Application of Physiologically Based Pharmacokinetic Model to Delineate the Impact of Aging and Renal Impairment on Ceftazidime Clearance

Abstract

The impact of physiological changes during aging on drug disposition has not always been thoroughly assessed in clinical studies. This has left an open question such as how and to what extent patho- and physiological changes in renal function can affect pharmacokinetics in the geriatric population. The objective of this work was to use a physiologically based pharmacokinetic (PBPK) model to quantify the impact of aging and renal impairment (RI) separately and together on ceftazidime pharmacokinetics (PK). The predicted plasma concentrations and PK parameters from the PBPK model were compared to the observed data in individuals of different ages with or without RI (16 independent studies were investigated in this analysis). Apart from clearance in one study, the predicted ceftazidime PK parameters of young adults, elderly, and in individuals with different levels of renal function were within 2-fold of the observed data, and the observed concentrations fell within the 5th-95th prediction interval from the PBPK model simulations. The PBPK model predicted a 1.2-, 1.5-, and 1.8-fold increase in the plasma exposure (AUC) ratio in individuals aged 40, 60, and 70 years old, respectively, with normal renal function for their age compared to 20-year-old individuals with normal renal function. The impact of RI on ceftazidime was predicted to be less marked in older individuals (a 1.04-, 1.43-, and 2.55-fold change in mild, moderate, or severe RI compared to a healthy age-matched control) than in younger individuals (where a 1.47-, 2.03-, and 3.50-fold increase was predicted in mild, moderate, or severe RI compared to a healthy age-matched control). Utilization of the applied population-based PBPK approach allows delineation of the effects of age from renal disease and can better inform future study design and dosing recommendations in clinical study of elderly patients depending on their age and renal function.

Keywords: GFR; PBPK model; ceftazidime; elderly; renal; renal impairment.

Figure 1

Predicted (vs. observed) ceftazidime PK profiles in young adults and elderly populations after i.v. administration. Solid lines = predicted means; dashed lines = 5th and 95th centiles; circles = observed concentration. All observed data in plots A [26], B [27], C [25], D [30], and E [28] represent the mean profile, except plot F [29] represent individuals. See Section 4/Appendix A for trial settings. Codes A1 to F correspond to those in Appendix A subsection 1 and Table 2.

Figure 2

(a) Predicted (vs. observed) ceftazidime profiles in adult population with or without renal impairment after i.v. administration of 500 mg. Solid lines = predicted means; dashed lines = 5th and 95th centiles; circles = observed concentration in plasma (plots A [32] and B [33]); squares in plots A [32] and B [33] = observed cumulative fraction of dose recovered in urine as ceftazidime (fe). See Section 4/Appendix A for trial settings. Codes A1 to B4 correspond to those in Appendix A sub-section 2 and Table 3. (b) Predicted (vs. observed) ceftazidime plasma concentration profiles in adult populations with or without renal impairment after i.v. administration. Solid lines = predicted means; dashed lines = 5th and 95th centiles; circles = observed concentration (plots C [34], D [35], F [40], H [39], and G [38]). See Section 4/Appendix A for trial settings.

Figure 2

(a) Predicted (vs. observed) ceftazidime profiles in adult population with or without renal impairment after i.v. administration of 500 mg. Solid lines = predicted means; dashed lines = 5th and 95th centiles; circles = observed concentration in plasma (plots A [32] and B [33]); squares in plots A [32] and B [33] = observed cumulative fraction of dose recovered in urine as ceftazidime (fe). See Section 4/Appendix A for trial settings. Codes A1 to B4 correspond to those in Appendix A sub-section 2 and Table 3. (b) Predicted (vs. observed) ceftazidime plasma concentration profiles in adult populations with or without renal impairment after i.v. administration. Solid lines = predicted means; dashed lines = 5th and 95th centiles; circles = observed concentration (plots C [34], D [35], F [40], H [39], and G [38]). See Section 4/Appendix A for trial settings.

Figure 3

Visual comparison of simulated PK profiles for ceftazidime in healthy individuals (center) with some model outputs at 20 (top left), 40 (bottom left), 60 (top right), and 70 (bottom right) years of age, with different levels of RI severity. For simplicity, only two arrows were linked from the normal group (center) to their locations in the other plots.