Open-Label, Dose-Escalation, Phase 1 Study of Safety and Single and Multiple-Dose Pharmacokinetics of Dichlorphenamide in Healthy Volunteers.

Single-and multiple-dose pharmacokinetics and safety were investigated in this phase 1 study of dichlorphenamide, a carbonic anhydrase inhibitor approved in the United States for treatment of primary periodic paralysis. Dichlorphenamide was administered to 6 cohorts (n = 6 each) of healthy adults. Cohorts A through E received single doses of 25-400 mg followed by 50-800 mg/day in divided doses for 10 total doses. Cohort F (safety analysis only) received up to 28 titrated doses from 100-800 mg/day. Plasma for pharmacokinetics sampling was obtained predose and up to 48 hours postdose. Twenty-five of 36 enrolled subjects completed. Median time to maximum plasma concentration ranged from 1.5-3 hours, and mean half-life from 32-68 hours. Mean area under the concentration-time curve from time 0 to tau (length of the dosing interval estimated using the trapezoidal method) and maximum observed plasma concentration increased dose-proportionally after multiple doses. The incidence and severity of adverse events (AEs) were dose-related, with at least one mild AE reported among 17%, 17%, and 67% of patients in cohorts A, B, and C, respectively; and at least one mild-to-moderate AE among 100% of subjects in cohorts D, E, and F. One serious AE of rash was reported in cohort F. Eleven subjects discontinued; 10 due to AEs at 400 or 800 mg/day (cohorts E and F), including 100% of cohort F. Hypokalemia contributed to 5 of 6 discontinuations in cohort F (all 800 mg/day).

Topical ocular hypotensive activity and ocular penetration of dichlorphenamide sodium in rabbits.

A single topical instillation (50 microliter) of the water soluble sodium salt of dichlorphenamide (10%) produced a pronounced and prolonged lowering of intraocular pressure (IOP), compared to suspensions of its free acid, in rabbits with alpha-chymotrypsin-induced ocular hypertension. In normal rabbits, instillation of dichlorphenamide sodium also produced a markedly elevated drug aqueous humor level relative to instillation of its free acid, indicating enhanced penetration into the eye. The IOP response after ocular instillation of dichlorphenamide sodium was equivalent to that produced by oral administration of 6 or 18 mg/kg dichlorphenamide sodium. Serum drug levels were lower and aqueous humor and iris-ciliary body levels were higher after instillation of dichlorphenamide sodium (10%) than after oral administration of 2 or 6 mg/kg. The data indicate that topically instilled dichlorphenamide sodium is capable of lowering IOP by a local action in the eye and provides a rationale for the potential utility of topical carbonic anhydrase inhibitors as a therapy for glaucoma in man.

Electron-capture GLC assay of dichlorphenamide.

GLC with electron-caputre detection was applied to the assay of the carbonic anhydrase inhibitor dichlorphenamide and demonstrated a sensitivity of 10 ng in 0.5 ml of rabbit serum or whole aqueous humor (congruent to 0.25 ml) from one rabbit eye. After extraction of the drug and internal standard (monochlorphenamide) from the biological fluid, these compounds were converted to their tetramethyl derivatives by a nucleophilic alkylation method. Dichlorphenamide contents of aqueous humor and serum of rabbits treated with this drug are reported.