Predicting intestinal precipitation--a case example for a basic BCS class II drug.
OBJECTIVE
To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans.


METHODS
Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses.


RESULTS
All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations.


CONCLUSIONS
This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.
Carlert
Sara
S
Department of Pharmacy, Uppsala University, Box 580, 75123 Uppsala, Sweden.
Pålsson
Anna
A
Hanisch
Gunilla
G
von Corswant
Christian
C
Nilsson
Catarina
C
Lindfors
Lennart
L
Lennernäs
Hans
H
Abrahamsson
Bertil
B
D001682:Biological Availability; D001826:Body Fluids / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D011232:Chemical Precipitation; D003460:Crystallization; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D015394:Molecular Structure; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D014018:Tissue Distribution
C514958:AZD0865; D007093:Imidazoles; D011725:Pyridines