Development and Evaluation of a Physiologically Based Pharmacokinetic Model of Labetalol in Healthy and Diseased Populations

Figures

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  Figure 1. The strategy adopted in the PBPK model of labetalol. GET gastric emptying time, GFR: glomerular filtration rate, IV: intravenous, log P: lipophilicity, pH: the potential of hydrogen, PK: pharmacokinetics, pKa: negative log of the acid dissociation constant, PBF: protein binding factor, SITT; small intestinal Transit time. The figure was created with BioRender.com with agreement number LY24EZHS7O.

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  Figure 2. Comparison of observed and predicted plasma concentration versus time profile in healthy subjects after IV administration at a dose of 0.5 mg/kg. (A) [24], (B) [25]: simulation for labetalol- glutethimide study, (C) [25]: simulation for the labetalol-cimetidine study. The solid line [―] indicates the arithmetic mean, dash line [----] maximum and minimum, the dotted line [….] 5th–95th percentile, red dots indicate observed data, and the solid line indicated predicted data.

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  Figure 3. Comparison of observed and predicted plasma concentration versus time profile in healthy subjects after oral administration at a dose of 200 mg. (A) [29], (B) [25]. The solid line [―] indicates the arithmetic mean, dash line [----] maximum and minimum, the dotted line [….] 5th–95th percentile, red dots indicate observed data, and the solid line indicated predicted data.

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  Figure 4. Comparison of observed and predicted plasma versus time profile in hepatic failure subjects after IV (A) [26] and oral (B) [26] administration at a dose of 0.5 mg/kg and 200 mg, respectively. The solid line [―] indicates the arithmetic mean, dash line [----] maximum and minimum, the dotted line [….] 5th–95th percentile, red dots indicate observed data, and the solid line indicated predicted data.

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  Figure 5. Box-whisker plots after (A) oral (200 mg) and (B) IV (0.5 mg/kg) dose of labetalol in healthy, CP-A, CP-B, and CP-C populations to compare AUC.

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  Figure 6. Comparison of observed and predicted plasma concentration versus time profile in renal failure subjects after IV [27] administered at a dose of 1 mg/kg. The solid line [―] indicates the arithmetic mean the dashed line [----] maximum and minimum, the dotted line [….] 5th–95th percentile, red dots indicate observed data and solid line indicated predicted data.

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  Figure 7. Box-whisker plots after IV (1 mg/kg) dose of labetalol in healthy, moderate kidney failure, and severe kidney failure populations to compare AUC.