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Published in: Clinical Pharmacokinetics 4/2016

01-04-2016 | Original Research Article

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

Authors: Kai Kaarniranta, Kirsi Ikäheimo, Eliisa Mannermaa, Auli Ropo

Published in: Clinical Pharmacokinetics | Issue 4/2016

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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.
Literature
1.
go back to reference The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429–40.CrossRef The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429–40.CrossRef
2.
go back to reference Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–13.CrossRefPubMed Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701–13.CrossRefPubMed
3.
go back to reference Leske MC, Heijl A, Hussein M, Bengtsson B, Hyma L, Komaroff E, The Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121:48–56.CrossRefPubMed Leske MC, Heijl A, Hussein M, Bengtsson B, Hyma L, Komaroff E, The Early Manifest Glaucoma Trial Group. Factors for glaucoma progression and the effect of treatment: the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2003;121:48–56.CrossRefPubMed
4.
go back to reference Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol. 2008;53:S3–10.CrossRefPubMed Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol. 2008;53:S3–10.CrossRefPubMed
5.
go back to reference European Glaucoma Society. Terminology and guidelines for glaucoma. 4th ed. Savona: PubliComm; 2014. p. 141–2. European Glaucoma Society. Terminology and guidelines for glaucoma. 4th ed. Savona: PubliComm; 2014. p. 141–2.
6.
go back to reference Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive treatment in patents with glaucoma or ocular hypertension an evidence based review. Ophthalmology. 2005;112:953–61.CrossRefPubMed Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance with ocular hypotensive treatment in patents with glaucoma or ocular hypertension an evidence based review. Ophthalmology. 2005;112:953–61.CrossRefPubMed
7.
go back to reference Denis P. Adverse effects, adherence and cost-benefits in glaucoma treatment. Eur Ophthalmic Rev. 2011;5:116–22.CrossRef Denis P. Adverse effects, adherence and cost-benefits in glaucoma treatment. Eur Ophthalmic Rev. 2011;5:116–22.CrossRef
8.
go back to reference Higginbotham EJ. Considerations in glaucoma therapy: fixed combinations versus their component medications. Clin Ophthalmol. 2010;4:1–9.PubMedPubMedCentral Higginbotham EJ. Considerations in glaucoma therapy: fixed combinations versus their component medications. Clin Ophthalmol. 2010;4:1–9.PubMedPubMedCentral
9.
go back to reference Pisella PJ, Debbasch C, Hamard P, Creuzot-Garcher C, Rat P, Brignole F, Baudouin C. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci. 2004;45:1360–8.CrossRefPubMed Pisella PJ, Debbasch C, Hamard P, Creuzot-Garcher C, Rat P, Brignole F, Baudouin C. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci. 2004;45:1360–8.CrossRefPubMed
10.
go back to reference Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490–6.CrossRefPubMed Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490–6.CrossRefPubMed
11.
go back to reference Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol. 2008;86:716–26.CrossRefPubMed Baudouin C. Detrimental effect of preservatives in eyedrops: implications for the treatment of glaucoma. Acta Ophthalmol. 2008;86:716–26.CrossRefPubMed
12.
go back to reference Liang H, Baudouin C, Pauly A, Brignole-Baudouin F. Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02 % benzalkonium chloride. Br J Ophthalmol. 2008;92:1275–82.CrossRefPubMedPubMedCentral Liang H, Baudouin C, Pauly A, Brignole-Baudouin F. Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02 % benzalkonium chloride. Br J Ophthalmol. 2008;92:1275–82.CrossRefPubMedPubMedCentral
13.
go back to reference Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312–34.CrossRefPubMed Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312–34.CrossRefPubMed
14.
go back to reference Tressler CS, Beatty R, Lemp MA. Preservative use in topical glaucoma medications. Ocul Surf. 2011;9:140–58.CrossRefPubMed Tressler CS, Beatty R, Lemp MA. Preservative use in topical glaucoma medications. Ocul Surf. 2011;9:140–58.CrossRefPubMed
15.
go back to reference Pellinen P, Huhtala A, Tolonen A, Lokkila J, Mäenpää J, Uusitalo H. The cytotoxic effects of preserved and preservative-free prostaglandin analogs on human corneal and conjunctival epithelium in vitro and the distribution of benzalkonium chloride homologs in ocular surface tissues in vivo. Curr Eye Res. 2012;37:145–54.CrossRefPubMed Pellinen P, Huhtala A, Tolonen A, Lokkila J, Mäenpää J, Uusitalo H. The cytotoxic effects of preserved and preservative-free prostaglandin analogs on human corneal and conjunctival epithelium in vitro and the distribution of benzalkonium chloride homologs in ocular surface tissues in vivo. Curr Eye Res. 2012;37:145–54.CrossRefPubMed
16.
