TY - JOUR
T1 - Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668
AU - Reid, Joel M.
AU - Walden, Chad A.
AU - Qin, Rui
AU - Allen Ziegler, Katie L.
AU - Haslam, John L.
AU - Rajewski, Roger A.
AU - Warndahl, Roger
AU - Fitting, Cindy L.
AU - Boring, Daniel
AU - Szabo, Eva
AU - Crowell, James
AU - Perloff, Marjorie
AU - Jong, Ling
AU - Bauer, Brent A.
AU - Mandrekar, Sumithra J.
AU - Ames, Matthew M.
AU - Limburg, Paul J.
PY - 2011/3
Y1 - 2011/3
N2 - SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC 0-∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC 0-∞ values were highest in the fed state (range = 122-439 ng/mL x hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2-6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.
AB - SR13668, an orally active Akt pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Healthy adult volunteers were randomly assigned to receive a single, 38-mg oral dose of SR13668 in one of five different formulations, with or without food. On the basis of existing animal data, SR13668 in a PEG400/Labrasol oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC 0-∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Participants (n = 20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC 0-∞ values were highest in the fed state (range = 122-439 ng/mL x hours) and were statistically significantly different across formulations (P = 0.007), with Solutol HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2-6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation-dependent. Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.
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U2 - 10.1158/1940-6207.CAPR-10-0313
DO - 10.1158/1940-6207.CAPR-10-0313
M3 - Article
C2 - 21372034
AN - SCOPUS:79955876707
SN - 1940-6207
VL - 4
SP - 347
EP - 353
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 3
ER -