Clinical Pharmacokinetics of Atropine Administered Ocularly Using an Ultrasensitive Bioanalytical Assay.

Abstract

Purpose: Previous pharmacokinetic studies conducted on atropine sulfate ophthalmical solution have utilized bioanalytical assays that lacked sufficient sensitivity to fully characterize the complete pharmacokinetic profile. To address these limitations, Pharma Medica Research Inc. has developed and validated an ultrasensitive bioanalytical method capable of accurately quantifying the active enantiomer, L-hyoscyamine, with a very low limit of quantitation of 0.500 pg/mL. The objective of this study was to evaluate the pharmacokinetics of L-hyoscyamine in healthy subjects using a highly sensitive bioanalytical assay. Methods: Ten subjects were administered 0.3 mg of Isopto Atropine solution into the conjunctival sac of the eye. Blood samples were taken as early as 2 min and up to 24 h following administration. The plasma samples were assayed for L-hyoscyamine using a chiral method with an analytical range of 0.500-500 pg/mL. The pharmacokinetic parameters were estimated using both a noncompartmental and compartmental approach. Results: The pharmacokinetics of L-hyoscyamine were fully characterized as there were no samples that were below the limit of quantitation following dosing. Using noncompartmental analysis, the mean C_max was 467.9 ± 159.4 pg/mL with a median (range) T_max of 0.5 (0.08-1) h. The mean area under the concentration-time curve was 1668.96 ± 436.02 h·pg/mL and the mean half-life was 3.91 ± 1.16 h. Overall, the study drug was well tolerated and no serious adverse events were reported. Conclusion: Through the utilization of a proprietary ultrasensitive bioanalytical method, a comprehensive investigation into the pharmacokinetics of L-hyoscyamine has been successfully conducted. This advanced method offers significant potential for optimizing study designs and facilitating in-depth examinations of the pharmacokinetics of ocularly administered atropine formulations.