A Bayesian Population PK–PD Model of Ispinesib-induced Myelosuppression

Abstract

The goal of the present analysis is to fit a Bayesian population pharmacokinetic pharmacodynomic (PK-PD) model to characterize the relationship between the concentration of ispinesib and changes in absolute neutrophil counts (ANC). Ispinesib, a kinesin spindle protein (KSP) inhibitor, blocks assembly of a functional mitotic spindle, leading to G2/M arrest. A first time in human, phase I open-label, non-randomized, dose-escalating study evaluated ispinesib at doses ranging from 1 to 21 mg/m(2). PK-PD data were collected from 45 patients with solid tumors. The pharmacokinetics of ispinesib were well characterized by a two-compartment model. A semimechanistic model was fit to the ANC. The PK and PD data were successfully modelled simultaneously. This is the first presentation of simultaneously fitting a PK-PD model to ANC using Bayesian methods. Bayesian methods allow for the use of prior information for some system-related parameters. The model may be used to examine different schedules, doses, and infusion times.

Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients

“…Actually, the estimates of the typical values of the system-related parameters, Circ 0 , MTT and γ, were similar to those obtained previously (14,21,23,(26)(27)(28)(29)(30)36,45,46,55,57), including MTT, which was estimated at the lower end of the values found in other studies (14,26). In addition, the graphical exploratory analysis of the effect of body weight, age, serum creatinine, alkalyne phosphatase, ALT, AST, LDH, total bilirubin and total proteins on the model parameter did not evidence any statistical significant correlation, which is consistent with the results of a recent publication where these covariates were not statistically associated or had no clinically relevant effect on the model parameters derived for docetaxel, paclitaxel etoposide and topotecan (27).…”

“…Initially, the model was successfully applied to different drugs such as docetaxel, paclitaxel, etoposide, 2-deoxy-2-methylidenecytidine, irinotecan and vinflunine (14). Later, it was applied to topotecan in adult (30) and pediatric populations (36), indisulam (57), pemetrexed (28,29), diflomotecan (55), ispinesib (26), trabectedin (21) and the combinations epirubicin-docetaxel (46) and fluorouracilepirrubicin-cyclophosphamide (45). However, this model has not been applied yet to analyze the ANC data following HDC and PBSC transplantation.…”

A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model

“…Five hundred data sets were simulated from the model and the confidence interval (shadow area) for the calculated median and 95% prediction interval were superimposed on the observed data (dots).The black lines are the corresponding median and 95% percentiles of the observed data authors stated in the development of the original model an Emax model was superior to a linear model for docetaxel [5]. Even though the data in this study supported a more complex drug-effect model, a few publications [7,12,14,25,29,42] have tested an Emax model for other types of anti-cancer drugs, but have not found it to significantly improve the fit. Then again, in this study of docetaxel an Emax model showed a relative low reduction in OFV, while a sigmoid Emax model greatly improved the fit.…”

“…This model has since the original publication been successfully applied to both leukocyte and neutrophil measurements following several additional anti-cancer drugs and regimens [6][7][8][9][10][11][12][13][14][15][16]. It has also been shown to satisfactorily describe thrombocyte and lymphocyte measurements following chemotherapy [17][18][19].…”

Pharmacokinetic and Pharmacodynamic Analysis of Hyperthermic Intraperitoneal Oxaliplatin-Induced Neutropenia in Subjects with Peritoneal Carcinomatosis

“…With respect to the system related parameters, the estimated of Circ 0 was consistent with ANC normal values. The MTT could not be estimated correctly with the available data and, therefore, was fixed to 118 h as previously reported in the literature (30,(44)(45)(46)(47)(48). The estimated γ value, 0.135, was also similar to those obtained previously for other anticancer drugs, such as irinotecan (0.132) or topotecan (0.120) (30,49).…”