Pharmacokinetics and urinary excretion of amikacin in low-clearance unilamellar liposomes after a single or repeated intravenous administration in the rhesus monkey

Liposomal aminoglycosides have been shown to have activity against intracel lular infections, such as those caused by Mycobacterium avium. Amikacin in small, low-clearance liposomes (MiKasome) also has curative and prophylacti c efficacies against Pseudomonas aeruginosa and Klebsiella pneumoniae. To d evelop appropriate dosing regimens for low-clearance liposomal amikacin, we studied the pharmacokinetics of liposomal amikacin in plasma, the level of exposure of plasma to free amikacin, and urinary excretion of amikacin aft er the administration of single-dose (20 mg/kg of body weight) and repeated -dose (20 mg/kg eight times at 48-h intervals) regimens in rhesus monkeys. The clearance of liposomal amikacin (single-dose regimen, 0.023 +/- 0.003 m l min(-1) kg(-1); repeated-dose regimen, 0.014 +/- 0.001 ml min(-1) kg(-1)) was over 100-fold lower than the creatinine clearance tan estimate of conv entional amikacin clearance). Half-lives in plasma were longer than those r eported for other amikacin formulations and declined during the elimination phase following administration of the last dose (from 81.7 +/- 27 to 30.5 +/- 5 h), Peak and trough (48 h) levels after repeated dosing reached 728 /- 72 and 418 +/- 60 mu g/ml, respectively. The levels in plasma remained > 180 mu g/ml for 6 days after the administration of the last dose. The free amikacin concentration in plasma never exceeded 17.4 +/- 1 mu g/ml and fell rapidly (half-life, 1.47 to 1.85 h) after the administration of each dose of liposomal amikacin, This and the low volume of distribution (45 ml/kg) i ndicate that the amikacin in plasma largely remained sequestered in long-ci rculating liposomes. Less than half the amikacin was recovered in the urine , suggesting that the level of renal exposure to filtered free amikacin was reduced, possibly as a result of intracellular uptake or the metabolism of liposomal amikacin, Thus, low-clearance liposomal amikacin could be admini stered at prolonged (2- to 7-day) intervals to achieve high levels of expos ure to liposomal amikacin with minimal exposure to free amikacin.