Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study

Abstract

Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10 mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24 h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice.

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

“…For this analysis, animal lung concentration data were available for anidulafungin (rat), bazedoxifene (rat), chloroquine (3 albino rat studies), favipiravir (monkey), hydroxychloroquine (2 albino rat studies), nitazoxanide (mouse), tamoxifen (rat), cyclosporine (rat), ritonavir (rat), azithromycin (mouse), dolutegravir (mouse), gilteritinib (albino rat), and lopinavir (rat). [23][24][25][26][27][28][29][30][31][32] Agreement between the predicted and measured K p was assessed by simple linear regression and by constructing Bland-Altman plots, the limits of agreement (mean ± 2 SD) were included in these plots as previously described. 33…”

Study of the structural, chemical descriptors and optoelectronic properties of the drugs Hydroxychloroquine and Azithromycin

“…Studies by some researchers, have shown that Azithromycin concentrations are highly accumulated in alveolar macrophages and lung which is 100% higher than that reported in plasma [ 23 , 30 ]. Based on these studies, Azithromycin has been largely recommended for the treatment of some respiratory diseases, sexually transmitted diseases, some skin diseases, and otitis media [ 23 , 31 ]. Among other reasons, this antibiotic formulated mainly as suspension or tablets is used in human and in veterinary medicine [ 23 ].…”

Hydroxychloroquine and azithromycin used alone or combined are not effective against SARS-CoV-2 ex vivo and in a hamster model

“…In the current study, we used a higher dose monotherapy of AZM (91 mg/kg/day) and found no reproducible antiviral effect, with unmodified lung infectious titres and viral RNA yields, and no improvement of pulmonary histopathological impairments. The good pulmonary diffusion of the molecule has been well documented in several animal models ( Davila et al, 1991 ; Resendiz et al, 2020 ; Rivulgo et al, 2013 ). In particular, a study assessed the lung diffusion of the drug after a single oral intake of 50 mg/kg in Syrian hamsters.…”