Dose-escalation study of ICA-17043 in patients with sickle cell disease.
OBJECTIVE
To determine the dose tolerance, safety, and pharmacokinetics of a single oral dose of ICA-17043 in patients with sickle cell disease.


METHODS
Phase I, randomized, double-blind, placebo-controlled, single-dose, dose-escalation study.


METHODS
Four university medical centers.


METHODS
Twenty-eight patients with sickle cell disease, aged 18-60 years, who were otherwise healthy and in a noncrisis state.


METHODS
Patients in three separate dose cohorts--50 mg, 100 mg, and 150 mg--received single doses of ICA-17043 or placebo.


RESULTS
The mean area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for ICA-17043 increased in a dose-related manner (11,827, 19,697, and 30,676 ng.hr/ml for 50, 100, and 150 mg, respectively). Overall mean half-life was 12.8 days. Mean peak plasma concentrations rose between the 50- and 100-mg dose levels but plateaued at 150 mg (59.1, 108.7, and 109.1 ng/ml, respectively). Weekly pharmacokinetic and safety assessments were conducted in each patient during the follow-up phase for 56 days. No dose-limiting adverse events were noted in any of the patients.


CONCLUSIONS
Total systemic exposure of ICA-17043 after a single oral dose, as measured by AUC(0-infinity), increased nearly proportionally with the dose. The rate of absorption, however, appeared to be delayed at doses greater than 100 mg. With the long half-life of ICA-17043 demonstrated in this study, once-daily dosing is probably adequate to maintain steady-state plasma concentrations. In addition, single doses of ICA-17043 were well tolerated.
Ataga
Kenneth I
KI
Division of Hematology-Oncology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7305, USA. kataga@med.unc.edu
Orringer
Eugene P
EP
Styles
Lori
L
Vichinsky
Elliott P
EP
Swerdlow
Paul
P
Davis
George A
GA
Desimone
Philip A
PA
Stocker
Jonathan W
JW
D000081:Acetamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D014320:Triphenylmethyl Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000081:Acetamides; D024681:Potassium Channels, Calcium-Activated; D014320:Triphenylmethyl Compounds; C472774:senicapoc