Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction

Figure 1 Linear correlation between drug clearance and the glomerular filtration rate as a measure of kidney function[20]. The dose can be adjusted in proportion to the reduced drug clearance, where Cl = Cl_ren + Cl_nonren. GFR: Glomerular filtration rate.

Figure 2 Dettli rules 1 and 2 for drug dose adjustment in kidney dysfunction. Dettli rule 1 leads to higher trough concentrations but lower peaks. To obtain an immediate antimicrobial effect, a loading dose must be given. With Dettli rules 1 and 2, the area under the curve AUC remains constant.

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Figure 3 It is most practical to keep the peak concentration constant when the drug dose is adjusted to impaired kidney function[9]. With the eliminated fraction rule (Dettli 3), any dose and any interval can be estimated and selected. The Kunin rule is a special case of the Dettli rule 3 for the condition C_trough = 1/2 C_peak. With the Kunin rule and the Dettli rule 3, the area AUC is higher than under conditions with normal kidney function.

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Figure 4 Pharmacodynamics. The threshold concentration CE₀₅ produces 5% and the ceiling concentration CE₉₅ produces 95% of the maximum effect. With a Hill coefficient of H = 1.0, the concentration is CE₀₅ = 0.5 units and the CE₉₅ = 190 units whereas for a higher Hill coefficient of H = 4.0, the threshold is high with CE₀₅ = 6.0 units but the ceiling is low with CE₉₅ = 21 units.

Figure 5 Pharmacodynamics of anti-infective drugs. The pharmacokinetics and the concentration curves are equal in both diagrams. Also the concentration producing the half-maximum effect is the same but the Hill coefficient is different. A: Concentration-dependent effect: With a Hill coefficient of H = 1.0, the calculated peak effect is only 60% and far from the ceiling effect CE₉₅. Thus, the concentration-dependent effect could be strengthened by increasing the dose; B: Time-dependent effect: With a Hill coefficient of H = 4.0, the calculated trough effect falls below the threshold concentration CE₀₅ at the second part of the administration interval. Thus, the time-dependent effect could be strengthened by dosing more frequently.

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Figure 6 Serum creatinine (Screa) and estimated kinetic glomerular filtration rate in acute kidney injury. The kinetic GFR can also be estimated during continuous renal replacement therapy continuous hemofiltration (CRRT)[14]. GFR: Glomerular filtration rate; AKI: Acute kidney injury.

Figure 7 The dose after dialysis (D_HD) replaces both the dose adjusted for kidney failure (D_fail), and the supplementary dose (D_suppl) that compensates for the fraction (FR) removed during hemodialysis (HD).

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