Pharmacokinetic study of AmB-NP-GR: A new granule form with amphotericin B to treat leishmaniasis and fungal infections

Amphotericin B (AmB) has been the gold standard to treat systemic fungal infections. The use of AmB is restricted to hospitals because it poses several risks, mainly risks related to its high nephrotoxicity. Given the importance of this drug in medicine, new therapeutics and AmB formulations with nanotechnological improvements are required and could bring many benefits to patients. A new drug formulation with gastro-resistant coated granules has been proposed. The lipid-based system containing AmB was produced and used as raw material in the granulation/coated process. The new developed formulation (AmB-NP-GR) was characterized by optical microscopy, granulometry, and atomic force microscopy (AFM) after disintegration test. AmB-NP-GR showed granular shape, with most granules measured between 250 and 500 mu m (37 +/- 7% w/w). The AFM images indicated that the granule formulation should disintegrate in the intestine, to release the lipid-based carriers, making them available for absorption and allowing them to reach the blood circulation. The developed formulation was administered to rats in a single dose of 4.0 or 8.0 mg kg(-1) and the pharmacokinetics was studied. The samples were analyzed by liquid chromatography coupled to mass spectrometry. Before the pharmacokinetic studies were conducted, the bioanalytical method was validated according to the EMA guideline and all evaluated parameters agreed with this guideline. The pharmacokinetic results showed that C-max was similar for both doses and that t(max) was reached at 4-12 h for dose of 4.0 mg kg(-1) and 4 h for dose of 8.0 mg kg(-1). The half-life related to the dose of 8.0 mg kg(-1) increased significantly compared to the dose of 4.0 mg kg(-1) an increase of more than 3 times). In addition, the mean residence time related to the dose of 8.0 mg kg(-1) was 4 times higher than for the lower dose. The clearance value showed to be higher for the lower dose. Together, these results provide important conclusions for experimental design of other in vivo safety and efficacy studies of AmB-NP-GR.

Automated summary

Amphotericin B (AmB) is the gold standard for treating systemic fungal infections, but its use is limited due to high nephrotoxicity. This study developed a new formulation of AmB with gastro-resistant coated granules. Pharmacokinetic studies in rats showed that the higher dosage of 8.0 mg/kg had a longer half-life and mean residence time compared to the lower dosage of 4.0 mg/kg. These findings provide valuable insights for further safety and efficacy studies of the new AmB formulation.