Effect of preservative removal from fixed-combination bimatoprost/timolol on intraocular pressure lowering: a potential timolol dose–response phenomenon

Figures & data

Figure 1 Summary of the article selection process.

Abbreviation: IOP, intraocular pressure.

Table 1 Summary of selected clinical trials

Publication	Study design	Patients, n	Washout	Timolol dosage	Measurements post-BL	Dose–response relationship with IOP (authors conclusions)
Katz et al^Citation38	Randomized, double-masked, placebo-controlled, dose escalation	30 healthy volunteers	NA	0.5%, 1.0%, and 1.5%, 1 drop on days 1, 7, and 14, respectively	1, 2, 3, 5, and 7 hours postdose on instillation days	All concentrations provided statistically significant IOP reduction versus placebo (Statistical analysis of between-concentration difference not provided)a
Zimmerman and Kaufman^Citation46	Randomized, double-masked, placebo-controlled, parallel groups	30 with OAG	≥7 days	0.5% or 1.5%, 1 drop	20 and 40 minutes, and 1, 1.5, 2, 3, 5, and 7 hours postdose	Both concentrations provided statistically significant IOP reduction versus placebo Essentially no difference between the two concentrations (Trend in favor of timolol 0.5% at 5 and 7 hours)a
Zimmerman andKaufman^Citation47	Randomized, double-masked, placebo-controlled, parallel groups	20 with OAG	1 week	0.1%, 0.25%, 0.5%, or 1.0%, 1 drop	2, 4, 8, 12, 24, 26, and 28 hours postdose	All concentrations provided statistically significant IOP reduction versus placebo Timolol 0.5% appeared to provide maximal IOP lowering (Statistical analysis of between-concentration difference not provided)a
Batchelor et al^Citation35	Randomized, double-masked, dose escalation	10 with OAG	7 days	0.25% and 0.5%, 1 drop BID on weeks 2 and 3, respectively (Placebo BID PO on weeks 1, 2, and 3)	1, 2, and 3 weeks	Timolol 0.25% provided statistically significant IOP reduction from BL Subsequent treatment with timolol 0.5% produced additional, numerical decrease that was not statistically significant (versus timolol 0.25%)
Zimmerman et al^Citation45	Randomized, double-masked, placebo-controlled, dose escalation	27 with OHT; 3 with OAG	1 week	0.1%, 0.25%, 0.5%, and 1.0%, 1 drop BID on weeks 2, 3, 4, and 5, respectively (Placebo BID on week 1)	1, 3, 6, 8, and 12 hours at 1, 2, 3, 4, and 5 weeks	All concentrations provided statistically significant IOP reduction versus placebo Timolol 0.5% as effective as 1.0% (P-value not provided)a
Krupin et al^Citation33	Dose escalation	25 with OHT (treatment-naïve)	NA	0.25%, 1 drop BID for 3–4 weeks, then 0.5%, 1 drop BID for 3–4 weeks	3–4 and 6–8 weeks	Both concentrations provided statistically significant IOP reduction from BL Increasing timolol from 0.25% to 0.5% did not result in significant additional IOP lowering
Rowley et al^Citation43	Randomized, double-masked, placebo-controlled, parallel groups	12 healthy volunteers	NA	0.25% or 0.5%, 1 drop	30, 60, and 90 minutes postdose	Both concentrations provided statistically significant IOP reduction versus placebo IOP reduction with timolol 0.25% was not significant at 30 minutes (Statistical analysis of between-concentration difference not provided)a
Mills^Citation41	Randomized, double-masked, parallel groups	30 with OAG	7 days (if previously treated)	0.25% or 0.5%, 1 drop BID	1, 3, 6, 9, and 12 months	Both concentrations provided statistically significant IOP reduction from BL When detected, statistically significant differences between concentrations favored timolol 0.25%
Uusitalo et al^Citation44	Randomized, double-masked, parallel groups	57 with OAG or OHT	7–14 days (if previously treated)	0.25% or 0.5%, 1 drop BID (Blocanol^® or Oftan^®-Timolol formulations)	1, 3, and 6 months	Both concentrations provided statistically significant IOP reduction from BL IOP-lowering of both concentrations was identical
Mottow-Lippa et al^Citation42	Randomized, double-masked, placebo-controlled, dose escalation	25 healthy volunteers	NA	0.008%, 0.025%, 0.08%, and 0.25%, 1 drop on days 1, 2, 3, and 4, respectively (over 1 week)	1, 2, 3, 4, 6, and 8 hours postdose	Only timolol 0.08% and 0.25% provided statistically significant IOP reduction from BL at all time points versus placebo (Statistical analysis of between-concentration difference not provided)a
Alm et al^Citation34	Randomized, double-masked, parallel groups	10 healthy volunteers	NA	0.25% or 0.5%, 1 drop	1, 2, 4, 8, 12, and 24 hours postdose	Both concentrations provided statistically significant IOP reduction from BL versus untreated eyes Effect of timolol 0.5% was not superior to that of 0.25%
Laurence et al^Citation39	Randomized, double-masked, placebo-controlled, single-dose arms with incomplete block crossover	55 with OHT	2–4 weeks	0.008% or 0.1%, 1 drop as gel or solution every 2 weeks	2, 4, 6, 8, 12, and 24 hours postdose	Both concentrations provided statistically significant IOP reduction versus placebo; gel was more effective than solution 0.1% formulations more effective than 0.008%
Campbell et al^Citation36	Randomized, double-masked, single-dose arms with two crossovers	40 with OAG or OHT	No; but IOP was tested 2 weeks after the change	0.25% (B) or 0.5% (A), 1 drop BID on ABA or BAB schedule, with changes at 4 and 8 weeks	2, 4, 6, 8, 10, and 12 weeks	Both concentrations provided statistically significant IOP reduction from BL No difference in IOP-lowering between the two concentrations
Letchinger et al^Citation40	Randomized, double-masked, placebo-controlled, single-dose arms with crossover	14 with POAG or OHT	2 weeks	0.25% or 0.5%, 1 drop QD for 13 days each (with 2-week washout in-between)	11, 12, and 13 days	Both concentrations provided statistically significant IOP reduction from BL No difference in IOP-lowering between the two concentrations
DuBiner et al^Citation37	Randomized, double-masked, parallel groups	371 with OAG or OHT	2–3 weeks	0.25% or 0.5%, 1 drop BID (as maleate or hemihydrate)	1, 2, 4, 8, and 12 weeks	Both concentrations provided statistically significant IOP reduction from BL Both formulations equally effective Both concentrations fulfilled predefined criteria for equivalence
Yamamoto et al^Citation48	Randomized, open-label, parallel groups	85 with POAG or OHT	14–28 days	0.25% or 0.5%, 1 drop QD as thermogel	2 hours postdose at 2, 4, 6, and 8 weeks	Both concentrations provided statistically significant IOP reduction from BL (Statistical analysis of between-concentration difference not provided)a
Olateju and Ajayi^Citation49	Randomized, single-masked, placebo-controlled, dose escalation	11 healthy volunteers	24 hours between doses	0.0625%, 0.125%, 0.25%, and 0.5%, 1 drop administered at ≥24-hour intervals	1, 2, 3, 4, 5, and 6 hours postdose	Only timolol 0.5% produced statistically significant IOP reductions from BL versus placebo

Note:

a Conclusions by the authors of this review (as opposed to authors from the original article cited).

Abbreviations: BID, twice daily; BL, baseline; IOP, intraocular pressure; NA, not applicable; OAG, open-angle glaucoma; OHT, ocular hypertension; PO, by mouth; POAG, primary open-angle glaucoma; QD, once daily.

Figure 2 Timolol 0.5% is at least as effective as timolol 1.0% and 1.5% at lowering IOP.

Notes: (A) IOP reduction from baseline in patients with OAG after a single instillation of timolol 0.5% (n=15) or 1.5% (n=15). Based on data from Zimmerman and Kaufman.⁴⁶ (B) IOP reduction from baseline in patients with OAG after a single instillation of timolol 0.5% (n=9) or 1.0% (n=5). Based on data from Zimmerman and Kaufman⁴⁷ (standard deviation values were not provided). (C) IOP reduction in healthy volunteers after a single instillation of timolol 0.5%, 1.0%, or 1.5%, relative to placebo treatment. The same participants (n=15) received timolol 0.5%, 1%, and 1.5% in a dose-escalating manner on days 1, 7, and 14. Based on data from Katz et al.³⁸ (D) Mean IOP in patients with OAG or OHT after 1 week of treatment with timolol 0.5% or 1.0% twice daily. The same patients (n=15) received timolol 0.5% (Phase I) and 1.0% (Phase II) in a dose-escalating manner (each treatment lasting 1 week). Based on data from Zimmerman et al⁴⁵ (standard deviation values were not provided).
Abbreviations: IOP, intraocular pressure; OAG, open-angle glaucoma; OHT, ocular hypertension.

Figure 3 IOP lowering with timolol 0.25% is greater than that with timolol 0.5%.

Notes: (A) IOP reduction from baseline in the right eye of patients with OAG after 12 months of treatment with timolol 0.25% or 0.5% twice daily (*P<0.05, timolol 0.25% versus 0.5%). Based on data from Mills.⁴¹ (B) IOP reduction from baseline in patients with primary OAG or OHT after 10 days of treatment with timolol 0.25% or 0.5%. Patients (n=14) received both treatments in a sequential study design. Based on data from Letchinger et al.⁴⁰
Abbreviations: IOP, intraocular pressure; OAG, open-angle glaucoma; OHT, ocular hypertension.

Figure 4 IOP lowering with timolol 0.5% is greater than that with timolol 0.25%.

Notes: IOP reduction from baseline in patients with open-angle glaucoma after a single instillation of timolol 0.25% (n=10) or 0.5% (n=9). Based on data from Zimmerman and Kaufman⁴⁷ (standard deviation values were not provided).
Abbreviation: IOP, intraocular pressure.

Figure 5 IOP lowering is similar with timolol 0.25% and 0.5%.

Notes: (A) IOP reduction from baseline in patients with OAG or OHT after 8 weeks of treatment with timolol 0.25% (n=46) or 0.5% (n=39) twice daily. Based on data from Yamamoto et al.⁴⁸ (B) IOP reduction from baseline in patients with OAG or OHT after 6 months of treatment with Blocanol^® 0.25% (n=14), Oftan^®-Timolol 0.25% (n=13), Blocanol^® 0.5% (n=15), or Oftan^®-Timolol 0.5% (n=15) twice daily. Blocanol^® and Oftan^®-Timolol are formulations of timolol available commercially (trademarks of Merck & Co, Kenilworth, NJ, USA, and Santen Pharmaceuticals, Emeryville, CA, USA, respectively). Based on data from Uusitalo et al.⁴⁴ (C) IOP reduction from baseline in healthy volunteers following a single application of timolol. All participants (n=10) received both concentrations in a randomized sequence, with a 1-week washout period between treatments. Based on data from Alm et al.³⁴ (D) IOP at baseline and after treatment with timolol hemihydrate 0.25% (n=91), timolol maleate 0.25% (n=92), timolol hemihydrate 0.5% (n=93), or timolol maleate 0.5% (n=95).³⁷ Reprinted from Am J Ophthalmol, 121/5, DuBiner HB, Hill R, Kaufman H, et al, Timolol hemihydrate vs timolol maleate to treat ocular hypertension and open-angle glaucoma, 522–528, Copyright 1996, with permission from Elsevier.³⁷ http://www.ajo.com/.
Abbreviations: IOP, intraocular pressure; OAG, open-angle glaucoma; OHT, ocular hypertension.

