Anthe S. Zandvliet

Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam

SummaryIndisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model.Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check.The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir.A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.

Population pharmacokinetics and pharmacodynamics for treatment optimization in clinical oncology.

Population pharmacokinetic and pharmacodynamic analysis is an important tool to support optimal treatment in clinical oncology. The population approach is suitable to explain variability between patients and to establish relationships between drug exposure and a relevant pharmacodynamic parameter. This can facilitate the selection of dosing schedules, the development of strategies for dose individualization and the application of therapeutic drug monitoring of anticancer agents. This review discusses the role of population pharmacokinetics and pharmacodynamics in clinical oncology to enhance the efficiency of drug development and to support the development of safe and effective dosing regimens for optimal treatment of cancer patients. An overview of published population studies of investigational anticancer agents and established treatment regimens is presented.

CYP2C9 and CYP2C19 Polymorphic Forms Are Related to Increased Indisulam Exposure and Higher Risk of Severe Hematologic Toxicity

Purpose: The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation. Experimental Design: Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL, Vmax, Km) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study. Results: The Michaelis-Menten elimination rate (Vmax) was decreased by 27% (P < 0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P < 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m2 per mutated allele may be required to normalize this risk. Conclusions: CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.

Population pharmacokinetic and pharmacodynamic analysis to support treatment optimization of combination chemotherapy with indisulam and carboplatin.

AIMS Indisulam and carboplatin have shown synergistic activity in preclinical studies. In a dose escalation study of the combination, a treatment delay was frequently required in a 3-weekly regimen to allow recovery from myelosuppression from previous cycles. A 4-weekly regimen was better tolerated, but had a decreased dose-intensity which may compromise efficacy. The aims of this study were (i) to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to describe the myelosuppressive effect of the combination, and (ii) to use this model to select a dosing regimen for Phase II evaluation. METHODS Sixteen patients were treated at four different dose levels of indisulam (1-h infusion on day 1) and carboplatin (30-min infusion on day 2). Pharmacokinetic data were analysed with nonlinear mixed effects modelling. A semiphysiological model describing chemotherapy-induced myelosuppression characterized the relationship between the pharmacokinetics and the haematological toxicity of indisulam and carboplatin. A simulation study was performed to evaluate the tolerability and dose-intensity for 3-weekly and 4-weekly treatment regimens. RESULTS The PK-PD model described the pharmacokinetics and the myelosuppressive effect of indisulam and carboplatin. The risk of a treatment delay at cycle 2 due to myelosuppression was unacceptably high (34-65%) in a 3-weekly regimen for various dose levels (350-600 mg m(-2) indisulam in combination with carboplatin to achieve an AUC of 4-6 mg min(-1) ml(-1)). This risk was acceptable for a 4-weekly regimen (9-24%), which is in line with the clinical study results. CONCLUSIONS This PK-PD study supports the selection of indisulam 500 mg m(-2) and a dose of carboplatin to achieve an AUC of 6 mg min(-1) ml(-1) in a 4-weekly regimen as the recommended dose for future studies.

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

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/m2 indisulam and 1,250 mg/m2 capecitabine twice daily was considered safe.

Performance of Methods for Handling Missing Categorical Covariate Data in Population Pharmacokinetic Analyses

In population pharmacokinetic analyses, missing categorical data are often encountered. We evaluated several methods of performing covariate analyses with partially missing categorical covariate data. Missing data methods consisted of discarding data (DROP), additional effect parameter for the group with missing data (EXTRA), and mixture methods in which the mixing probability was fixed to the observed fraction of categories (MIXobs), based on the likelihood of the concentration data (MIXconc), or combined likelihood of observed covariate data and concentration data (MIXjoint). Simulations were implemented to study bias and imprecision of the methods in datasets with equal-sized and unbalanced category ratios for a binary covariate as well as datasets with non-random missingness (MNAR). Additionally, the performance and feasibility of implementation was assessed in two real datasets. At either low (10%) or high (50%) levels of missingness, all methods performed similarly well. Performance was similar for situations with unbalanced datasets (3:1 covariate distribution) and balanced datasets. In the MNAR scenario, the MIX methods showed a higher bias in the estimation of CL and covariate effect than EXTRA. All methods could be applied to real datasets, except DROP. All methods perform similarly at the studied levels of missingness, but the DROP and EXTRA methods provided less bias than the mixture methods in the case of MNAR. However, EXTRA was associated with inflated type I error rates of covariate selection, while DROP handled data inefficiently.

