Serum cystatin C is a better marker of topotecan clearance than serum creatinine.
OBJECTIVE
To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics. Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance.


METHODS
Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients).


RESULTS
Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06](-0.60) [IBW (kg) / 57](0.95). Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area.


CONCLUSIONS
Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.
Hoppe
Antje
A
EA 3035 and Department of Clinical Biology, Institut Claudius-Regaud, Toulouse, France.
Séronie-Vivien
Sophie
S
Thomas
Fabienne
F
Delord
Jean-Pierre
JP
Malard
Laurence
L
Canal
Pierre
P
Chatelut
Etienne
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D003401:Creatine / Q000097:blood*; D055316:Cystatin C; D015891:Cystatins / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D015415:Biomarkers; C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D019772:Topotecan; D003401:Creatine