A PBPK modeling approach for personalized dose optimization of nicardipine in renal and hepatic dysfunction

Figures

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  Fig. 1. (A) Framework for defining a strategic methodology to develop the PBPK model and attain results. IV intravenous, CKD chronic kidney disease, LC liver cirrhosis, MW molecular weight, pKa acid dissociation constant, CLR renal clearance, CLH hepatic clearance, PK pharmacokinetic, PBPK model physiologically based pharmacokinetic model. (B) Whole body physiologically based pharmacokinetic model in PK-Sim software, QH, QHA, QPV, QIC, QOC are blood flows in hepatic vein, hepatic artery, hepatic portal vein, blood flows into and out of other compartments, EG and EH represent fractions undergoing first pass metabolism in GIT and liver.

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  Fig. 2. The contrast of reported and anticipated systemic concentration vs. time profiles of nicardipine following Intravenous doses of; (A) 210 ug/kg for 30 mins38, (B) 0.16 mg/kg33, (C) Infusion of 5 mg/h over 3 hr34, (D) 0.885 mg35, (E) 1.05 mg36, (F) 5 mg37, respectively. (Red dots): Values of observed data, (straight line): Arithmetic mean prediction, (dashed line): dashed lines-maximum and minimum values, (black dotted line): dotted lines-5th and 95th percentile.

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  Fig. 3. The contrast of reported and anticipated systemic concentration vs. time profiles of nicardipine following oral doses (in mg) of; (A) 30 mg34, (B) 30 mg36, (C) 30 mg40, (D) 20 mg41, (E) 30 mg41, (F) 20 mg42, (G) 40 mg39, respectively. (Red dots): Values of observed data, (straight line): Arithmetic mean prediction, (dashed line): dashed lines-maximum and minimum values, (dotted line): dotted lines-5th and 95th percentile.

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  Fig. 4. The contrast of mean (Rpred/obs) ratios for the (A) area underneath the curve from time zero to infinity (AUC0–∞), (B) Maximal plasma concentration (Cmax), and (C) Clearance (CL) amongst healthy individuals, and chronic kidney disease (CKD) and liver cirrhosis (LC) patients. The findings are reported alongside a 95% confidence interval (CI).

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  Fig. 5. The contrast of predicted and observed concentration vs. time curves following oral administration of 30 mg39 nicardipine in mild liver cirrhotic (CP-A) patients. (Red dots): Values of observed data, (straight line): Arithmetic mean prediction, (dashed line): dashed lines-maximum and minimum values, (dotted line): dotted lines-5th and 95th percentile.

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  Fig. 6. The contrast of predicted and observed concentration–time curves following oral administration of nicardipine in renal impairment (RI) patients at dosages of (A) 20 mg41 (Moderate RI), (B) 30 mg41 (Severe RI), respectively. (Red dots): Values of observed data, (straight line): Arithmetic mean prediction, (dashed line): dashed lines-maximum and minimum values, (dotted line): dotted lines-5th and 95th percentile.

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  Fig. 7. Box plots illustrate the simulated AUC0–∞ with the 5th − 95th percentiles following a 30 mg oral dose of nicardipine in both healthy individuals and those with hepatic dysfunction (a). Suggested dosage reductions for patients with mild (CP-A), moderate (CP-B), and severe (CP-C) are presented in (b) for comparison with the exposure levels in healthy individuals. AUC0–∞ area underneath the curve from time zero to infinity.

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  Fig. 8. Box plots illustrate the simulated AUC0–∞ with the 5th − 95th percentiles following a 30 mg oral dose of nicardipine in both healthy individuals and those with chronic kidney disease (CKD) (a). Suggested dosage reductions for patients with moderate and severe renal impairment are presented in (b) for comparison with the exposure levels in healthy individuals. AUC0–∞: area underneath the curve from time zero to infinity.