title: Advances and challenges in PBPK modeling--Analysis of factors contributing to the oral absorption of atazanavir, a poorly soluble weak base.
abstract: Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market.
authors: Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
authors: Mark
authors: M
authors: Berlin
authors: Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
authors: Aaron
authors: A
authors: Ruff
authors: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., West Point, PA, USA.
authors: Filippos
authors: F
authors: Kesisoglou
authors: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., West Point, PA, USA.
authors: Wei
authors: W
authors: Xu
authors: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co., Inc., West Point, PA, USA.
authors: Michael Hong
authors: MH
authors: Wang
authors: Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany. Electronic address: dressman@em.uni-frankfurt.de.
authors: Jennifer B
authors: JB
authors: Dressman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000069446:Atazanavir Sulfate / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D005215:Fasting / Q000378:metabolism; D005750:Gastric Juice / Q000737:chemistry; D065569:Gastrointestinal Absorption; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007419:Intestinal Secretions / Q000737:chemistry; D008297:Male; D008954:Models, Biological; D010539:Permeability; D019518:Postprandial Period; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D000069446:Atazanavir Sulfate
keywords: Absorption; Atazanavir; Dissolution; Formulation development; Gastric emptying; Pharmacokinetics; Physiologically based pharmacokinetic model; Precipitation; Supersaturation