Physiologically based pharmacokinetic modelling to predict exposure differences in healthy volunteers and subjects with renal impairment: Ceftazidime case study.

Abstract

Ceftazidime is a widely used β-lactam antibiotic and almost entirely excreted via glomerular filtration in kidney. The objective of this analysis was to assess the ability of physiologically based pharmacokinetic (PBPK) model to predict ceftazidime exposure in healthy volunteers and subjects with renal impairment. A full PBPK model of ceftazidime was developed using physiochemical properties and clinical data. The total clearance of 115mL/min and renal clearance of 100mL/min were obtained from ceftazidime package insert. Healthy and chronic kidney disease (CKD) populations were applied for sampling of virtual subjects. The established PBPK model predicted mean plasma AUCinf were 138.5±19.6, 230.7±22.2, 369.3±53.1 and 561.8±92.4hµg/mL in healthy, mild, moderate and severe renal impairment subjects, respectively, after administration of 1g ceftazidime intravenous bolus dose. The predicted values were in close agreement with the weighted mean of the five reported clinical studies. The exposure was slightly under predicted in subjects with severely impaired renal function, but still within 1.5-fold range. The concentration-time profiles of ceftazidime were also well captured in healthy volunteers and subjects with renal impairment. The developed PBPK model along with systems pharmacokinetics (PK) (renal impaired populations) well predicted the ceftazidime exposure. PBPK models verified with clinical study in healthy volunteers could be potentially applied to predict PK and recommend dose adjustment for CKD patients.