Population pharmacokinetics of flucytosine: Comparison and validation of three models using STS, NPEM, and NONMEM

The objective of this study is to compare and validate three models of fluc ytosine (5-FC) population pharmacokinetics using three methods of analysis to elucidate which model describes 5-FC pharmacokinetics most accurately an d which method is the most suitable for this purpose. Retrospectively, demo graphic and clinical data of two similar sets of a total of 88 intensive ca re unit (ICU) patients were gathered for calculation and validation of 5-FC pharmacokinetics respectively. Three pharmacokinetic models were analyzed: a one-compartment with renal elimination (renal model), a one-compartment with renal and metabolic elimination (mixed model), and a two-compartment w ith renal elimination (two-compartment model). Population pharmacokinetic p arameters were calculated using the standard two-stage method (STS), NONMEM , and NPEM. Furthermore, a covariate model was built by NONMEM. Validation of the 10 calculated pharmacokinetic models showed that NONMEM is most suit able for predicting 5-FC population pharmacokinetics. Based upon AIC values , bias and precision, the best results are obtained using a two-compartment model with renal elimination(k(elr) = 0.000858 +/- 0.000143 l/h per mt per min, k(12) = 0.0313 +/- 0.0168 h(-1), k(21) = 0.0353 +/- 0.0145 h(-1), and V-d = 0.541 +/- 0.084 L/kg; bias = -13.16; 95% CI = -16.77; -9.55; precisi on = 30.50; 95% CI = 27.47; 33.26) or a two-compartment covariate model as built by NONMEM [V-d (L) = 0.572.WT, Cl-5FC (L/h) = 1.69 +/- 0.0273(Cl-cr ( mL/min)- 52.5), k(12) = 0.0235 +/- 0.0107 h(-1), and k(21) = 0.0375 +/- 0.0 147 h(-1); bias = -8.29; 95% CT = -11.63; -4.95; precision = 26.77; 95% CI = 24.24; 29.07]. In conclusion, this study shows that a two-compartment mod el with renal elimination best describes 5-FC population pharmacokinetics a nd NONMEM is able to build a two-compartment covariate model that predicts 5-FC levels equally well in our population of ICU patients. Furthermore, NO NMEM appeared to be the most suitable method of population pharmacokinetics in our population and for this purpose it offers more reliable and accurat e results than NPEM or the STS method.