go back to reference Stalmans I, Sunaric MG, Cordeiro MF, Hommer A, Rossetti L, Goñi F, Heijl A, Bron A. Preservative-free treatment in glaucoma: who, when, and why. Eur J Ophthalmol. 2013;23:518–25.CrossRefPubMed Stalmans I, Sunaric MG, Cordeiro MF, Hommer A, Rossetti L, Goñi F, Heijl A, Bron A. Preservative-free treatment in glaucoma: who, when, and why. Eur J Ophthalmol. 2013;23:518–25.CrossRefPubMed
17.
18.
go back to reference Rossi GC, Pasinetti GM, Scudeller L, Raimondi M, Lanteri S, Bianchi PE. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol. 2013;23:296–302.CrossRefPubMed Rossi GC, Pasinetti GM, Scudeller L, Raimondi M, Lanteri S, Bianchi PE. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol. 2013;23:296–302.CrossRefPubMed
19.
go back to reference Boimer R, Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: the PESO study. J Glaucoma. 2013;22:730–5.CrossRefPubMed Boimer R, Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: the PESO study. J Glaucoma. 2013;22:730–5.CrossRefPubMed
20.
go back to reference Mastropasqua L, Agnifili L, Mastropasqua R, Fasanella V. Conjunctival modifications induced by medical and surgical therapies in patients with glaucoma. Curr Opin Pharmacol. 2013;13:56–64.CrossRefPubMed Mastropasqua L, Agnifili L, Mastropasqua R, Fasanella V. Conjunctival modifications induced by medical and surgical therapies in patients with glaucoma. Curr Opin Pharmacol. 2013;13:56–64.CrossRefPubMed
21.
go back to reference Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol. 2002;86:418–23.CrossRefPubMedPubMedCentral Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol. 2002;86:418–23.CrossRefPubMedPubMedCentral
22.
go back to reference Jaenen N, Baudouin C, Pouliquen P, Manni G, Figueiredo A, Zeyen T. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol. 2007;17:341–9.PubMed Jaenen N, Baudouin C, Pouliquen P, Manni G, Figueiredo A, Zeyen T. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol. 2007;17:341–9.PubMed
23.
go back to reference Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350–5.CrossRefPubMed Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350–5.CrossRefPubMed
24.
go back to reference Crichton AC, Vold S, Williams JM, Hollander DA. Ocular surface tolerability of prostaglandin analogs and prostamides in patients with glaucoma or ocular hypertension. Adv Ther. 2013;30:260–70.CrossRefPubMed Crichton AC, Vold S, Williams JM, Hollander DA. Ocular surface tolerability of prostaglandin analogs and prostamides in patients with glaucoma or ocular hypertension. Adv Ther. 2013;30:260–70.CrossRefPubMed
25.
go back to reference Mathews PM, Ramulu PY, Friedman DS, Utine CA, Akpek EK. Evaluation of ocular surface disease in patients with glaucoma. Ophthalmology. 2013;120:2241–8.CrossRefPubMed Mathews PM, Ramulu PY, Friedman DS, Utine CA, Akpek EK. Evaluation of ocular surface disease in patients with glaucoma. Ophthalmology. 2013;120:2241–8.CrossRefPubMed
26.
go back to reference Yee RW. The effect of drop vehicle on the efficacy and side effects of topical glaucoma therapy: a review. Curr Opin Ophthalmol. 2007;18:134–9.CrossRefPubMed Yee RW. The effect of drop vehicle on the efficacy and side effects of topical glaucoma therapy: a review. Curr Opin Ophthalmol. 2007;18:134–9.CrossRefPubMed
27.
go back to reference Niwano Y, Iwasawa A, Ayaki M. Ocular surface cytotoxicity and safety evaluation of tafluprost, a recently developed anti-glaucoma prostaglandin analog. Ophthalmol Eye Dis. 2014;6:5–12.PubMedPubMedCentral Niwano Y, Iwasawa A, Ayaki M. Ocular surface cytotoxicity and safety evaluation of tafluprost, a recently developed anti-glaucoma prostaglandin analog. Ophthalmol Eye Dis. 2014;6:5–12.PubMedPubMedCentral
28.
