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P. L. Goldschmidt, F. Chiambaretta, R. Garraffo, K. Tabbara, P. Pouliquen, L. Delval, P. Elena, C. Chaumeil, I. Cochereau; Tear Concentrations of Azithromycin (AZM) Following a Single Instillation and a Bid Dosing Regimen for 3 Days of T1225 0.5%, 1.0% and 1.5% Eye-Drops. Invest. Ophthalmol. Vis. Sci. 2007;48(13):773.
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Assess in tears of healthy volunteers the antibiotic levels after topical administration of a stable solution of AZM (T1225), a macrolide highly active against most of the bacteria responsible for purulent conjunctivitis and against C.trachomatis (bacteria with intracellular life-cycle), after a single instillation (Study No.1) and after a BID dosing regimen for 3 days (Study No.2).
AZM levels in tears were determined by HPLC-MS in two randomised, double-masked trials in which safety parameters were also assessed. Study No.1: Subjects received one drop of either T1225 0.5% (n =23), 1.0% (n=38) or 1.5%(n=38). The Pharmacokinetic /Pharmacodynamic (PK/PD) surrogate marker for time-dependant bactericidal antimicrobials (Area Under the Inhibitory Curve-AUIC) was calculated on the basis of tear concentrations at 0.17 hours (=10 min), H0.5, H2, H4, H8, H12, and H24. Study No.2: Tear concentrations were measured 12 hours after the last instillation of a BID dosing regimen for 3 days with T1225 1.0% (n = 12) or 1.5% (n = 12) or the vehicle (n = 12).
Study N°1:T1225 1.0% and 1.5% reached higher levels than T1225 0.5% with similar PK profiles. The calculated AUICs (from 47 to 90: for a MIC of 4 mg/L), BID dosing regimen indicates that T1225 reaches the values necessary for efficacy against most of the Gram+ and Gram - bacteria infecting the eye surface. Results from Study No. 2 showed that T1225 1.5% was able to reach and maintain higher tear AZM levels than T1225 1.0%. Hundred % of T1225 1.5% treated-subjects had AZM tear concentrations above the MIC of 0.5 µg/g tear and 67% reached AZM concentrations higher than 4 µg/g. Both concentrations were safe for the ocular surface.
These PK trials show that T1225 1.5% (2xd/3d) provides the appropriate levels of AZM that are necessary for antibacterial activity. In patients with purulent conjunctivitis and in children with active trachoma, pivotal trials conducted very recently showed when comparing to the reference treatments, equivalent clinical efficacy for this AZM dosing regimen (2xd/3d).
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