Pharmacometrics-guided drug development of antihyperhidrosis agents.
The objective of the present work was to use modeling and simulation to inform trial design of a proof-of-concept study for agents used in the treatment of hyperhidrosis. Data were available from 36 subjects who received the vehicle, 2% or 4% topical glycopyrrolate wipes daily for 4 weeks, with response (hyperhidrosis disease severity scale [HDSS] and sweat production [SP]) measured weekly. The HDSS and SP time courses were best described using a longitudinal model with maximum response achieved by 1 week. Glycopyrrolate 4% had a higher HDSS responder rate than 2% (50% vs 33%) and placebo (0%) at week 1. Mean change from baseline (mg/5 min [SD]) in SP at week 1 was -90 (220), -185 (214), and -271 (265) for placebo, 2%, and 4% glycopyrrolate, respectively. Subjects with higher baseline SP had higher sweat reduction from baseline. Virtual clinical trials were simulated and analyzed using conventional (at the end of the study) versus model-based methods to determine sample size for achieving 80% power to identify a dose-response relationship. Twenty-seven subjects compared with at least 120 subjects would be needed using model-based and conventional methods, respectively. Thus, the model-based method using longitudinal data required fewer subjects than the conventional single-point method.
Center for Translation Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
Shailly
S
Mehrotra
Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline (GSK), Research Triangle Park, NC, USA.|Presently at Nuventra Pharma Sciences.
Virginia D
VD
Schmith
Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline (GSK), Research Triangle Park, NC, USA.
Teodora Pene
TP
Dumitrescu
Center for Translation Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
Jogarao
J
Gobburu
D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006024:Glycopyrrolate / Q000627:therapeutic use*; D006801:Humans; D006945:Hyperhidrosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D018401:Sample Size; D012720:Severity of Illness Index; D013546:Sweating / Q000187:drug effects; D055815:Young Adult
D018727:Muscarinic Antagonists; D006024:Glycopyrrolate
Hyperhidrosis Disease Severity Scale (HDSS); glycopyrrolate; modeling and simulation; sweat production (SP)