Utilizing a novel tandem oral dosing strategy to enhance exposure of low-solubility drug candidates in a preclinical setting.
Time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical drug discovery programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical and pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity that creates an issue for efficacy and target safety studies, where high drug exposures are desired. When solubility issues are encountered, enabling formulations are often used to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. In our study, two drug candidates with poor aqueous solubility were dosed in rats as simple suspension formulations using a novel tandem dosing strategy, which employs dosing orally in 2.5 h increments up to three times to simulate an oral infusion by avoiding saturation of absorption associated with bolus dosing. These compounds were also dosed using the same suspension formulations and a standard dosing strategy. The resulting in vivo exposures were compared. It was found that this novel tandem dosing strategy significantly improved the in vivo exposures.
Chiang
Po-Chang
PC
Pfizer Global Research and Development, St. Louis Laboratories, 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA. Pochangchiang@Att.net
South
Sarah A
SA
Foster
Kimberly A
KA
Daniels
J Scott
JS
Wene
Steve P
SP
Albin
Lesley A
LA
Thompson
David C
DC
D000284:Administration, Oral; D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008297:Male; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D004364:Pharmaceutical Preparations