Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration.
OBJECTIVE
To quantitatively compare in vitro dissolution data in biorelevant and compendial media, to investigate whether in vitro differences are reflected in the simulated plasma profile and to specify under which circumstances prediction of the plasma profile of orally administered lipophilic drugs can be achieved.


METHODS
Previously published dissolution data from seven products of four lipophilic drugs were compared using the first order model, the RRSBW distribution, and a model based on the Noyes-Whitney theory. Simulated plasma profiles were then obtained using a model-dependent approach. Simulated and observed plasma profiles were compared with the difference factor, f1.


RESULTS
No model consistently provided the best fit to the in vitro data, which varied significantly with medium composition. Prediction of the plasma profile was possible (9.6 < or = f1 < or = 34.2) in seven out of eleven cases.


CONCLUSIONS
Although prediction of the plasma profile of lipophilic drugs solely on the basis of in vitro data remains an ambitious target, this study shows that the plasma profile of a lipophilic drug can be predicted with appropriate in vitro dissolution data, provided that the absolute bioavailability of the drug is known and the drug has dissolution limited absorption.
Nicolaides
E
E
Laboratory of Biopharmaceutics and Pharmacokinetics, University of Athens, Greece.
Symillides
M
M
Dressman
J B
JB
Reppas
C
C
D000218:Adamantane / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics; D053626:Atovaquone; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002839:Chromans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007769:Lactams; D008055:Lipids / Q000737:chemistry; D008956:Models, Chemical; D009285:Naphthoquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010599:Pharmacokinetics; D010671:Phenylurea Compounds / Q000097:blood / Q000493:pharmacokinetics; D012995:Solubility; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D045162:Thiazolidinediones; D000077288:Troglitazone
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D002839:Chromans; C111554:GV 150013X; D007004:Hypoglycemic Agents; D007769:Lactams; D008055:Lipids; D009285:Naphthoquinones; D004364:Pharmaceutical Preparations; D010671:Phenylurea Compounds; D013844:Thiazoles; D045162:Thiazolidinediones; C104757:sanfetrinem; D000077288:Troglitazone; D000218:Adamantane; D053626:Atovaquone