A low and highly variable bioavailability is often the main reason for the failure of the development of a drug intended for oral delivery. Focusing on absorption instead of bioavailability from oral administration enables the identification and understanding of key causes of low and erratic absorption to improve drug performance in early development. In the work carried out as part of this thesis, the in silico estimation of drug absorption (fa*fg) was carried out. The use of a population pharmacokinetic approach was proposed, as implemented in NONMEM, to estimate fa*fg and variability from phase I clinical studies (AstraZeneca database). This work enabled the identification of the rate limiting step in oral drug absorption, and allowed for comparisons of fa*fg and inter-subject variability for different drug formulations. Solubility/dissolution and permeability were investigated in vitro in terms of their variability for two model drugs – dipyridamole and furosemide. Physiological parameters such as bile salt concentrations and pH were simulated in vitro to understand their effects on the absorption process. Dipyridamole saturated solubility and dissolution are pH and bile salt dependent. However, when both dissolution and permeability were tested simultaneously, it was found that pH plays an important factor in the permeation of dipyridamole rather than bile salt concentration. This can explain to some extent the variability between individuals in the absorption of dipyridamole. Furosemide solubility experiments showed that pH, buffer capacity and, to a lesser extent, bile salt concentration affect its saturated solubility. Surprisingly, almost complete drug release was observed under all simulated conditions with a clinical dose. Similarly, the permeation of furosemide did not differ under different conditions. It was suggested that with this clinical dose, other physiological parameters contribute to variability in furosemide absorption, such as gastric emptying time. Moreover, the efficacy of three formulations (solid dispersion, Self Micro Emulsifying Drug Delivery systems and nano-particles) in increasing solubility\ dissolution in vitro and in vivo in the rat model was compared. Lack of IVIVC was observed. It was suggested that the missing link is the human absorption estimation that can be resolved by the proposed population pharmacokinetics approach presented herein.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:647289 |
| Date | January 2015 |
| Creators | Rabbie, S. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1463880/ |
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