Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease

Abstract

Pharmacokinetics and pharmacodynamics follow the logic of cause and consequence. Receptor-mediated and reversible effects can be distinguished from direct and irreversible effects. Reversible effects are capacity-limited and saturable whereas irreversible effects are limited only by the number of viable targets. In the case of receptor-mediated and reversible effects a threshold and a ceiling concentration can be defined. Antimicrobial drugs with concentration-dependent action are distinguished from drugs with time-dependent action. Concentration-dependent effects are associated with a high ceiling concentration and the target is the high peak. Time-dependent effects are associated with a high threshold concentration and the target is the high trough. During kidney dysfunction, alterations of drug response are usually attributed to pharmacokinetic but rarely to pharmacodynamic changes. Dose adjustment calculations, therefore, tacitly presume that pharmacodynamic parameters remain unchanged while only pharmacokinetic parameters are altered in kidney failure. Kidney dysfunction influences the pharmacokinetic parameters of at least 50% of all essential drugs. Clinicians usually consider pharmacokinetics when kidney disease is found, but pharmacodynamics is as important. Alterations of pharmacodynamic parameters are conceivable but only rarely reported in kidney failure. Sometimes surprising dosing adjustments are needed when pharmacodynamic concepts are brought into the decision process of which dose to choose. Pharmacokinetics and pharmacodynamics should both be considered when any dosing regimen is determined.

Keywords: Tacrolimus; chemotherapy; kidney failure; pharmacokinetics.

Figure 1.

Pharmacodynamics (PD) follow pharmacokinetics (PK). The time-dependent course of the effect can be modeled by inserting the time-dependent concentration decline (C) into the equation for the pharmacodynamic Emax model (E). In contrast to an irreversible effect, reversible effects (E) concomitantly diminish when concentrations (C) decline with time (t). The effect bisection time will rise in proportion to the T_1/2 (T_1/2→TED₅₀). This suggests to extend the administration interval when the elimination is impaired in kidney failure (T_1/2: 12→24). Emax, maximum effect; CE₅₀, concentration producing half-maximum effect; TED₅₀, effect bisection time.

Figure 2.

Pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban (12). Pharmacodynamics (right): The effect bisection time (TED₅₀) can be read off at approximately 15 hours for apixaban (red arrow) and at 29 hours for rivaroxaban (blue arrow). The time after dosing when 50% of maximum effect (Emax) is produced is 15 hours with apixaban but 29 hours with rivaroxaban. Pharmacokinetics (left): At 27 hours (=12+15), the concentration producing 50% of Emax (CE₅₀) can visually be determined with CE₅₀=50 µg/L for apixaban (red) but at 29 hours with CE₅₀=20 µg/L for rivaroxaban (blue).

Figure 3.

Carboplatin and kidney failure: Near-normal elimination kinetics can be established by hemodialysis (HD) initiated 2 hours after carboplatin infusion.

Figure 4.

The effect (E) depends on concentrations (C) according to the sigmoid Emax model. Pharmacodynamic parameters as determined for normal kidney function potentially might change due to kidney failure: When the Hill coefficient decreases (H: →1.0) the dose must be increased. When the maximum effect is diminished (Emax: →50) more of the drug or another drug should be given. When the effects of two drugs are additive (Emax: →150) the combination has advantages. When the concentration producing the half-maximum effect increases (CE₅₀: →40) a higher dose will be needed. Conversely, when the sensitivity increases (CE₅₀: →10) the dose must be reduced. Most frequently, but not exclusively so, the dosage should be reduced in kidney failure.