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

Kenneth Ataga, Eugene P. Orringer, Lori Styles, Elliott P. Vichinsky, Paul Swerdlow, George A. Davis, Philip A. DeSimone, Jonathan W. Stocker

Research output: Contribution to journalArticle

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Abstract

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-∞ ) 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-∞ , 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.

Original languageEnglish (US)
Pages (from-to)1557-1564
Number of pages8
JournalPharmacotherapy
Volume26
Issue number11
DOIs
StatePublished - Nov 1 2006
Externally publishedYes

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Sickle Cell Anemia
Area Under Curve
Half-Life
Pharmacokinetics
Placebos
Safety
senicapoc

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)

Cite this

Ataga, K., Orringer, E. P., Styles, L., Vichinsky, E. P., Swerdlow, P., Davis, G. A., ... Stocker, J. W. (2006). Dose-escalation study of ICA-17043 in patients with sickle cell disease. Pharmacotherapy, 26(11), 1557-1564. https://doi.org/10.1592/phco.26.11.1557

Dose-escalation study of ICA-17043 in patients with sickle cell disease. / Ataga, Kenneth; Orringer, Eugene P.; Styles, Lori; Vichinsky, Elliott P.; Swerdlow, Paul; Davis, George A.; DeSimone, Philip A.; Stocker, Jonathan W.

In: Pharmacotherapy, Vol. 26, No. 11, 01.11.2006, p. 1557-1564.

Research output: Contribution to journalArticle

Ataga, K, Orringer, EP, Styles, L, Vichinsky, EP, Swerdlow, P, Davis, GA, DeSimone, PA & Stocker, JW 2006, 'Dose-escalation study of ICA-17043 in patients with sickle cell disease', Pharmacotherapy, vol. 26, no. 11, pp. 1557-1564. https://doi.org/10.1592/phco.26.11.1557
Ataga K, Orringer EP, Styles L, Vichinsky EP, Swerdlow P, Davis GA et al. Dose-escalation study of ICA-17043 in patients with sickle cell disease. Pharmacotherapy. 2006 Nov 1;26(11):1557-1564. https://doi.org/10.1592/phco.26.11.1557
Ataga, Kenneth ; Orringer, Eugene P. ; Styles, Lori ; Vichinsky, Elliott P. ; Swerdlow, Paul ; Davis, George A. ; DeSimone, Philip A. ; Stocker, Jonathan W. / Dose-escalation study of ICA-17043 in patients with sickle cell disease. In: Pharmacotherapy. 2006 ; Vol. 26, No. 11. pp. 1557-1564.
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abstract = "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-∞ ) 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-∞ , 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.",
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