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Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

ABSTRACT: Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure.This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml-1 , 25 ?l) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study.Thirty-six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600-700-fold lower than after multiple oral administration of 160 mg day-1 , the dose approved in cancer indications.These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml-1 tid for use in clinical studies.

SUBMITTER: Zimmermann T

PROVIDER: S-EPMC5903260 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

Zimmermann Torsten T Höchel Joachim J Becka Michael M Boettger Michael K MK Rohde Beate B Schug Barbara B Kunert Kathleen S KS Donath Frank F

British journal of clinical pharmacology 20180301 5

<h4>Aim</h4>Regorafenib is a multikinase inhibitor under investigation for use in neovascular age-related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy volunteers to provide information on safety, tolerability and systemic exposure.<h4>Methods</h4>This was a single-centre, randomized, double-masked, parallel-group, dose-escalation, placebo-controlled study. Subjects received regorafenib eye drops (30 mg ml<sup>-1</sup> , 25 μl) as a 0.75 mg singl ...[more]

PMID: 29315699

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Project description:PurposeTo evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD).DesignThis multicenter group-sequential dose escalation phase I study consisted of a placebo-controlled double-masked study of healthy volunteers (cohorts 1 and 2) and an open-label study of patients with nAMD (cohort 3).ParticipantsHealthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness (CST) ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye.MethodsIn the single-dose cohort of healthy men (cohort 1: steps 1-5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (cohort 2: steps 1-6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily in 1 eye for 21 days. In the multiple-dose cohort of patients with nAMD (cohort 3, steps 1-3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered 3 times daily in 1 affected eye for 21 days.Main outcome measuresThe safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, CST was evaluated.ResultsIn total, 40, 48, and 28 participants were enrolled in cohorts 1, 2, and 3, respectively. Serious AEs did not occur in cohorts 1 to 3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to day 22 were -27.6 ± 54.88 (0.5 w/v%; 1 drop, 3 times daily), -35.6 ± 49.64 (1.0 w/v%; 1 drop, 3 times daily), and -43.7 ± 55.19 μm (1.0 w/v%; 2 drops, 3 times daily).ConclusionsTivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Project description:IntroductionOcular pain is a common complication following photorefractive keratectomy (PRK). The level of patient satisfaction with current pain control strategies is not high. This study aims to assess the efficacy and safety of a novel regimen of preservative-free oxybuprocaine hydrochloride 0.4% unit-dose eye drops for post-PRK pain control.MethodsIn a contralateral eye study, 144 eyes of 72 patients who underwent bilateral transepithelial PRK (TransPRK) were stratified into experimental and control groups. The experimental group received preservative-free oxybuprocaine hydrochloride 0.4% unit-dose eye drops five times daily postoperatively until complete epithelial healing, while the control group received sodium hyaluronate 0.2% instead. The main outcome measures were pain scores assessed by the verbal rating scale and visual analogue scale (VRS, VAS), the corneal epithelial defect (CED) area, epithelial healing duration evaluated by slit-lamp biomicroscopy and anterior segment optical coherence tomography (AS-OCT), and endothelial cell density (ECD) measured before and 1 month after surgery.ResultsPain scores assessed by VRS and VAS were significantly lower in the experimental group 8 h after surgery, and 1, 2, and 3 days postoperatively (P < 0.001). The mean CED area showed no significant differences between the two groups at different follow-ups (P value > 0.05). The corneal epithelial healing had a mean duration of 3.32 ± 0.47 days in both studied groups and was parallel in both eyes of each patient. In each group, 49 eyes (68%) and 72 eyes (100%) had a fully epithelialized surface on the third and fourth postoperative days, respectively. No significant changes were observed in the mean ECD 1 month following surgery in both groups (P value > 0.05).ConclusionPreservative-free oxybuprocaine hydrochloride 0.4% unit-dose eye drops are effective and safe in controlling early postoperative pain following TransPRK. The availability of the single-dose unit preparation can overcome the problem of topical anesthetic abuse.Trial registrationClinicalTrials.gov Identifier: NCT05733741.

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Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

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Topical administration of regorafenib eye drops: phase I dose-escalation study in healthy volunteers.

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