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The Impact of Dosing Interval in a Novel Tandem Oral Dosing Strategy: Enhancing the Exposure of Low Solubility Drug Candidates in a Preclinical Setting

By Po-Chang Chiang, Sarah A. South and Steve P. Wene

Abstract

In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhanced in vivo exposures in rats. In this study, a refined time interval versus dose theory was tested. The resulting in vivo exposures based on altering frequency and doses were compared, and significant impacts were found

Topics: Research Article
Publisher: Hindawi Publishing Corporation
OAI identifier: oai:pubmedcentral.nih.gov:3065744
Provided by: PubMed Central

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Citations

  1. (2008). A .M a s o o d ,A .N a d e e m ,S .J .M u s t a f a ,a n dJ .M .O ’ D o n n e l l , “Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice,”
  2. (2003). A physiologic model for simulating gastrointestinal flow and drug absorption in rats,”
  3. (2001). Anatomical and physiologicalparametersaffectinggastrointestinalabsorptioninhumans and rats,”
  4. (2009). Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling,”
  5. (1990). B r a z e a ua n dH .L .F u n g ,“ E ffect of organic cosolventinducedskeletalmuscledamageonthebioavailabilityofintramuscular [14C]diazepam,”
  6. (1995). Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals,”
  7. (1999). Drug screening—beyond the bottleneck,”
  8. (1995). Effects of dietary fiber on gastrointestinal transit time, fecal properties and fat absorption in rats,” The Tohoku journal of experimental medicine,
  9. (2000). G r a u ,O .K a y s e r ,a n dR .H .M¨ uller, “Nanosuspensions of poorly soluble drugs—reproducibility of small scale production,”
  10. (2001). Gastric emptying and intestinal transit of liquid and solid markers in rats with chronic uremia,”
  11. (2007). h i a n g ,J .L .W a h l s t r o m
  12. (2001). Handbook of Essential Pharmacokinetics, Pharmacodynamics, and Drug Metabolism for Industrial Scientists,
  13. (2002). Hydrolysis of Nmethyl-D-aspartate receptor-stimulated cAMP and cGMP by PDE4 and PDE2 phosphodiesterases in primary neuronal cultures of rat cerebral cortex and hippocampus,”
  14. (2002). Intravenous administration of poorly soluble new drug entities in early drug discovery: the potential impact of formulation on pharmacokinetic parameters,”CurrentOpinioninDrugDiscoveryandDevelopment,vol.
  15. (2004). Nanosuspensions in drug delivery,”
  16. (1994). New challenges in biomaterials,”
  17. (1993). Physiological parameters in laboratory animals and humans,”
  18. (2005). Physiological variation in laboratory animals and humans,”
  19. (1976). Polyethylene glycol as a solvent for diazepam: bioavailability and clinical effectsafterintramuscularadministration,comparisonoforal, intramuscular and rectal administration, and precipitation fromintravenoussolutions,”ActaPharmacologicaetToxicologica,
  20. (2006). Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs,”
  21. (1981). Present and future applic a t i o n so fb i o m a t e r i a l si nc o n t r o l l e dd r u gd e l i v e r ys y s t e m s ,
  22. S.E.Smith,“Physiologyofthegastrointestinaltractinrelation to drug absorption,”
  23. (1993). The effect of liquid fibre on gastric emptying in the rat and humans and the distribution of small intestinal contents in the rat,”
  24. (1990). The influence of the interdigestive migrating myoelectric complex on the gastric emptyingofliquids,”Gastroenterology,vol.99,no.5,pp.1275– 1282,
  25. (2007). Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors,”
  26. (2010). Utilizing a noveltandemoraldosingstrategytoenhanceexposureoflowsolubility drug candidates in a preclinical setting,”