PK/PD Model of Indisulam and Capecitabine: Interaction Causes Excessive Myelosuppression

Abstract

The anticancer agent indisulam was evaluated in a dose-escalation study in combination with capecitabine. Severe myelotoxicity was observed after multiple treatment cycles. We hypothesized that capecitabine inhibits the synthesis of CYP2C9, which metabolizes indisulam. The objectives were to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the combination treatment and to estimate the impact of a drug-drug interaction on the safety of various dose levels. NONMEM was used to develop a PK/PD model, including the impact of capecitabine coadministration on indisulam pharmacokinetics. A simulation study was performed to evaluate the risk of dose-limiting neutropenia. A time-dependent pharmacokinetic drug-drug interaction resulted in increased exposure to indisulam and in increased myelotoxicity. The risk of dose-limiting neutropenia increased with treatment duration and with dose. The excessive myelosuppression after multiple cycles may be explained by a pharmacokinetic interaction between indisulam and capecitabine. The combination of 550 mg/m(2) indisulam and 1,250 mg/m(2) capecitabine twice daily was considered safe.

Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies

“…Therefore, only linear models were implemented and estimated. As in previous analyses with this compound [32, 33], the Circ 0 parameter was not estimated, instead observed baseline ANCs were used, thereby assuming no error in baseline measurement. Different methods of incorporating baseline with measurement error are available [34].…”

Mechanism-Based Pharmacodynamic Modeling

“…7, bottom panel), and 2′-deoxy-2′-methylidenecyti-dine for a range of dose levels and various dosing regimens. This same structural model has been used to describe indisulam-induced mye-losuppression (24), as well as the drug–drug interactions between indisulam and capecitabine (25), and pemetrexed and BI2536 (26). …”

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

“…It has also been shown to satisfactorily describe thrombocyte and lymphocyte measurements following chemotherapy [17][18][19]. Some minor modifications of the original model have been introduced in a few publications to improve the model's predictability following various types of anti-cancer drugs.…”

“…Proposed alterations of the model structure include a log-linear drug effect model instead of a linear or Emax model [10], an addition of an effect delay compartment to account for the distribution of drug from the plasma to the bone marrow [10] and an addition of a neutrophil pool to describe an early increase of neutrophil count after dosage [20]. The model has further been extended to describe the combined drug effect following combination therapy of anticancer drugs [13,17,18,[21][22][23][24], to incorporate the effect of administrated exogenous G-CSF [22,25,26] and to capture the time-course of neutrophils following peripheral blood stem-cell transplantation [26]. Additionally covariates [6,9,10,20,[27][28][29][30] and inter-occasion variability [16] have been explored using the model.…”