Level A in vitro-in vivo correlation (IVIVC) model with Bayesian approach to formulation series.
In vitro-in vivo correlation (IVIVC) models for formulation series are useful in drug development, but the current models are limited by their inability to include data variability in the predictions. Our goal was to develop a level A IVIVC model that provides predictions with probabilities. The Bayesian approach was used to describe uncertainty related to the model and the data. Three bioavailability studies of levosimendan were used to develop IVIVC model. Dissolution was tested at pH 5.8 with basket. The IVIVC model with Bayesian approach consisted of prior and observed data. All observed data were fitted to the one-compartment model together with prior data. Probability distributions of pharmacokinetic parameters and concentration time profiles were obtained. To test the external predictability of IVIVC model, only dissolution data of formulations E and F were used. The external predictability was good. The possibility to utilize all observed data when constructing IVIVC model, can be considered as a major strength of Bayesian approach. For levosimendan capsule data traditional IVIVC model was not predictable. The usefulness of IVIVC model with Bayesian approach was shown with our data, but the same approach can be used more widely for formulation optimization and for dissolution based biowaivers.
Kortejärvi
H
H
Research and Development, Orion Pharma, P.O. Box 65, 02101 Espoo, Finland. hanna.kortejarvi@orionpharma.com
Malkki
J
J
Marvola
M
M
Urtti
A
A
Yliperttula
M
M
Pajunen
P
P
D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001499:Bayes Theorem; D001682:Biological Availability; D002316:Cardiotonic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D006801:Humans; D006835:Hydrazones / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008954:Models, Biological; D010710:Phosphates / Q000737:chemistry; D011724:Pyridazines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D000077464:Simendan; D012995:Solubility; D014665:Vasodilator Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D003692:Delayed-Action Preparations; D006835:Hydrazones; D010710:Phosphates; D011724:Pyridazines; D014665:Vasodilator Agents; D000077464:Simendan