ROCKLATAN(netarsudil and latanoprost ophthalmic solution)0.02%/0.005%, for topical ophthalmic(五)
ated IOP represents a major risk factor for glaucomatous fieldloss. The higher the level of IOP, the greater the likelihood of optic nerve damage and glaucomatousvisual field loss.
ROCKLATAN is believed to reduce IOP by increasing the outflow of aqueous humor.
12.3 Pharmacokinetics
Absorption
The systemic exposures of netarsudil and its active metabolite, AR-13503, were eva luated in 18 healthysubjects after topical ocular administration of netarsudil ophthalmic solution 0.02% once daily (1 dropbilaterally in the morning) for 8 days. There were no quantifiable plasma concentrations of netarsudil
(lower limit of quantitation (LLOQ) 0.100 ng/mL) post dose on Day 1 and Day 8. Only 1 plasmaconcentration at 0.11 ng/mL for the active metabolite was observed for 1 subject on Day 8 at 8 hourspost-dose.
Distribution
The distribution volume in humans is 0.16 ± 0.02 L/kg. Latanoprost is absorbed through the cornea wherethe isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. The acid oflatanoprost can be measured in aqueous humor during the first 4 hours, and in plasma only during the firsthour after local administration.
Metabolism
After topical ocular dosing, netarsudil is metabolized by esterases in the eye to an active metabolite,AR-13503.
Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically activeacid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liverto the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
Excretion
The elimination of the acid of latanoprost from human plasma is rapid (t½ = 17 min) after both intravenousand topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepaticβ-oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of theadministered dose are recovered in the urine after topical and intravenous dosing, respectively.
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisLong-term studies in animals have not been performed to eva luate the carcinogenic potential of netarsudil.
Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of upto 170 mcg/kg/day (approximately 2800 times the RHOD) for up to 20 and 24 months, respectively.
Mutagenesis
Netarsudil was not mutagenic in the Ames test, in the mouse lymphoma test, or in the in vivo ratmicronucleus test.
Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests.
Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro and in vivostudies on unscheduled DNA synthesis in rats were negative.
Impairment of FertilityStudies to eva luate the effects of netarsudil on male or female fertility in animals have not beenperformed.
Latanoprost has not been found to have effects on male or female fertility in animal studies.
14. CLINICAL STUDIES
ROCKLATAN (netarsudil and latanoprost ophthalmic solution) 0.02%/0.005% was eva luated in2 randomized and controlled clinical trials, namely PG324-CS301 (NCT 02558400, referred to asStudy 301) and PG324-CS302 (NCT 02674854, referred to as Study 302) in patients with open-angleglaucoma and ocular hypertension. Studies 301 and 302 enrolled subjects with IOP < 36 mmHg andcompared IOP lowering effect of ROC |
