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Altered Tissue Distribution and Elimination of Amikacin Encapsulated in Unilamellar, Low-Clearance Liposomes (MiKasome®)

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Abstract

Purpose. Amikacin in small unilamellar liposomes (MiKasome®) has prolonged plasma residence (half-life > 24hr) and sustained efficacy in Gram-negative infection models. Since low-clearance liposomes may be subject to a lower rate of phagocytic uptake, we hypothesized this formulation may enhance amikacin distribution to tissues outside the mononuclear phagocyte system.

Methods. Rats received one intravenous dose (50 mg/kg) of conventional or liposomal amikacin. Amikacin was measured for ten days in plasma, twelve tissues, urine and bile.

Results. Liposomal amikacin increased and prolonged drug exposure in all tissues. Tissue half-lives (63−465 hr) exceeded the plasma half-life (24.5 hr). Peak levels occurred within 4 hours in some tissues, but were delayed 1−3 days in spleen, liver, lungs and duodenum, demonstrating the importance of characterizing the entire tissue concentration vs. time profile for liposomal drugs. Predicted steady-state tissue concentrations for twice weekly dosing were >100 μg/g. Less than half the liposomal amikacin was recovered in tissues and excreta, suggesting metabolism occurred. Amikacin was not detected in plasma ultrafiltrates. Tissue-plasma partition coefficients (0.2-0.8 in most tissues) estimated from tissue-plasma ratios at Tmax were similar to those estimated from tissue AUCs.

Conclusions. Low-clearance liposomal amikacin increased and prolonged drug residence in all tissues compared to conventional amikacin. The long tissue half-lives suggest liposomal amikacin is sequestered within tissues, and that an extended dosing interval is appropriate for chronic or prophylactic therapy with this formulation.

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Authors and Affiliations

  1. Biologistic Services, Boulder, Colorado, 80302

    Robert M. Fielding

  2. Biopharmaceutics Group, NeXstar Pharmaceuticals, Inc., Boulder, Colorado, 80301

    Ramilla O. Lewis & Lotus Moon-McDermott

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  1. Robert M. Fielding
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  2. Ramilla O. Lewis
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  3. Lotus Moon-McDermott
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Fielding, R.M., Lewis, R.O. & Moon-McDermott, L. Altered Tissue Distribution and Elimination of Amikacin Encapsulated in Unilamellar, Low-Clearance Liposomes (MiKasome®). Pharm Res 15, 1775–1781 (1998). https://doi.org/10.1023/A:1011925132473

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