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Pharmacokinetics, Efficacy, and Safety of the Preservative-free Fixed Combination of Tafluprost 0.0015 % and Timolol 0.5 % in Healthy Volunteers: A Phase I Comparison vs. the Corresponding Preservative-free Monotherapies

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Abstract

Purpose

Plasma concentrations of tafluprost acid and timolol were compared after single (Day 1) and repeated (Day 8) instillations of once-daily tafluprost 0.0015 %-timolol 0.5 % preservative-free (PF) fixed-dose combination (FDC), once-daily PF tafluprost 0.0015 %, and twice-daily PF timolol 0.5 %.

Patients and methods

Fifteen healthy volunteers were randomized to this double-masked, single-center, three-period cross-over study. A wash-out interval of at least 4 weeks separated each three 8-day dosing period. Blood samples were drawn on the first and last day of each dosing period, prior to the morning dose, as well as 5, 10, 15, 30, and 45 min, and 1, 1.5, 2, 4, 8, and 12 h post-dosing. Sample plasma concentrations of tafluprost acid and/or timolol were determined and maximum concentration (C max), area under the concentration-over-time curve from time zero to the last time point with a quantifiable measurement (AUC0–last), and time to maximum concentration were calculated. Intraocular pressure (IOP), adverse events, and ocular/systemic safety variables were also evaluated.

Results

Plasma concentrations of tafluprost acid were low, with similar levels measured subsequent to either single or repeated dosing of PF FDC and PF tafluprost. On both sampling days, concentrations peaked at 10 min after the dose, and were cleared from the blood circulation by 30 min; average C max ranged from 17 to 24 pg/mL, and AUC0–last from 3 to 5 pg*h/mL. Plasma concentrations of timolol were comparable after the first dose of PF FDC or PF timolol. Concentrations peaked at 15 min post-dose and diminished in a similar manner after 2 h; average C max was 800 pg/mL and AUC0–last 3900 pg*h/mL. As expected, PF timolol produced a higher Day 8 pre-dose timolol concentration than PF FDC (235 vs. 37 pg/mL; p < 0.001, respectively). The Day 8 post-dose changes in timolol concentrations were relative to this pre-dose difference. All study treatments were well tolerated and safe. PF FDC seemed to provide the best IOP reduction.

Conclusions

PF FDC demonstrated good IOP-lowering efficacy and displayed similar pharmacokinetic characteristics to the monotherapy agents. Exposure to timolol was reduced via the halved dosing.

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Acknowledgments

The authors received editorial and writing support in the preparation of this manuscript, funded by Santen Oy, Tampere, Finland. The authors were fully responsible for the text, data, and editorial decisions for the paper. The authors would like to thank Oy 4Pharma Ltd, Finland, especially Jouni Vuorinen for writing assistance and Tommi Pesonen for performing the statistical analyses.

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Authors and Affiliations

  1. Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, P.O. Box 100, FI 70029 KYS, Kuopio, Finland

    Kai Kaarniranta, Kirsi Ikäheimo & Eliisa Mannermaa

  2. Santen Oy, Tampere, Finland

    Auli Ropo

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  1. Kai Kaarniranta
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Correspondence to Kai Kaarniranta.

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All the authors have received funding from Santen Oy, Tampere, Finland for the research carried out in this paper; Auli Ropo is an employee of Santen Oy. The manuscript has not been presented at any meetings.

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Kaarniranta, K., Ikäheimo, K., Mannermaa, E. et al. Pharmacokinetics, Efficacy, and Safety of the Preservative-free Fixed Combination of Tafluprost 0.0015 % and Timolol 0.5 % in Healthy Volunteers: A Phase I Comparison vs. the Corresponding Preservative-free Monotherapies. Clin Pharmacokinet 55, 485–494 (2016). https://doi.org/10.1007/s40262-015-0331-x

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