Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs.
OBJECTIVE
Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs.


METHODS
Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made.


RESULTS
A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha1-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction.


CONCLUSIONS
These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.
Kloft
Charlotte
C
Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, Germany. ckloft@zedat.fu-berlin.de
Wallin
Johan
J
Henningsson
Anja
A
Chatelut
Etienne
E
Karlsson
Mats O
MO
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077143:Docetaxel; D004347:Drug Interactions / Q000276:immunology; D005047:Etoposide / Q000009:adverse effects; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009503:Neutropenia / Q000139:chemically induced*; D009504:Neutrophils / Q000187:drug effects; D017239:Paclitaxel / Q000009:adverse effects; D012727:Sex Characteristics; D043823:Taxoids / Q000009:adverse effects; D019772:Topotecan / Q000009:adverse effects
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D005047:Etoposide; D019772:Topotecan; D017239:Paclitaxel