Physiologically Based Pharmacokinetic (PBPK) Model to Describe Absorption and Disposition of Inhaled Capreomycin

Authors: Mullin JM, Lukacova V, Bolger MB, Woltosz WS
Conference: RDD
Keywords: ADMET, capreomycin, intravenous, IV, lung, PBPK, PBPKPlus, pcat, PEAR, Population Estimates for Age-Related (PEAR™) Physiology™, pulmonary, Pulmonary Compartmental and Absorption and Transit (PCAT™), pulmonary playlist, tissue:plasma
Software: ADMET Predictor®, GastroPlus®
Division: Simulations Plus

Abstract

Introduction: The current work describes the simulation of capreomycin pharmacokinetics (PK) after IV and pulmonary administration. Capreomycin is an antibiotic used to treat tuberculosis. It is eliminated mainly by renal secretion and is poorly absorbed from the gastrointestinal tract. It is administered by intravenous (IV) or intramuscular (IM) injection. Preclinical studies showed poor distribution of capreomycin into lung from the systemic circulation [1]. Effective treatment of tuberculosis requires adequate exposure in lung and systemic circulation (for extrapulmonary sites of infections) [2]. Inhaled administration offers the potential to achieve sufficient drug exposure in both lung and systemic circulation and PBPK modeling can help in the development of such formulations.

Methods: Capreomycin pulmonary absorption and pharmacokinetics were simulated using GastroPlus™ 9.0 (Simulations Plus, Inc., Lancaster, CA). Capreomycin distribution pharmacokinetics was simulated using the PBPKPlus™ module in GastroPlus:

  • A PBPK model with all permeability-limited tissues was used
  • Human organ weights, volumes, and blood perfusion rates were generated by the program’s internal Population Estimates for Age-Related (PEAR™) Physiology™.
  • Tissue/plasma partition coefficients (Kp’s) were calculated using Poulin’s equation for drug partitioning into extracellular space (Poulin 2002) from in vitro and in silico physicochemical properties (ADMET Predictor™ 7.2, Simulations Plus, Lancaster, CA).
  • The specific permeability-surface area product (PStc per mL tissue) was fit against reported PK parameters (CL, Vss, AUC) after IV administration of capreomycin in subjects with normal and mild/moderate renal impairment. PStcs for individual tissues were calculated as a product of the specific PStc and the total cell volume of each tissue.
  • Renal clearance was calculated as the product of fraction unbound in plasma (fup) and glomerular filtration rate (GFR).

The Pulmonary Compartmental and Absorption and Transit (PCAT™) model within the GastroPlus Additional Dosage Routes Module™ was used to model pulmonary deposition, absorption, and transit.

  • Total lung deposition was set to 55% based on in vitro data [3], while distribution of drug in different lung regions was estimated from particle size distribution using the built-in ICRP66 [4] deposition model. Methods
  • Permeability in different lung regions was estimated using the built-in model.
  • The systemic absorption rate coefficient (the diffusion rate between lung tissue and systemic circulation) was fit against the plasma concentration-time (Cp-time) profile for a 25-mg inhaled dose.
  • The model was used without further changes to predict Cp-time profiles after inhalation of 75, 150, and 300 mg of capreomycin.

Respiratory Drug Delivery (RDD), April 17-21, 2016, Scottsdale, AZ

By James Mullin, Viera Lukacova, Michael Bolger, Walter S. Woltosz