Abstract
Purpose :
Using normotensive New Zealand White Rabbits (NZWs), we assessed a drug-dispensing contact lens (DDCL) to deliver timolol compared to an eye drop. In phase 1, we measured the pharmacokinetic (PK) bioavailability of timolol; in phase 2 we measured pharmacodynamic (PD) effects on the intraocular pressure (IOP). The DDCL delivered neat, solid timolol maleate (TM-N; 14.4 ug) via microscale trans-corneal dosing whereas the eye drop was a standard timolol maleate ophthalmic solution (TM-OS; 0.5%, 50 uL, 250 ug).
Methods :
The PK phase included 33 animals, which were fit with activated DDCLs loaded with TM-N bilaterally, and a control arm (n=8), which received TM-OS bilaterally. At time points between 0.5 and 6 h, timolol levels in ocular tissues and blood were sampled.
The PD phase compared TM-N administered via DDCL to TM-OS with dosing on 3 consecutive days per modality in a crossover design (n=4 in each arm). The DDCL was worn for 6 h (days 1&2) and 8 h (day 3). IOP was measured before drug instillation and at time points between 0.5 and 8 h. The DDCL was removed for IOP measurements. After 3 d of one modality, both arms underwent 2 d washout and repeated the procedure with the alternate modality. IOP change was calculated for each eye by subtracting IOP at 6 h from IOP at 0 h each day.
Unpaired and paired t-tests were used to compare PK and PD data, respectively.
Results :
In the PK phase, the area under the aqueous humor concentration curve (AUC) in the study arm was 1255 ± 603 ng-h/mL greater than in the control arm but without significance (p=0.07). The levels of timolol maleate in the blood plasma at 1 h were 9.4 ± 2.3 ng/mL (p<0.001) lower in the study arm than in the control arm.
In the PD phase, at 0 h and at 6 h untreated IOPs were 18.0 ± 1.1 mmHg and 18.2 ± 1.7 mmHg for the DDCL, and 18.1 ± 1.2 mmHg and 21.6 ± 2.5 mmHg for TM-OS, respectively. The aggregated diurnal IOP change accounting for the crossover design from baseline to 6 h per eye for the DDCL was 3.5 ± 0.6 mmHg lower compared to TM-OS (p<0.0001, n=48 eye-days).
Conclusions :
A single DDCL dose of TM-N matched a single eye drop of TM-OS in delivering timolol to the AH by AUC with undetectable plasma levels, despite containing only 5.8% w/w of the TM-OS dose. TM-N delivered via the DDCL also lowered IOP significantly more than did TM-OS, supporting continued study of the DDCL for glaucoma drug delivery.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.