Dose-escalation study of ICA-17043 in patients with sickle cell disease.

STUDY OBJECTIVE

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

DESIGN

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

SETTING

Four university medical centers.

PATIENTS

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

INTERVENTION

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

MEASUREMENTS AND MAIN 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.

CONCLUSION

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.