Physiologically Based Pharmacokinetic Modeling of Buspirone and the Effect of Liver Cirrhosis on Its Deposition

Authors: Macwan J, Fraczkiewicz G, Lukacova V, Bolger MB, Woltosz WS
Conference: AAPS
Keywords: ACAT, Advanced Compartmental Absorption and Transit (ACAT™) model, buspirone, cirrhosis, liver, PBPK, PBPKPlus, PEAR, Population Estimates for Age-Related (PEAR™) Physiology™
Software: ADMET Predictor®, GastroPlus®
Division: Simulations Plus

Abstract

Purpose: The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) model of buspirone following oral administrations in healthy volunteers, and to extend this model to predict the effects of physiological changes associated with liver cirrhosis in compensated and decompensated hepatic impairment patients.

Methods:

  • The GastroPlus™ 8.5 (Simulations Plus, Inc.) Advanced Compartmental Absorption and Transit™ (ACAT™ ) model and PBPKPlus™ module were used to build the buspirone model for absorption, distribution, and clearance mechanisms.
  • Physicochemical and biochemical parameters that predict absorption and distribution were obtained from literature or were predicted from structure with ADMET Predictor™ 6.5 (Simulations Plus, Inc.).
  • Human organ weights, volumes, and blood perfusion rates were generated by the Population Estimates for Age-Related (PEAR™) Physiology module.
  • Individual tissues were represented as perfusion-limited (blood-fiow-limited) models. Tissue/plasma partition coefficients (Kps) were calculated using the Lukacova method (1] from in vitro and in silico physicochemical properties.
  • The metabolic clearances of buspirone and its 1-pyrimidinylpiperazine metabolite in gut and liver were estimated from in vitro enzyme kinetic constants for CYP3A4 (2] and CYP2D6 13], respectively, along with GastroPlus’ built-in expression levels for both enzymes in gut and liver.
  • The model was validated by comparing simulated and observed plasma concentration-time profiles for the parent drug and its two major metabolites (1-pyrimidinylpiperazine and 6-hydroxybuspirone), obtained after multiple oral administrations of buspirone across several different dose levels (5, 7.5, 15, 20 and 30 mg) in healthy volunteers [4].
  • Physiological changes including cardiac output, cytochrome P450 (CYP) enzyme expressions, liver size, hepatic blood flow, renal function, and levels of plasma proteins, all associated with different degrees of severity of liver cirrhosis (5], were incorporated into the PBPK model. Moreover, changes in small intestinal transit time (6] and stomach pH related to liver cirrhosis [7] were included in physiology.
  • The final validated model was used to predict concentration-time profiles of buspirone and 1-pyrimidinylpiperazine metabolite in patients with both compensated and decompensated hepatic impairment 18].

American Association of Pharmaceutical Scientists (AAPS), November 2-6, 2014, San Diego, CA

By Joyce S. Macwan, Grazyna Fraczkiewicz, Viera Lukacova, Michael. B. Bolger, Walter S. Woltosz