Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN® or TRAVATAN®

Robert Faulkner, Najam A. Sharif, Susan Orr, Kenneth Sall, Harvey Dubiner, Jess T. Whitson, Marlene Moster, E. Randy Craven, Michael Curtis, Cynthia Pailliotet, Kimberly Martens, David Dahlin

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Abstract

Purpose: To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN® and TRAVATAN®, respectively, in patients awaiting cataract surgery. Methods: In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN® (bimatoprost ophthalmic solution, 0.03%) or TRAVATAN® (travoprost ophthalmic solution, 0.004%) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. Results: AH concentrations of BFA (17-phenyl-trinor PGF) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (Cmax) of BFA was 30.9 ± 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a Cmax of 6.81 ± 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA Cmax of 3.91 ± 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean ± SEM). Conclusions: Once daily topical ocular administration of LUMIGAN® or TRAVATAN® for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN ® and travoprost in TRAVATAN® are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.

Original languageEnglish (US)
Pages (from-to)147-156
Number of pages10
JournalJournal of Ocular Pharmacology and Therapeutics
Volume26
Issue number2
DOIs
StatePublished - Apr 1 2010

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Aqueous Humor
Cataract
Acids
Amides
Ophthalmic Solutions
Anterior Chamber
Bimatoprost
Travoprost
Ophthalmic Administration
Paracentesis
Trabecular Meshwork
Topical Administration
Dinoprost
Prodrugs
Glaucoma
Muscle Cells
Esters

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Ophthalmology
  • Pharmacology

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Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN® or TRAVATAN® . / Faulkner, Robert; Sharif, Najam A.; Orr, Susan; Sall, Kenneth; Dubiner, Harvey; Whitson, Jess T.; Moster, Marlene; Craven, E. Randy; Curtis, Michael; Pailliotet, Cynthia; Martens, Kimberly; Dahlin, David.

In: Journal of Ocular Pharmacology and Therapeutics, Vol. 26, No. 2, 01.04.2010, p. 147-156.

Research output: Contribution to journalArticle

Faulkner, Robert ; Sharif, Najam A. ; Orr, Susan ; Sall, Kenneth ; Dubiner, Harvey ; Whitson, Jess T. ; Moster, Marlene ; Craven, E. Randy ; Curtis, Michael ; Pailliotet, Cynthia ; Martens, Kimberly ; Dahlin, David. / Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN® or TRAVATAN® In: Journal of Ocular Pharmacology and Therapeutics. 2010 ; Vol. 26, No. 2. pp. 147-156.
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abstract = "Purpose: To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN{\circledR} and TRAVATAN{\circledR}, respectively, in patients awaiting cataract surgery. Methods: In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN{\circledR} (bimatoprost ophthalmic solution, 0.03{\%}) or TRAVATAN{\circledR} (travoprost ophthalmic solution, 0.004{\%}) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. Results: AH concentrations of BFA (17-phenyl-trinor PGF2α) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (Cmax) of BFA was 30.9 ± 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a Cmax of 6.81 ± 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA Cmax of 3.91 ± 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean ± SEM). Conclusions: Once daily topical ocular administration of LUMIGAN{\circledR} or TRAVATAN{\circledR} for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN {\circledR} and travoprost in TRAVATAN{\circledR} are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.",
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T1 - Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN® or TRAVATAN®

AU - Faulkner, Robert

AU - Sharif, Najam A.

AU - Orr, Susan

AU - Sall, Kenneth

AU - Dubiner, Harvey

AU - Whitson, Jess T.

AU - Moster, Marlene

AU - Craven, E. Randy

AU - Curtis, Michael

AU - Pailliotet, Cynthia

AU - Martens, Kimberly

AU - Dahlin, David

PY - 2010/4/1

Y1 - 2010/4/1

N2 - Purpose: To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN® and TRAVATAN®, respectively, in patients awaiting cataract surgery. Methods: In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN® (bimatoprost ophthalmic solution, 0.03%) or TRAVATAN® (travoprost ophthalmic solution, 0.004%) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. Results: AH concentrations of BFA (17-phenyl-trinor PGF2α) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (Cmax) of BFA was 30.9 ± 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a Cmax of 6.81 ± 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA Cmax of 3.91 ± 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean ± SEM). Conclusions: Once daily topical ocular administration of LUMIGAN® or TRAVATAN® for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN ® and travoprost in TRAVATAN® are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.

AB - Purpose: To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN® and TRAVATAN®, respectively, in patients awaiting cataract surgery. Methods: In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN® (bimatoprost ophthalmic solution, 0.03%) or TRAVATAN® (travoprost ophthalmic solution, 0.004%) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. Results: AH concentrations of BFA (17-phenyl-trinor PGF2α) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (Cmax) of BFA was 30.9 ± 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a Cmax of 6.81 ± 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA Cmax of 3.91 ± 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean ± SEM). Conclusions: Once daily topical ocular administration of LUMIGAN® or TRAVATAN® for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN ® and travoprost in TRAVATAN® are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.

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