Population Pharmacokinetic-Pharmacodynamic Model for Neutropenia with Patient Subgroup Identification: Comparison across Anticancer Drugs

Abstract

Purpose: 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 systemrelated pharmacodynamic variable between drugs. Experimental Design: 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 physiologybased 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 a 1 -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 drugspecific 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.In cancer chemotherapy, despite dose adaptation to body surface area, the degree of interpatient variability in effects is large (1, 2). Some patients fail to respond, whereas others experience unacceptable toxicity (3). Myelosuppression is the most common, often dose-limiting toxicity. Neutropenia makes patients highly susceptible to pathogens resulting in lifethreatening infections or even death.Empirical pharmacodynamic models accounting for the entire concentration-time profile of neutrophils have been developed (4,5). Recently, also (semi-)mechanistic models (6, 7) and a physiology-based pharmacokinetic-pharmacodynamic model describing neutropenia for several drugs (8) have been introduced. Mechanistic models have the great advantage that estimated variables may be attributed and compared with physiologic values.The contribution of pharmacokinetic or pharmacodynamic variability to the variable clinical outcome has clearly been shown (9, 10). A more rational approach for optimal dosing is based on elucidating the sources of variabil...

Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression

“…Th e myelosuppression model could well characterize the neutrophil-time course following both the single-agent and combination therapy for all the investigated datasets and resulted in similar systemrelated parameter estimates as previously observed for other data sets [8,28]. For 5-fl uorouracil, Slope was not signifi cantly diff erent from zero i.e.…”

Pharmacodynamic model for chemotherapy-induced anemia in rats

“…This approach has been widely applied to various anticancer agents [10,[37][38][39] since it is simple in nature to operate with minimum number of parameters while accounting for the time delay for onset of responses and rebound phase typically observed in myelosuppression profiles. A similar approach has been also applied to chemotherapy-related thrombocytopenia [40].…”

Semi-mechanistic population pharmacokinetic/pharmacodynamic model for neutropenia following therapy with the Plk-1 inhibitor BI 2536 and its application in clinical development

“…Several authors have suggested that female gender is among others a significant predictor of neutropenia and is considered a risk factor in the Guidelines for the use of Colony-Stimulating factors in Managing Neutropenia [27]. However, gender was not found as a clinically relevant covariate in PK/PD models for neutropenia although a statistical significance was shown [19,28]. For BI 2536, the gender and BSA effects were not supported by recent data obtained in a Phase II study (data not shown) and therefore dose adjustment due to gender or BSA is not warranted.…”