Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol

Abstract

Merck KGaA observed slight differences in the dissolution of Concor^® (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space." A PBBM for bisoprolol was built using in vitro, in silico, and clinical data. We evaluated potential influences of variability in dissolution of bisoprolol batches on its clinical performance through PBBM and virtual bioequivalence (BE) trials. We demonstrated that in vitro dissolution was not critical for the clinical performance of bisoprolol over a wide range of tested values. Based on virtual BE trials, safe space expansion was explored using hypothetical dissolution data. A formulation with in vitro dissolution reaching 70% dissolved in 15 min and 79.5% in 30 min was shown to be BE to classical fast dissolution of bisoprolol (>85% within 15 min), as point estimates and 90% confidence intervals of the maximum plasma concentration and area under the concentration-time curve were within the BE limits (0.8-1.25).

FIGURE 1

Literature mean observed (symbols) and simulated (lines) bisoprolol plasma concentrations in the fasted state following (a,b) 10 mg intravenous bolus dose, ³ (c,d) a single oral dose of 20 mg solution, ³ (e,f) a single oral dose of a 5 mg immediate release (IR) tablet, ¹¹ (g,h) a single oral dose of a 40 mg (4 × 10) IR tablet, ¹¹ and (i,j) once‐a‐day oral doses of a 10 mg IR tablet for 7 days. ¹² Concentrations are shown on linear scales (a,c,e,g,i) as well as on log scales (b,d,f,h,j). Error bars represent the percent coefficient of variation. (c,d) Literature ³ mean observed (symbols) and simulated (lines) bisoprolol urine concentrations. Cumulative amount excreted in urine (purple) are shown as percent of the administered dose (y axis on the right)

FIGURE 2

Merck clinical studies of the mean observed (symbols) and simulated (lines) bisoprolol plasma concentrations in the fasted state following (a,b) a single oral dose of a 10 mg immediate release (IR) tablet (study ALO‐P8‐481), (c,d) once‐a‐day doses of a 10 mg IR tablet for 5 days (study ESO‐P0‐180), (e,f) a single oral dose of a 10 mg IR tablet (study EMR200006‐001), and (g,h) a single oral dose of a 10 mg IR tablet (study CAEP 43.001.15). Concentrations are shown on linear scales (a,c,e,g,i) as well as on log scales (b,d,f,h,j). Error bars represent the percent coefficient of variation

FIGURE 3

Observed (symbols) (study ALO‐P8‐481) and simulated (lines) bisoprolol plasma concentrations after a single oral dose of a 10 mg immediate release (IR) tablet in the fasted state with default (a,b) and modified (c,d) percent coefficient of variation in population simulation. The pink square symbols are the observed plasma concentration data in 27 subjects, and the solid line corresponds to the mean simulated plasma concentrations; 90% CI is displayed as a green band, and the light blue lines represent the probability contours. Concentrations are shown on linear scales (a,c) as well as on log scales (b,d)

FIGURE 4

Experimental (the three fastest) and hypothetical examples (the three slowest) of the dissolution profiles for a 10 mg immediate release tablet