Multiplicative dependence of the first order rate constant and its impact on clinical pharmacokinetics and bioequivalence.
The purpose of the study was to investigate the factors upon which the first order rate constant depends in order to assess the impact on the body-drug concentration when it changes throughout a treatment. A reasoning for linking the first order rate constants with several factors in a multiplicative way was proposed out taking into account kinetic and thermodynamic aspects. A multi-compartment model for drug disposition was analyzed and compartment mean drug concentrations at steady state were obtained as a function of the model kinetic constants. At the moment, only four factors were identified as responsible for the actual rate constant value. Apart from an intrinsic kinetic constant, they are the inverse of compartment volume, the transfer surface area, the fraction of mass able to be transferred, and the fraction of mass that effectively can be transferred. In clinical practice some of these factors might change throughout time (because of chronophysiological rhythms or drug availability at the action sites) and consequently, an inconstant extra-plasma/plasma drug concentration ratio could be obtained. In conclusion, therapeutic response prediction for a treatment does not upon plasma drug concentration monitoring. Equivalence in plasma drug exposure should not mean therapeutic equivalence, because differences in the rate and in the extent between test and reference products may induce a change in the action site/plasma drug concentration ratio.
Fagiolino
Pietro
P
Pharmacology & Biopharmaceutics Department, Faculty of Chemistry, Montevideo, Uruguay.
D008962:Models, Theoretical; D010601:Pharmacology, Clinical / Q000379:methods*; D013810:Therapeutic Equivalency