Netildex versus Tobradex®: Ocular Pharmacokinetic/Pharmacodynamic After a Single Dose and After One-Day Treatment in Pigmented Rabbits

Abstract

Purpose:: This study aimed at investigating the in vivo ocular distribution of netilmicin and tobramycin contained respectively in Netildex (0.3% netilmicin /0.1% dexamethasone) and Tobradex (0.3% tobramycin / 0.1% dexamethasone), after single dose or one-day treatment in pigmented rabbits.

Methods:: Single Dose: A volume of 50µl of Netildex or Tobradex was instilled into both eyes of pigmented rabbits. Sampling was performed 0.5, 1, 2, 4, 6 and 12 hours after treatment. One-day treatment: Four instillations of 50µl of the two fixed antibiotic/corticosteroid combinations were carried out into the right eye of pigmented rabbits every 6 hours during one day. Sampling was performed one hour after the last instillation. LC/MS-MS was used to determine the concentrations of netilmicin and tobramycin in cornea, conjunctiva, aqueous humour and plasma. Quotient of Inhibition (QI= C_max/MIC₉₀) of each antibiotic was determined as the ratio between the C_max detected in the ocular tissues analyzed and the Minimum Inhibitory Concentrations (MIC₉₀) assessed for isolates of Staphylococcus aureus and Staphylococcus epidermidis.

Results:: Single dose: The data showed that in conjunctiva netilmicin reached C_max (408.9 ng/g) and AUC_0-12 (1393.9 hr x ng/g) values similar to those of tobramycin (601.3 ng/g and 1169.5 hr x ng/g respectively). While in cornea the C_max and AUC_0-12 of netilmicin was 10 and 30 fold respectively higher than tobramycin (C_max 825.9 ng/g respect to C_max 74.01 ng/g ; AUC_0-12 3116.8 hr x ng/g respect to AUC_0-12 101.2 hr x ng/g). However, the QI values were >1 in both tissues conjunctiva and cornea only for netilmicin, because its MICs values against St. aureus and St. epidermidis isolates were lower than tobramycin. In the aqueous humour, antibiotic concentration was under the detection limit. One-day treatment: Netilmicin and tobramycin reached respectively, one hour after the last instillation, the concentrations of 0.71µg/g and 0.21 µg/g in conjunctiva, 1.02 µg/g and 0.30 µg/g in cornea , 4.8 µg/g and 0.00 µg/g in sclera and 0.025 µg/g and 0.00 in aqueous humour.

Conclusions:: In this study netilmicin activity and its kinetic profile indicated that Netildex has better efficacy than Tobradex already after single dose. During the first day of treatment only Netildex reached active concentrations against St. aureus and St. epidermidis isolates.

Keywords: antibiotics/antifungals/antiparasitics • anterior segment