lipoprotein distribution profile from that of the conventional AmB formulation, with L-AmB preferentially associated with HDL in plasma. The inverse correlation of L-AmB clearance to its HDL distribution contributes to the difference in the pharmacokinetic profile of L-AmB.
Hong
Ying
Y
Faculty of Pharmacy, University of Sydney, Pharmacy Building (A15), Sydney, NSW 2006, Australia.
Shaw
Peter J
PJ
Tattam
Bruce N
BN
Nath
Christa E
CE
Earl
John W
JW
Stephen
Katherine R
KR
McLachlan
Andrew J
AJ
D000666:Amphotericin B / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007223:Infant; D008074:Lipoproteins / Q000097:blood* / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects; D008081:Liposomes; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011485:Protein Binding; D053719:Tandem Mass Spectrometry; D014462:Ultrafiltration
D000935:Antifungal Agents; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008081:Liposomes; D000666:Amphotericin B