Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d‐tubocurarine

Abstract

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

“…PK and PKPD analysis was achieved by use of the compartmental modeling SAAM II software system (SAAM Institute, Seattle, WA, USA). A link compartment representing stimulation of the locomotor behavior was used to describe the data (Sheiner et al 1979). Integration of mephedrone pharmacokinetics and pharmacodynamics was based on the relationship between mean plasma mephedrone concentration-time profile for i.v.…”

An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as “bath salts”

“…A link compartment representing stimulation of the locomotor behavior was used to describe the data (Sheiner et al, 1979). Integration of methylone pharmacokinetics and pharmacodynamics was based on the relationship between mean plasma methylone concentration-time profile for i.v.…”

“…This hysteresis can be explained by the appearance of active metabolites (Mandema et al, 1992); by indirect mechanisms of drug action (Dayneka et al, 1993) or by an imbalance between the site of action (the brain) and the plasmatic compartment (Sheiner et al, 1979).…”

Pharmacokinetic–pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients

“…Plasma concentrations of the parent drug and of its metabolite Perindopril and perindoprilat plasma concentrations (ng ml x1 ) were determined from venous blood samples by radioimmunoassay as previously described [20]. Measurements were performed before and 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,10,12,16,20,24,48 and 72 h after drug intake in HV. In CHF patients, the same schedule was used except that the two samples drawn at 16 and 20 h were replaced by a single one drawn at 18 h. The detection limit of the assay was 0.4 ng ml x1 for both perindopril and perindoprilat.…”