Single and multidose ocular kinetics and stability analysis of extemporaneous formulation of topical voriconazole in humans.
OBJECTIVE
The purpose of the present study was to evaluate the kinetics of single and multiple doses of topical, non-preserved voriconazole (VZ) in human eyes.


METHODS
For single dose kinetics, 119 patients undergoing cataract surgery were divided into group I and group II and each group received a single drop (30 µl) of either 1% or 0.1% VZ formulation. Aqueous humor was collected at designated time intervals. For multidose kinetics, a single drop of 1% VZ was instilled 5 times either hourly or every 2 hr. The aqueous humor was tested for VZ at the 5th hr and 9th hr, respectively, after initial instillation. The stability and efficacy of the reconstituted VZ formulations were also evaluated after 30 days.


RESULTS
Single dose ocular kinetics of 1% VZ resulted in a maximum mean aqueous concentration of 3.333 ± 1.61 µg/ml in 30 min whereas 0.1% showed a maximum mean aqueous concentration of 0.817 ±.36 µg/ml. In the multidose kinetic study, hourly and bi-hourly dosing resulted in mean aqueous concentrations of 7.47 ± 2.14 µg/ml and 4.69 ± 2.7 µg/ml, respectively. The reconstituted VZ formulations were stable at all studied temperatures, and their efficacy was maintained throughout the study period.


CONCLUSIONS
The present study showed that the achieved mean concentration of VZ in both single dose and multi dose kinetic studies satisfactorily met the MIC(90) for almost all causative fungal organisms. The frequency of instillation may be designed for an "every 2 hr regimen" to maintain a therapeutic concentration for successful therapy.
Department of Ocular Pharmacology, Aravind Medical Research Foundation, Dr. G. Venkataswamy Eye Research Institute, #1, Anna Nagar, Madurai, Tamilnadu, India. ss_kumari@hotmail.com
Srinivasan
S
Senthilkumari
Prajna
P
Lalitha
Namperumalsamy Venkatesh
NV
Prajna
Aravind
A
Haripriya
Jeyabalan
J
Nirmal
Pankaj
P
Gupta
Thirumurthy
T
Velpandian
D000287:Administration, Topical; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000378:metabolism*; D019540:Area Under Curve; D002387:Cataract Extraction; D002851:Chromatography, High Pressure Liquid; D003320:Corneal Ulcer / Q000517:prevention & control; D004355:Drug Stability; D015821:Eye Infections, Fungal / Q000517:prevention & control; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011310:Preservatives, Pharmaceutical / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D065819:Voriconazole
D000935:Antifungal Agents; D011310:Preservatives, Pharmaceutical; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole