Susan Raber

Latanoprost systemic exposure in pediatric and adult patients with glaucoma: a phase 1, open-label study.

OBJECTIVE To evaluate short-term safety and steady-state systemic pharmacokinetics (PK) of latanoprost acid in pediatric subjects with glaucoma or ocular hypertension who received the adult latanoprost dose. DESIGN Phase 1, open-label, multicenter study. PARTICIPANTS Pediatric patients of 3 age groups (<3, 3-<12, and 12-<18 years) and adults (≥18 years) receiving latanoprost ophthalmic solution 0.005% once daily in 1 or both eyes for ≥2 weeks. INTERVENTION Latanoprost was administered in both eyes each morning post-screening. Subjects returned 3 to 28 days later for evaluation of plasma concentrations, withholding morning latanoprost. At the clinic, a single drop of latanoprost ophthalmic solution was instilled into both eyes. Plasma latanoprost acid concentrations were collected predose and 5, 15, 30, and 60 minutes after administration. MAIN OUTCOME MEASURES Latanoprost acid plasma exposure. RESULTS The evaluable PK analysis set included data from 39 of 47 enrolled subjects. The median peak plasma concentration value was higher in the <3-year age group (166 pg/ml) versus other groups (49, 16, and 26 pg/ml for the 3-<12-year, 12-<18-year, and ≥18-year age groups, respectively). The median area under the concentration-time curve from zero to last measurable concentration value was also higher in the <3-year age group (2716 pg/min/ml) versus other groups (588, 106, and 380 pg/min/ml for the 3-<12-year, 12-<18-year, and ≥18-year age groups, respectively). Latanoprost acid was rapidly eliminated from the blood, with plasma concentrations undetectable within 10 to 30 minutes postdose in all but the <3-year age group. There were no discontinuations or dose reductions due to adverse events or treatment-emergent adverse events. CONCLUSIONS Latanoprost acid systemic exposure was higher in younger children versus adolescents and adults, attributed primarily to lower body weight and smaller blood volume. Latanoprost acid was eliminated rapidly in all age groups and resulted in only a brief period of systemic exposure after once-daily dosing. Higher systemic exposure was not accompanied by adverse events, and on the basis of extrapolation of safety data from adults, this pilot study suggests an adequate safety margin for systemic adverse effects with use of the adult topical dose of latanoprost in pediatric patients. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosures may be found after the references.

A Phase 2, Randomized, Dose-Response Trial of Taprenepag Isopropyl (PF-04217329) Versus Latanoprost 0.005% in Open-Angle Glaucoma and Ocular Hypertension

Purpose: To evaluate the safety of escalating doses of taprenepag isopropyl (PF-04217329), a selective EP2 receptor agonist administered as a topical ophthalmic solution, versus its vehicle (Stage I), and dose-response of taprenepag isopropyl alone and in unfixed combination with latanoprost ophthalmic solution 0.005% versus latanoprost alone (Stage II). Subjects and Methods: Randomized, vehicle- and active-controlled, double-masked, two-stage, dose-finding trial in primary open-angle glaucoma (POAG) or ocular hypertension; first taprenepag isopropyl study in patients (NCT00572455). Study eye: 26 mmHg ≤ intraocular pressure (IOP) <36 mmHg at 8 am and 22 mmHg ≤ IOP <36 mmHg at 10 am, 1 pm, 4 pm. Stage I: 3 cohorts (total n = 67) received 1 drop of taprenepag isopropyl unit dose formulation qPM/eye for 14 days: low dose: 0.0025%, 0.005%, vehicle; middle dose: 0.01%, 0.015%, vehicle; high dose: 0.02%, 0.03%, vehicle. Stage II: 7 groups (total n = 250) received 1 drop of taprenepag isopropyl multidose formulation qPM/eye for 28 days: 0.005%, 0.01%, 0.015% monotherapy; each in unfixed combination with latanoprost 0.005%, or latanoprost monotherapy. Main outcomes: mean change in diurnal IOP, baseline to last visit; adverse events. Results: Stage I at Day 14: statistically significantly greater IOP reductions were observed at all taprenepag isopropyl doses versus vehicle. Stage II at Day 28: statistically significantly greater IOP reductions were observed at all doses of the unfixed combination versus latanoprost monotherapy. At least 1 treatment-emergent adverse event reported for 29/67 (43.3%) subjects in Stage I and 158/250 (63.2%) in Stage II. Conclusions: Taprenepag isopropyl significantly reduces IOP in POAG and ocular hypertension. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. As demonstrated in this report, the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications.

Subclinical Increased Anterior Stromal Reflectivity With Topical Taprenepag Isopropyl

Purpose: To assess the effect of topical taprenepag isopropyl on each layer of the cornea by confocal microscopy. Methods: Thirty-two ocular hypertensive or glaucoma patients were randomized into a 2-period, crossover study of 14 days of 0.1% taprenepag alone and in unfixed combination with 0.005% latanoprost (combination therapy). Baseline and sequential slit-lamp biomicroscopy, fluorescein staining, central ultrasonic pachymetry, and confocal microscopy were performed. Confocal images were analyzed for the density of the central superficial and basal epithelium, midstromal keratocytes, and endothelium, as well as endothelial coefficient of variation and percentage of hexagonal cells, and reflectivity of anterior stromal and midstromal layers. Results: Corneal staining increased from baseline, reaching a peak at day 13 (69% and 63% of subjects treated with monotherapy and combination therapy, respectively), which resolved by day 35. A statistically significant increase in mean corneal thickness for both eyes and both treatments occurred on days 7 and 13 (range, 20–27 &mgr;m; P < 0.001) but recovered (⩽6 &mgr;m) by day 35. No statistically significant changes were observed in the basal epithelial, midstromal, or endothelial cells. Mean ratio of average reflectivity of anterior stroma to midstroma increased on days 13 and 35 in period 1 for each treatment (range, 1.2–1.9; P < 0.001), and this increase persisted during period 2. Conclusions: Anterior stromal reflectivity may remain increased even when biomicroscopic and confocal images of corneal layers remain normal or have recovered after topical taprenepag. This subclinical measure may be useful to detect a persistent adverse effect of a topical agent on the cornea.

THU0126 Evaluation of the Effect of Tofacitinib on Measured Glomerular Filtration Rate in Patients with Active Rheumatoid Arthritis

Background In the clinical development programme of the novel oral Janus kinase inhibitor tofacitinib for the treatment of rheumatoid arthritis (RA), small mean increases in serum creatinine (SCr) (<4 μmol/L least mean squares difference from placebo [PBO] for tofacitinib 5 and 10 mg twice daily [BID] at Month 3) were observed and which plateaued early. In studies to date, with up to 5 years follow-up on and over 12,000 patient (pt)-years of exposure to tofacitinib,1,2 mean increases in SCr remain small (mean change from baseline <8.84 μmol/L). While <5% of pts discontinued per protocol for SCr increases greater than 50% above baseline, these increases were generally not associated with clinical events of renal failure. Objectives To assess changes in measured glomerular filtration rate (mGFR) with tofacitinib relative to PBO in pts with active RA. Methods In this double-blind, PBO-controlled, Phase 1 study (NCT01484561) RA pts were randomised 2:1 to one of two fixed sequences (Seq): Seq 1 received oral tofacitinib 10 mg BID in Period 1 (P1) then PBO BID in Period 2 (P2); Seq 2 received oral PBO BID in both P1 and P2. P1and P2 were 6-7 and 4-5 weeks in duration, respectively. Each pt underwent mGFR evaluations by iohexol serum clearance at 4 time points (run-in, pre-dose 1 in P1, end of P1, and end of P2); estimated GFR (eGFR) was calculated using the Cockcroft-Gault equation. The primary endpoint was the geometric mean change in mGFR from baseline to end of P1. Secondary endpoints included the geometric mean change in mGFR from baseline to end of P2 and from end of P1 to end of P2; change in eGFR and SCr; RA clinical efficacy and safety. Results 148 pts were randomised to Seq 1 (N=97) and Seq 2 (N=51). Baseline characteristics were similar between groups. In Seq 1, tofacitinib treatment in P1 was associated with a reduction of 8% (90% confidence interval [CI]: 2%, 14%) from baseline in geometric mean mGFR vs Seq 2. The reduction in geometric mean mGFR associated with tofacitinib in P1 reversed on PBO in P2, and there was no difference vs Seq 2 in the adjusted geometric mean fold change of mGFR at the end of the study (Seq 1:Seq 2: 1.04; 90% CI: 0.97, 1.11). However, from P1 to P2 there was a 5% reduction (90% CI: 1%, 10%) in mGFR in Seq 2 (PBO). eGFR and SCr showed similar changes to mGFR in Seq 1 but remained constant in Seq 2 (Table). Clinical efficacy and safety were consistent with prior studies. Conclusions This study suggests that small mean increases in SCr and mean decreases in eGFR in pts with RA treated with tofacitinib occur in parallel with small mean decreases in mGFR, and that changes in these parameters with short term tofacitinib treatment appear reversible after discontinuation. Safety monitoring will continue in ongoing and future clinical trials and routine pharmacovigilance. References Isaacs JD et al. Ann Rheum Dis 2012; 71 (Suppl 3): 672. Wollenhaupt J et al. Arthritis Rheum 2013; 65(Suppl 10): S993. Acknowledgements This study was sponsored by Pfizer Inc. Medical writing support was provided by AM Reid, PhD, of CMC and funded by Pfizer Inc. Disclosure of Interest : J. Kremer Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, A. Kivitz Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, J. Simon-Campos: None declared, E. Nasanov: None declared, H. Tony: None declared, B. Vlahos Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Hammond Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bukowski Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Li Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Schulman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Raber Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Zuckerman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Isaacs Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.2492