2008 - Marseille - France

PAGE 2008: Applications
Alwin Huitema

Application of modelling and simulation in clinical oncology

Alwin D.R. Huitema

Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands

Most of the cytotoxic agents currently used in cancer chemotherapy have been discovered decades ago. Dosing of these agents is usually based on the concept of the maximum tolerated dose (MTD) as assessed in phase I study in cancer patients. As a result, treatment with these drugs is often a delicate balance between dose intensity and toxicity. Most cytotoxic drugs have haematological toxicity as dose limiting toxicity but also severe (cumulative) organ toxicity may occur.

Modelling and simulation may provide an efficient tool for treatment optimization of these cytotoxic drugs. Retrospective population pharmacokinetic studies have characterized the pharmacokinetics and metabolism of many cytotoxic drugs and effects like saturable elimination, auto-induction and drug-drug interactions have been quantified.

Several approaches for treatment optimization have been explored. Co-variate based dosing has frequently been investigated, but co-variates (including body surface area) usually only explain a minor part of the observed pharmacokinetic variability. Pharmacokinetically guided dosing has also been investigated, but, prospective studies are scarce.

A (semi)-physiological PK/PD model for haematological toxicity has been developed and has been validated for a wide range of cytotoxic drugs. Subsequently, this model has been used for optimization of treatment regimens. Under the concept that cytotoxic drugs should be dosed at the MTD, this PK/PD model can be used to select the optimal dose or combination. In the clinical development of the investigational anticancer agent indisulam, this approach has led to the establishment of optimal doses of combination regimens with indisulam and for a dosing algorithm of this drug based on patient characteristics. Moreover, this PK/PD model may allow for a more efficient phase I program of novel agents with haematological toxicity as dose-limiting toxicity as assessed in a simulation study.

The last decade an increasing number of targeted agents has been introduced in clinical oncology. These agents (monoclonal antibodies and small molecules) have a completely different toxicity profile compared to the cytotoxic agents. Furthermore, the MTD concept for dosing, may not be valid for these drugs. Biomarkers for quantification of the pharmacodynamic effects of these drugs are in development as is PK/PD modelling and simulation of these drugs.

Reference: PAGE 17 (2008) Abstr 1422 [www.page-meeting.org/?abstract=1422]
Oral Presentation: Applications