Figure 6 Illustration of the inverted, U-shaped dose–response curve for the IOP-lowering effect of timolol.

Abbreviations: bim/tim, bimatoprost/timolol; IOP, intraocular pressure; PF, preservative-free.

KatzIMHubbardWAGetsonAJGouldALIntraocular pressure decrease in normal volunteers following timolol ophthalmic solutionInvest Ophthalmol19761564894926402

 PubMedGoogle Scholar

ZimmermanTJKaufmanHETimolol: a β-adrenergic blocking agent for the treatment of glaucomaArch Ophthalmol1977954601604322648

 PubMedGoogle Scholar

ZimmermanTJKaufmanHETimolol: dose response and duration of actionArch Ophthalmol1977954605607322649

 PubMedGoogle Scholar

BatchelorEDO’DayDMShandDGWoodAJInteraction of topical and oral timolol in glaucomaOphthalmology19798616065394062

 PubMed Web of Science ®Google Scholar

ZimmermanTJKassMAYablonskiMEBeckerBTimolol maleate: efficacy and safetyArch Ophthalmol1979974656658371597

 PubMedGoogle Scholar

KrupinTSingerPRPerlmutterJKolkerAEBeckerBOne-hour intraocular pressure response to timolol. Lack of correlation with long-term responseArch Ophthalmol19819958408417236087

 PubMedGoogle Scholar

RowleySStauntonJEToschAStewart-JonesJHEdgarDFTurnerPA noninvasive tonometer in the measurement of the effects of pindolol and timolol on intraocular pressure in normal subjectsBr J Ophthalmol19816585365387295615

 PubMed Web of Science ®Google Scholar

MillsKBBlind randomised non-crossover long-term trial comparing topical timolol 0.25% with timolol 0.5% in the treatment of simple chronic glaucomaBr J Ophthalmol19836742162196338905

 PubMed Web of Science ®Google Scholar

UusitaloRJPalkamaAStjernschantzJA study of the efficacy of two commercial preparations of timolol maleate with special reference to side effectsActa Ophthalmol (Copenh)19856366346413913273

 PubMed Web of Science ®Google Scholar

Mottow-LippaLSLippaEANaidoffMAClementiRBjornssonTJonesK008% timolol ophthalmic solution. A minimal-effect dose in a normal volunteer modelArch Ophthalmol1990108161642404487

 PubMedGoogle Scholar

AlmAKoskelaTTaarnhøjJEffects of D-timolol and L-timolol eye drops on intraocular pressure and aqueous flow. A dose-response study in normal eyesActa Ophthalmol (Copenh)199068119222336928

 PubMed Web of Science ®Google Scholar

LaurenceJHolderDVogelRA double-masked, placebo-controlled evaluation of timolol in a gel vehicleJ Glaucoma19932317718219920515

 PubMedGoogle Scholar

CampbellSHHickey-DwyerMHardingSPDouble-masked three-period crossover investigation of timolol in control of raised intraocular pressureEye (Lond)1993711051088325398

 PubMed Web of Science ®Google Scholar

LetchingerSLFrohlichsteinDGlieserDKCan the concentration of timolol or the frequency of its administration be reduced?Ophthalmology19931008125912628341511

 PubMed Web of Science ®Google Scholar

DuBinerHBHillRKaufmanHTimolol hemihydrate vs timolol maleate to treat ocular hypertension and open-angle glaucomaAm J Ophthalmol199612155225288610795

 PubMed Web of Science ®Google Scholar

YamamotoTKitazawaYAzumaITsukaharaSNakashimaMfor the WP-934 Study GroupClinical evaluation of a new formula of timolol maleate (WP-934 ophthalmic solution)Jpn J Opthalmol1997414244250

 Web of Science ®Google Scholar

OlatejuSOAjayiAAThe lack of efficacy of topical beta-blockers, timolol and betaxolol on intraocular pressure in Nigerian healthy volunteersEye (Lond)199913Pt 675876310707140

 PubMed Web of Science ®Google Scholar