DEVELOPMENT CONCEPT OF PHARMACOKINETICS SIMULATION TO PREDICT CHRONOKINETICS PROFILE OF DIGOXIN ON MULTIPLE DOSAGE REGIMEN

Background: Pharmacokinetic simulation is a method that can be used to estimate the concentration profile of drugs in blood, especially in determining the level of drug safety. One of the phenomena related to drug safety is chronopharmacokinetic. Chronopharmacokinetic can cause deviations in drug kinetics profiles due to biological rhythms. This is important to note especially in narrow therapeutic index drugs such as digoxin, because sudden changes in drug kinetics are very susceptible to toxic effects. Strengthening the concept of this phenomenon is needed through the development of a simulation model of chronopharmacokinetic digoxin in multiple-doses. Methods: A pre-experimental study of a one shot case study approach was carried out. The case’s data were then be remodeled, re-simulated, and re-analyzed in accordance with the concept of simulation development. Result: The digoxin pharmacokinetics equation on average at 07.00 AM is PC = 1.667 e-0.418.t + 0.986 e-0.022.t – 0.860 e-1.519.t and at 04.00 PM is PC = 1.438 e- 0.562.t + 1.354 e-0.020.t – 1.066 e-1.098.t. The results of statistical tests of digoxin kinetic parameters showed, volume distribution (VD) was significantly higher in the morning compared to the afternoon. Absorption rate, elimination, drug clearance, digoxin at 07.00 AM have a higher tendency than at 04.00 PM, while the half-life of elimination, AUC, steady-state plasma concentrations tend to be lower at 07.00 AM compared to 04.00 PM. Conclusion: Modeling the deviation of the drug kinetics profile was successfully developed. The Chronopharmacokinetic phenomenon needs to be watched out especially on drugs with a narrow therapeutic index. Keywords: Pharmacokinetics Simulation, Chronopharmacokinetic, Digoxin, Multiple Dosage Regimen, Pharmacokinetics Modelling.