Kinetic nomograms assist individualization of drug regimens
Marouani Hafedh 1 PhD, Zografidis Anastasios 2 PhD, Iliadis Athanassios 1 Pr
(1) Dpt. of Pharmacokinetics, UMR-MD3, Univ. of Méditerranée, Marseilles, France, (2) University of Athens, School of Pharmacy, Panepistimiopolis, 15771 Athens, Greece
Objective: The aim of this work is to propose a rapid and simple drug dosage adjustment method. Develop a useful tool in achieving individual drug blood levels within its therapeutic window with few samples and in a short period of time, rendering the procedure a simplified bedside application.
Methods: The procedure is codified by kinetic nomograms. To obtain these, statistical description of the inter-individual variability provided by the population pharmacokinetic study (prior information) and assayed drug concentrations from two blood samples in a given individual (individual information) are required. The kinetic nomogram is built as a collection of time-concentration curves following a fixed "identification protocol". The time-concentration curves divide the "time-concentration space" in several areas each of them corresponding to a given adjusted dose. One has only to locate the assayed drug concentration and then, read the dose corresponding to the area containing this location. Kinetic nomograms are simplified alternatives to the Bayesian procedure [1] followed by dosage adjustment procedures. Evaluation of kinetic nomogram performances was done by a simulation study using as example rapamycin (sirolimus®), an immunosuppressant drug indicated for the prophylaxis of renal allograft rejection [2]. All calculations were performed with the MATLAB software [3].
Results: The simulation study confirmed the need for individual dosage adjustment, 71.6% of individuals underwent modification of the identification protocol of 1 mg b.i.d. in order to reach steady-state trough levels at 8 ng/ml. When regimens were adjusted by kinetic nomograms and Bayesian procedure, the minimum steady-state concentrations of sirolimus showed low variability (CV of 23.4 and 18.2%, respectively) as compared to those obtained by standard recommended protocols of 4 mg o.i.d. (68.6%). Doses adjusted by kinetic nomograms and Bayesian procedure are linearly linked and highly correlated (r = 0.97), and both provided efficient control (87.9 and 99.6% of cases between 6 and 20 ng/ml respectively).
Conclusion: Kinetic nomograms allowing rapid dosage adjustment after beginning the drug therapy represent reliable alternatives to the cumbersome Bayesian procedure. They could be tailored for several clinical situations and different schedules. The presented kinetic nomograms can highly promote other population studies aiming at dose individualization with direct application in current clinical settings.
References:
[1]. Iliadis A, Brown AC, Huggins ML. APIS: A software for identification, simulation and dosage regimen calculations in clinical and experimental pharmacokinetics. Computer Methods and Programs in Biomedicine 1992;38(4):227-239.
[2]. Djebli N, Rousseau A, Hoizey G, Rerolle JP, Toupance O, LeMeur Y, et al. Sirolimus population pharmacokinetic/pharmacogenetic analysis and Bayesian modelling in kidney transplant recipients. Clinical Pharmacokinetics 2006;45(11):1135-1148.
[3]. MATLAB. High-performance Numeric Computation and Visualization Software. In. 7.0 ed. Natick MA: The Math Works; 2004.
