Abstract

Objective: To simulate and predict the absorption and pharmacokinetics(PK) of budesonide following intravenous(IV) and oral(PO) administrations.

Methodology: Budesonide is a glucocorticosteroid with high local anti‐inflammatory effects. Its absorption, distribution, and systemic PK or, collectively, ‘disposition’ was modeled and simulated using GastroPlus™ v8.5 [1]. Biopharmaceutical properties were obtained from in silico predictions [2] and in vitro measurements [3‐5] and are listed in Table 1 below. Systemic PK was simulated using a physiologically based pharmacokinetic (PBPK) model with all perfusion‐limited tissues. Human organ weights, volumes, and blood perfusion rates were generated by the built‐in age‐, gender‐ and body‐weight‐dependent Population Estimates for Age‐Related (PEAR™) Physiology™. Tissue/plasma partition coefficients (Kp’s) were calculated using the default Lukacova method [6]. Budesonide is cleared predominantly by CYP3A4, which is abundant in both liver and GI tract. A linear systemic (liver) clearance (CL) was fitted against the observed plasma concentration‐time (Cp‐time) profiles following IV infusion of 0.1 mg budesonide [7] in healthy male subjects. The minor contribution to renal clearance was estimated using the fraction of budesonide unbound in blood plasma (fup) and glomerular filtration rate (GFR). This systemic PBPK model was further validated by predicting the Cp‐time profile after IV infusion of 1 mg of budesonide in a different (mixed gender) population [8]. For, the latter, a higher liver clearance was used to represent increased expression of CYP3A4 in female livers [9] The validated PBPK model, combined with the GI absorption (ACAT™) model within GastroPlus was used to simulate the Cp‐time profile after PO administration of a 4 mg budesonide immediate‐release tablet [10]. The in vivo GI permeability was obtained by converting the in vitro measurement in Pgp‐inhibited Caco‐2 cells using the built‐in Absorption Systems correlation [1]. For the PO dose, the only adjusted parameters were a fixed intestinal first‐pass extraction (FPE) against its Cp‐time profile (at the lack of in silico or in vitro estimations) and the stomach transit time (as reported in the study [10]).

American Association of Pharmaceutical Scientists (AAPS), November 10-14, 2013, San Antonio, TX

By S. Ray Chaudhuri, Viera Lukacova, Walter S. Woltosz