go back to reference Uusitalo H, Kaarniranta K, Ropo A. Pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost in healthy volunteers. Acta Ophthalmol Suppl (Oxf). 2008;242:7–13.CrossRef Uusitalo H, Kaarniranta K, Ropo A. Pharmacokinetics, efficacy and safety profiles of preserved and preservative-free tafluprost in healthy volunteers. Acta Ophthalmol Suppl (Oxf). 2008;242:7–13.CrossRef
29.
go back to reference Hamacher T, Airaksinen J, Saarela V, Liinamaa MJ, Richter U, Ropo A. Efficacy and safety levels of preserved and preservative-free tafluprost are equivalent in patients with glaucoma or ocular hypetension: results from a pharmacodynamics analysis. Acta Ophthalmol Suppl (Oxf). 2008;242:14–9.CrossRef Hamacher T, Airaksinen J, Saarela V, Liinamaa MJ, Richter U, Ropo A. Efficacy and safety levels of preserved and preservative-free tafluprost are equivalent in patients with glaucoma or ocular hypetension: results from a pharmacodynamics analysis. Acta Ophthalmol Suppl (Oxf). 2008;242:14–9.CrossRef
30.
go back to reference Uusitalo H, Chen E, Pfeiffer N, Brignole-Baudouin F, Kaarniranta K, Leino M, Puska P, Palmgren E, Hamacher T, Hofmann G, Petzold G, Richter U, Riedel T, Winter M, Ropo A. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmol. 2010;88:329–36.CrossRefPubMed Uusitalo H, Chen E, Pfeiffer N, Brignole-Baudouin F, Kaarniranta K, Leino M, Puska P, Palmgren E, Hamacher T, Hofmann G, Petzold G, Richter U, Riedel T, Winter M, Ropo A. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmol. 2010;88:329–36.CrossRefPubMed
31.
go back to reference Mastropasqua L, Agnifili L, Fasanella V, Curcio C, Ciabattoni C, Mastropasqua R, Toto L, Ciancaglini M. Conjunctival goblet cells density and preservative-free tafluprost therapy for glaucoma: an in vivo confocal microscopy and impression cytology study. Acta Ophthalmol. 2013;91:e397–405.CrossRefPubMed Mastropasqua L, Agnifili L, Fasanella V, Curcio C, Ciabattoni C, Mastropasqua R, Toto L, Ciancaglini M. Conjunctival goblet cells density and preservative-free tafluprost therapy for glaucoma: an in vivo confocal microscopy and impression cytology study. Acta Ophthalmol. 2013;91:e397–405.CrossRefPubMed
32.
go back to reference Lorenz L, Pfeiffer N. Efficacy and safety of tafluprost 0.0015 % and timolol maleate 0.5 % fixed combination in patients with ocular hypertension or open-angle glaucoma. Expert Opin Pharmacother. 2014;15:2255–62.CrossRefPubMed Lorenz L, Pfeiffer N. Efficacy and safety of tafluprost 0.0015 % and timolol maleate 0.5 % fixed combination in patients with ocular hypertension or open-angle glaucoma. Expert Opin Pharmacother. 2014;15:2255–62.CrossRefPubMed
33.
go back to reference Holló G, Topouzis F, Fechtner RD. Fixed-combination intraocular pressure-lowering therapy for glaucoma and ocular hypertension: advantages in clinical practice. Expert Opin Pharmacother. 2014;15:1737–47.CrossRefPubMed Holló G, Topouzis F, Fechtner RD. Fixed-combination intraocular pressure-lowering therapy for glaucoma and ocular hypertension: advantages in clinical practice. Expert Opin Pharmacother. 2014;15:1737–47.CrossRefPubMed
34.
go back to reference Pfeiffer N, Traverso CE, Lorenz K, Saarela V, Liinamaa J, Uusitalo H, Astakhov Y, Boiko E, Ropo A. A, 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015 % and timolol 0.5 % versus each of its individual preservative-free components. Adv Ther. 2014;31:1228–46.CrossRefPubMedPubMedCentral Pfeiffer N, Traverso CE, Lorenz K, Saarela V, Liinamaa J, Uusitalo H, Astakhov Y, Boiko E, Ropo A. A, 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015 % and timolol 0.5 % versus each of its individual preservative-free components. Adv Ther. 2014;31:1228–46.CrossRefPubMedPubMedCentral
35.
