(no subject)

Dear NMusers, We have a small series of some 100 blood measurements in 13 neutropenic patients for a specific intravenous antibiotic. A population PK model for this antibiotic has already been published, based on about 300 patients, probably with very few neutropenic cases (neutropenia has not been tested as a covariate). The 2 compartment model includes 4 PK parameters (CL, V1, V2, Q), each with inter-individual variability, plus 7 coefficients applying to significant covariates and 1 residual variability. Rather than re-inventing a pop-PK model for our 13 neutropenic patients, we just wanted to check whether the model already published applied to them. Then we planned to use model-derived MAP values for AUC and Cmin. So we first ran the model on these 13 patients with all 16 parameters fixed/bound to their published reference value, and we obtained a value of the objective function (say OF_ref), along with estimates of AUC and Cmin. Thereafter, we estimated all parameters (except one that needed to be kept fixed) and we obtained another value of the objective function (say OF_fit). The parameter values obtained after fitting did not differ much from their published reference values, comprised in +/- 2SE for all except one; however, most SEs were of course large due to our small number of patients. PRED vs OBS scatter plots were not suggestive of bias; PRED_ref vs PRED_fit plots were well correlated. The fit decreased the objective function (OF_ref - OF_fit) by about 40 points. We have a rather elementary question here : can this decrease in objective function be used to test statistically whether our 13 neutropenic patients globally differ from the population PK profile described in the published reference model? Can we simply interpret the drop from OF_ref to OF_fit as following a Chi-square distribution with 15 degrees of freedom under the null hypothesis (i.e. neutropenic patients belong to the same population as the reference)? Or should we privilege more sophisticated approaches to answer this question? We searched the NMusers archive without finding much about this point. Thanks in advance Thierry Buclin, Aziz Chaouch University Hospital CHUV, Lausanne, Switzerland