Understanding the time course of pharmacological effect: a PKPD approach

Abstract

The key concepts that underpin the choice of drug and dosing regimen are an understanding of the drugs' effectiveness, the potential for adverse effects, and the expected time course over which both desired and adverse effects are likely to occur. Research in clinical pharmacology should therefore address three fundamental questions: (1) What is the magnitude of drug effects (beneficial or adverse) from a given dose? (2) How quickly will any given effects occur? (3) How long will these effects last? Under steady-state conditions, only the magnitude of drug effects can be examined. This requires researchers to consider non-steady-state conditions, which require more complex models and an understanding of the mechanisms that drive the time course of drug effect. The aim of this review is to provide a conceptual framework for understanding the time course of drug effects using pharmacokinetic-pharmacodynamic models. Key examples will illustrate how this can inform the optimal use of drugs in the clinic.

Figure 1

Schematic depicting pharmacokinetic (PK) and pharmacodynamic (PD) models used in clinical pharmacology

Figure 2

Conceptual framework for pharmacokinetic–pharmacodynamic models. By combining the time element from pharmacokinetics (A) and the effect data from pharmacodynamic analysis (B) it is possible to explore the time course of drug effect (C)

Figure 3

Schematic of a biophase model. The hypothetical effect compartment C_e (or biophase) acts as a link between the pharmacokinetic and pharmacodynamic models

Figure 4

Schematic of a turnover model. The four proposed mechanisms are (A) reduced production of an intermediary/response function, (B) enhanced production of an intermediary/response function, (C) reduced degradation of an intermediary/response function and (D) enhanced degradation of an intermediary/response function (after Jusko & Ko [32])

Figure 5

Warfarin plasma concentrations (A) appear in the plasma within an hour or two of dosing, yet the peak drug effect on PCA (B) is significantly delayed. PCA = prothrombin complex activity, [warfarin]= plasma total (R- and S-) warfarin concentration, normalized to dose. Data from O'Reilly et al. [37], and O'Reilly and Aggeler [38]

Figure 6

Furosemide and schedule dependence. AUCe = the area under the effect curve which in this case is Na⁺ excretion. A single 120-mg dose of furosemide results in less total diuresis over 12 h than three 40-mg doses. 40 mg × 3. AUCe = 600 mmol Na⁺ 12 h⁻¹ (); 120 mg × 1. AUCe = 430 mmol Na⁺ 12 h⁻¹ ()