Prediction of modified release pharmacokinetics and pharmacodynamics from in vitro, immediate release, and intravenous data

AAPS J. 2009 Jun;11(2):323-34. doi: 10.1208/s12248-009-9107-2. Epub 2009 May 9.


The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlus (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration-time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs' bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.

MeSH terms

  • Administration, Oral
  • Adrenergic beta-Antagonists / administration & dosage
  • Adrenergic beta-Antagonists / pharmacokinetics
  • Algorithms
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacokinetics
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / pharmacokinetics
  • Chemistry, Pharmaceutical*
  • Colon / blood supply
  • Colon / metabolism
  • Computer Simulation
  • Forecasting
  • Humans
  • Infusions, Intravenous
  • Intestinal Absorption
  • Metoprolol / administration & dosage
  • Metoprolol / pharmacokinetics
  • Pharmaceutical Preparations / administration & dosage*
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*
  • Regional Blood Flow / physiology
  • Software
  • Solubility


  • Adrenergic beta-Antagonists
  • Antidepressive Agents
  • Pharmaceutical Preparations
  • Benzodiazepines
  • Metoprolol
  • adinazolam