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AL Robin, R Faulkner, M Curtis, S Patil, G McCarty, W Clifford, DC Dahlin; Safety and Pharmacokinetics of Travoprost a Potent Prostaglandin F (FP) Receptor Agonist, in Patients With Renal and Hepatic Impairment . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4106.
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Purpose:In two separate studies, the steady-state pharmacokinetics and safety of travoprost (AL-6221) and its active free acid metabolite (AL-5848) were investigated in normal subjects and in patients with varying degrees of hepatic or renal impairment following multiple once-daily topical ocular administration of TRAVATAN®(travoprost ophthalmic solution) 0.004%. Methods:The overall study population consisted of 12 normal, adult, male and female subjects (ages 43-81 yrs); 18 patients with renal impairment (creatinine clearance (CLcr) from 14 to 77 mL/min/1.73m2) and 18 patients with hepatic function impairment (as defined by «Childs-Pugh’ classification A, B and C for hepatic impairment. Each subject or patient received 1 drop in each eye once in the morning for seven (7) days. Plasma and urinary excretion samples were obtained on Days 1 and 7, and were analyzed by an LC/MS-MS method with a quantification limit of 10 pg/mL. Results:Travoprost (an isopropyl ester) is rapidly converted to the active acid metabolite AL-5848 by esterase hydrolysis following ocular administration. Peak plasma concentrations of AL-5848 were observed within 15-30 minutes after topical dosing and ranged from below the quantitation limit (BLQ) to 32 pg/mL in normal subjects, from BLQ to 17 pg/ mL in renally impaired subjects and from BLQ to 52 pg/mL in hepatically impaired subjects. No correlation was found between AL-5848 Cmax and either CLcr or Childs-Pugh classification. Half-life estimates in subjects with measurable plasma drug levels ranged from 17-86 minutes. Urinary recovery of AL-5848 represented less than 1% of the topical ocular dose in those subjects with measurable levels. No serious AE’s were reported during the study and no subjects discontinued the study due to AE’s. No clinically significant mean changes from baseline were seen in vital signs or in serum chemistries including hepatic function tests (transaminases, LDH, alkaline phosphatase, bilirubin), renal function tests (creatinine, BUN) in any of the study populations studied. Conclusion:TRAVATAN®administered QD is safe and well-tolerated in normal subjects and in patients with mild, moderate or severe renal or hepatic impairment. No clinically significant changes were observed in blood chemistries in any subjects or patients. Findings support no need to adjust the dose of travoprost in patients with compromised renal or hepatic function.
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