962. Cutaneous Leishmaniasis: Investigating Skin Drug Levels to Optimize Liposomal Amphotericin Dosing

Abstract

BackgroundLiposomal amphotericin B (L-amB, AmBisome®) is popular for off-label use in the treatment of cutaneous leishmaniasis (CL) using dosing of 3 mg/kg/day for days 1–5, 8, 9, or days 1–5, 10 with reported clinical cure rates of 46–84%. In rodents, the skin concentration of L-amB is 40-fold less than that in visceral organs. We hypothesize that a specific L-amB regimen targeted to skin concentrations could maximize a beneficial treatment response in CL.MethodsSKH1 477 Elite hairless mice (Charles River), 5 per group, received intravenous L-amB at doses of (A) 3 mg/kg/day for days 1–5, 8, 9, (B) 5 mg/kg/day for 4 days, (C) 10 mg/kg load than 5 mg/kg/day for 3 days, (D)10 mg/kg/day for 2 days, (E) 15 mg/kg/day for 2 days. Serum and skin (back) punch biopsies were collected on day 0, 2, 5, 14, and 21. Nasal mucosa was biopsied on day 21. Tissue samples were homogenized and L-amB was extracted with methanol and acetonitrile. Liquid chromatography–mass spectrometry was performed using these extracted samples on an Agilent 1200 series HPLC and an AB Sciex Q-Trap 4000 mass spectrometer. Experiment conducted twice for confirmation.ResultsL-amB doses were well tolerated by the mice, except weight loss was seen in regimen E. Day 21 serum L-amB levels were 82 ± 3.2 (ng/mL) regimen A, 91 ± 4.2 in B, 89 ± 4 in C, 118 ± 3.7 in D, 98 ± 1.5 in E. Mean L-amB nasal tissue levels on day 21 were 1.33 + 3.2 (ng/mg tissue) regimen A and 6.5 ± 3 in D (P = 0.031). Mean L-amb skin levels on day 14 were 8.4 ± 5.6 (ng/mg tissue) in regimen A, 4.0 ± 1.7 in B, 6.2 ± 3.3 in C, 13.9 ± 7.1 in D, 33.9 ± 24.7 in E. Skin L-amB levels at day 21 were less than 5 (ng/mg tissue) except for regimen D 9.3 ± 4.2 and regimen E 7.8 ± 2.6. SKH1 477 Elite mice did not permit an adequate Leishmania major infection (very tiny lesions when compared with other murine species) to correlate these results clinically in this specific murine model.ConclusionWhile regimens A–D received similar total dosages of L-amB, the skin and nasal mucosal levels were significantly higher in the short, high daily dose regimens compared with the L-amB regimen that is currently used in CL patients. This suggests that better clinical results might be seen by using a L-amB dosing regimen for CL of 10 mg/kg for 2 days, a dose regularly used in the treatment of pediatric visceral leishmaniasis.Disclosures All authors: No reported disclosures.