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

• Published in: Clinical pharmacology in drug development Vol. 8; no. 1; pp. 87 - 94
• Main Author: Cohen, Fredric
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2019; John Wiley and Sons Inc
• Subjects: Adult; Antibiotics; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - administration & dosage; Carbonic Anhydrase Inhibitors - adverse effects; Carbonic Anhydrase Inhibitors - blood; Carbonic Anhydrase Inhibitors - pharmacokinetics; Clinical trials; dichlorphenamide; Dichlorphenamide - administration & dosage; Dichlorphenamide - adverse effects; Dichlorphenamide - blood; Dichlorphenamide - pharmacokinetics; Drug Administration Schedule; Female; Healthy Volunteers; Humans; Inhibitor drugs; Male; Middle Aged; Original Manuscript; periodic paralysis; Pharmacokinetics; Pharmacology; Plasma; Single-Blind Method; sulfonamide; pharmacokinetics; periodic paralysis; Carbonic anhydrase; sulfonamide; dichlorphenamide
• ISSN: 2160-763X; 2160-7648; 2160-7648
• DOI: 10.1002/cpdd.464

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).