Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

Abstract

Aim: To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment.

Methods: Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients.

Results: The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C(max), and T(max)) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles.

Conclusion: The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.

Figure 1

Schematic structure of the whole-body PBPK model used to predict in vivo behaviors of bisoprolol in different human populations. The blood flow rates associatied with the 14 compartments- lung (Lu), liver (Li), spleen (Sp), gut (AC), adipose (Ad), muscle (Mu), heart (He), brain (Br), kidney (Ki), skin (Sk), reproductive organ (RO), red marrow (RM), yellow marrow (YM), rest of body (ROB), — are represented by Q, subscripted with the corresponding compartment. Q_ha is the blood flow rate to the liver via hepatic artery (ha).

Figure 2

Simulated (line) and observed (points) plasma concentration-time profiles of bisoprolol after 10 mg intravenous administration in healthy men (37 years old, Western).

Figure 3

Simulated (lines) and observed (points) plasma concentration-time profiles of bisoprolol after 10 mg oral administration in healthy men (37 years old, Western). STT, stomach transit time.

Figure 4

Parameter sensitivity analysis for 10 mg bisoprolol single oral administration. StTransTime, stomach transit time; SITT, small intestine transit time; RefSol, reference solubility; CTranT, colon transit time; P_eff=permeability. (A) parameter sensitivity analysis of the T_max; (B) parameter sensitivity analysis of the C_max; (C) parameter sensitivity analysis of the AUC after 10 mg bisoprolol single oral administration.

Figure 5

Simulated (lines) and observed (points) plasma concentration-time profiles (A) and urine excretion-time profile of bisoprolol (B) after 20 mg oral administration in healthy men (53 years old, Western).

Figure 6

Simulated (lines) and observed (points) plasma concentration-time profiles of bisoprolol after 5 mg oral administration in healthy men (22 years old, Asian).

Figure 7

Simulated (lines) and observed (points) plasma concentration-time profiles of bisoprolol after 10 mg oral multiple doses in healthy adults and patients with impaired renal function.

Figure 8

Virtual trial simulation for 8 healthy subjects (A) and 11 patients with impaired renal function (B) after 7-d repeated oral administration of 10 mg bisoprolol. A solid black line adjacent to the middle of the concentration-time profile represents the mean of the predictive values. Solid black squares represent the observed clinical concentration-time data. The grey shaded area represents the 90% confidence interval for the simulated data, and the grey solid, and dotted lines represent individual simulated results that include 100% and 75% of the range of simulated individual data.