go back to reference Holló G, Hommer A, López A, Ropoo A. Efficacy, safety, and tolerability of preservative-free fixed combination of tafluprost 0.0015 %/timolol 0.5 % versus concomitant use of the ingredients. J Ocula Pharmacol Ther. 2014;30:468–75.CrossRef Holló G, Hommer A, López A, Ropoo A. Efficacy, safety, and tolerability of preservative-free fixed combination of tafluprost 0.0015 %/timolol 0.5 % versus concomitant use of the ingredients. J Ocula Pharmacol Ther. 2014;30:468–75.CrossRef
36.
go back to reference Holló G, Vuorinen J, Tuominen J, Huttunen T, Ropo A, Pfeiffer N. Fixed-dose combination of tafluprost and timolol in the treatment of open-angle glaucoma and ocular hypertension: comparison with other fixed-combination products. Adv Ther. 2014;31:932–44.CrossRefPubMedPubMedCentral Holló G, Vuorinen J, Tuominen J, Huttunen T, Ropo A, Pfeiffer N. Fixed-dose combination of tafluprost and timolol in the treatment of open-angle glaucoma and ocular hypertension: comparison with other fixed-combination products. Adv Ther. 2014;31:932–44.CrossRefPubMedPubMedCentral
37.
go back to reference Locke CS. Use of a more general model for bioavailability studies. Commun Stat Theory Methods. 1990;19:3361–73.CrossRef Locke CS. Use of a more general model for bioavailability studies. Commun Stat Theory Methods. 1990;19:3361–73.CrossRef
38.
go back to reference European Medicines Agency. Guideline on the investigation of bioequivalence. London: EMEA/CHMP; 2010. European Medicines Agency. Guideline on the investigation of bioequivalence. London: EMEA/CHMP; 2010.
39.
go back to reference Konstas AGP, Haidich A-B, Rossetti L, Webers C. Prostaglandin-timolol fixed combinations efficacy: myth or reality? Eur J Ophthalmol. 2012;22:1–4.CrossRefPubMed Konstas AGP, Haidich A-B, Rossetti L, Webers C. Prostaglandin-timolol fixed combinations efficacy: myth or reality? Eur J Ophthalmol. 2012;22:1–4.CrossRefPubMed
40.
go back to reference Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I. Prostaglandin analogs and timol-fixed versus unfixed combinations or monotherapy for open-angle glaucoma: a systematic review and meta-analysis. J Ocul Pharmacol Ther. 2013;29:382–9.CrossRefPubMed Quaranta L, Biagioli E, Riva I, Rulli E, Poli D, Katsanos A, Floriani I. Prostaglandin analogs and timol-fixed versus unfixed combinations or monotherapy for open-angle glaucoma: a systematic review and meta-analysis. J Ocul Pharmacol Ther. 2013;29:382–9.CrossRefPubMed
41.
go back to reference Juzych MS, Zimmerman TJ. Beta blockers. In: Zimmerman TJ, Kooner KS, Sharil M, Fechtner RD, editors. Textbook of ocular pharmacology. Philadelphia: Lippincott-Raven; 1977. p. 261–75. Juzych MS, Zimmerman TJ. Beta blockers. In: Zimmerman TJ, Kooner KS, Sharil M, Fechtner RD, editors. Textbook of ocular pharmacology. Philadelphia: Lippincott-Raven; 1977. p. 261–75.
42.
go back to reference Uusitalo H, Niño J, Tahvanainen K, Turjanmaa V, Ropo A, Tuominen J, Kähönen M. Efficacy and systemic side-effects of topical 0.5 % timolol aqueous solution and 0.1 % timolol hydrogel. Acta Ophthalmol Scand. 2005;83:723–8.CrossRefPubMed Uusitalo H, Niño J, Tahvanainen K, Turjanmaa V, Ropo A, Tuominen J, Kähönen M. Efficacy and systemic side-effects of topical 0.5 % timolol aqueous solution and 0.1 % timolol hydrogel. Acta Ophthalmol Scand. 2005;83:723–8.CrossRefPubMed
Metadata
Title
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
Authors
Kai Kaarniranta
Kirsi Ikäheimo
Eliisa Mannermaa
Auli Ropo
Publication date
01-04-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 4/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0331-x

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