Physiologically Based Pharmacokinetic Model To Predict Metoprolol Disposition in Healthy and Disease Populations

Figures

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  Figure 1. Workflow diagram for creating a PBPK model of metoprolol. ADME: absorption, distribution metabolism, and elimination, PBPK: Physiologically based pharmacokinetic modeling, fu: fraction unbound, pKa: dissociation constant, CYP2D6: cytochrome P4502D6, log P: Lipophilicity, Vmax: reaction’s maximal velocity, Km: concentration of substrate at half of maximal velocity, B:P: blood to plasma ratio, AUC0–t: area under the curve from time 0 to t, Cmax: Maximal concentration of plasma, CL: Clearance, AMI: Acute myocardial infarction, IV: Intravenous. Parts of the figure were drawn by using pictures from Servier Medical Art (SMART). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

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  Figure 2. Comparison between observed and simulated concentration vs time profiles after IV administration of metoprolol at doses (in mg) of (a) 20,33 (b) 20,35 (c) 15,36 (d) 5,34 (e) 10,34 (f) 15,34 (g) 20,34 (h) 88.5,37 and (i) 532 correspondingly. Red colored dots describe the reported data values, the mean solidified line indicates the simulated data values, the dashed line represents the maximum and minimum values, and the dotted line depicts the 5th and 95th percentiles. IV: Intravenous route of administration.

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  Figure 3. Comparison between observed and simulated concentration vs time profiles after oral administration of metoprolol at doses (in mg) of (a) 50,33 (b) 50,35 (c) 40,39 (d) 100,40 (e) 25,38 (f) 50,38 (g) 20,34 (h) 50,34 (i) 100,34 and (j) 532 correspondingly. Red colored dots describe the reported data values, mean solidified line indicates the simulated data values, the dashed line represents the maximum and minimum values, and the dotted line depicts the 5th and 95th percentiles.

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  Figure 4. The comparison of the mean (Robs/pre) for (i) maximal concentration of plasma (Cmax) (ii) area under the curve from time 0 to t (AUC0–t), and (iii) drug clearance (CL) among healthy, AMI, and renal failure patients. The outcomes are presented along with a confidence interval (C.I) of 95%. IV: Intravenous route of administration. ** In the case of renal failure IV and AMI, due to the presence of only two profiles, the results are presented as a mean with the range.

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  Figure 5. Comparison between observed and simulated concentration vs time profiles after IV administration of metoprolol at doses (in mg) of (a) 20,35 and oral dose (mg) of (b) 5035 in chronic kidney failure (CKD) containing profiles of all subjects individually and their mean, (c) 5035 in 3 subjects with moderate CKD, (d) 5035 in 4 subjects with severe CKD) while an IV dose (mg) of (c) 6417 without ST-segment changes in electrocardiogram, and (e) 9117 with ST-segment changes in AMI patients correspondingly. Red colored dots describe the reported data values, the mean solidified line indicates the simulated data values, the dashed line represents the maximum and minimum values and the dotted line depicts the 5th and 95th percentiles. In CKD, patient-specific changes such as plasma protein (albumin), gastric emptying time, hematocrit, and small intestinal transit time eGFR were incorporated. In AMI, no changes were added because of the unavailability of reported values. In (b), red dots present mean data, dark blue dots the subject AO, green dots the subject BH, purple dots the subject IP, pink dots the subject JZ, yellow dots the subject LA I, dark sea-green dots the subject LA II, and…

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  Figure 6. Graphical representation of simulated AUC0–t and AUC0–t(unbound) as well as 5th and 95th percentiles employing box plots after administering 20 mg IV dose (a, b) in both populations (healthy and renal failure). For comparison with healthy exposure, dosage reduction in renal failure (moderate & severe) is indicated in (c, d). AUC0–t(unbound): area under the plasma concentration–time curve from time 0 to t unbound, AUC0–t: area under the plasma concentration-time curve from time 0 to t bound, RF: Renal failure, IV: Intravenous route of administration.

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  Figure 7. Graphical representation of simulated AUC0–t and AUC0–t(unbound) as well as 5th and 95th percentiles employing box plots after administering 50 mg oral dose (a, b) in both populations (healthy and renal failure). For comparison with healthy exposure, dosage reduction in renal failure (moderate & severe) is indicated in (c, d). AUC0–t(unbound): area under the plasma concentration-time curve from time 0 to t unbound, AUC0–t: area under the plasma concentration–time curve from time 0 to t bound, RF: Renal failure.