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

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 µg/ml.

[1]  M. Gibaldi,et al.  Kinetics of the Elimination and Neuromuscular Blocking Effect of d-Tubocurarine in Man , 1972, Anesthesiology.

[2]  L. Sheiner,et al.  Modelling of individual pharmacokinetics for computer-aided drug dosage. , 1972, Computers and biomedical research, an international journal.

[3]  L. Benet,et al.  The pharmacokinetics of d-tubocurarine in man with and without renal failure. , 1977, The Journal of pharmacology and experimental therapeutics.

[4]  P. Meffin,et al.  Response optimization of drug dosage: Antiarrhythmie studies with tocainide , 1977, Clinical pharmacology and therapeutics.

[5]  W. Kalow Urinary excretion of d-tubocurarine in man. , 1953, The Journal of pharmacology and experimental therapeutics.

[6]  H. H. Ali,et al.  A New Approach to the Study of Four Nondepolarizing Relaxants in Man , 1974, Anesthesia and analgesia.

[7]  G Levy,et al.  Kinetics of pharmacologic effects , 1966, Clinical pharmacology and therapeutics.

[8]  G. Levy,et al.  RELATIONSHIP BETWEEN ELIMINATION RATE OF DRUGS AND RATE OF DECLINE OF THEIR PHARMACOLOGIC EFFECTS. , 1964, Journal of pharmaceutical sciences.

[9]  J. Dillon,et al.  Durations of action of d-tubocurarine and gallamine. , 1968, Anesthesiology.

[10]  V. Barnett,et al.  Applied Linear Statistical Models , 1975 .

[11]  E. Eger,et al.  The Dependence of Pancuronium- and d‐Tubocurarine- induced Neuromuscular Blockades on Alveolar Concentrations of Halothane and Forane , 1972, Anesthesiology.

[12]  S. Sharpless,et al.  The rapid development of physical dependence on barbiturates. , 1965, The Journal of pharmacology and experimental therapeutics.

[13]  D. Waud On biological assays involving quantal responses. , 1972, The Journal of pharmacology and experimental therapeutics.

[14]  S. Spector,et al.  Determination of serum d-tubocurarine concentration by radioimmunoassay. , 1973, The Journal of pharmacology and experimental therapeutics.