Two-stage model-based clinical trial design to optimize phase I development of novel anticancer agents

SummaryBackground The phase I program of anticancer agents usually consists of multiple dose escalation studies to select a safe dose for various administration schedules. We hypothesized that pharmacokinetic and pharmacodynamic (PK–PD) modeling of an initial phase I study (stage 1) can be used for selection of an optimal starting dose for subsequent studies (stage 2) and that a post-hoc PK–PD analysis enhances the selection of a recommended dose for phase II evaluation. The aim of this analysis was to demonstrate that this two-stage model-based design, which does not interfere in the conduct of trials, is safe, efficient and effective. Methods PK and PD data of dose escalation studies were simulated for nine compounds and for five administration regimens (stage 1) for drugs with neutropenia as dose-limiting toxicity. PK–PD models were developed for each simulated study and were used to determine a starting dose for additional phase I studies (stage 2). The model-based design was compared to a conventional study design regarding safety (number of dose-limiting toxicities (DLTs)), efficiency (number of patients treated with a dose below the recommended dose) and effectiveness (precision of dose selection). Retrospective data of the investigational anticancer drug indisulam were used to show the applicability of the model-based design. Results The model-based design was as safe as the conventional design (median number of DLTs = 3) and resulted in a reduction of the number of patients who were treated with a dose below the recommended dose (−27%, power 89%). A post-hoc model-based determination of the recommended dose for future phase II studies was more precise than the conventional selection of the recommended dose (root mean squared error 8.3% versus 30%). Conclusions A two-stage model-based phase I design is safe for anticancer agents with dose-limiting myelosuppression and may enhance the efficiency of dose escalation studies by reducing the number of patients treated with a dose below the recommended dose and by increasing the precision of dose selection for phase II evaluation.

A phase I and pharmacokinetic study of indisulam in combination with carboplatin

Indisulam (E7070) is an anticancer agent that is currently being evaluated in phase II clinical studies. A significant reduction in glutathione synthetase and glutathione reductase transcripts by indisulam provided a molecular basis for its combination with platinum agents. Indisulam demonstrated high anti-tumour activity in various preclinical cancer models. The objectives of this study were (1) to determine the recommended dose of indisulam in combination with carboplatin in patients with solid tumours and (2) to evaluate the pharmacokinetics of the combination. Patients with solid tumours were treated with indisulam in combination with carboplatin. Indisulam (350, 500, or 600 mg m−2) was given as a 1-hour intravenous infusion on day 1 and carboplatin (5 or 6 mg min ml−1) as an intravenous infusion over 30 min on day 2 of a three-weekly cycle. Sixteen patients received study treatment and were eligible. Thrombocytopenia was the major dose limiting toxicity followed by neutropenia. Both drugs contributed to the myelosuppressive effect of the combination. Indisulam 500 mg m−2 in combination with carboplatin 6 mg min ml−1 was identified not to cause dose limiting toxicity, but a delay of re-treatment by 1 week was required regularly to allow recovery from myelosuppression. The recommended dose and schedule for an envisaged phase II study in patients with non-small cell lung cancer is indisulam 500 mg m−2 in combination with carboplatin 6 mg min ml−1 repeated four-weekly. Patients who do not experience severe thrombocytopenia at cycle 1 will be permitted to receive an escalated dose of indisulam of 600 mg m−2 from cycle 2 onwards.

Saturable Binding of Indisulam to Plasma Proteins and Distribution to Human Erythrocytes

The anticancer agent indisulam has a nonlinear pharmacokinetic profile, which may be partly related to saturable binding to blood constituents. To gain insight into the complex nonlinear behavior of indisulam, we investigated binding to plasma proteins and erythrocytes. The purpose of the study was to develop a physiological model for the distribution of indisulam in blood. Concentrations of radiolabeled indisulam were measured in vitro 1) in total plasma and in ultrafiltrate to investigate plasma protein binding, 2) in erythrocytes and in plasma to investigate distribution to erythrocytes, and 3) in erythrocyte membranes to investigate nonspecific binding in erythrocytes. For in vivo assessment, 21 patients received 400 to 900 mg/m2 indisulam in a 1- or 2-h infusion. Total and free concentrations in plasma and concentrations in erythrocytes were determined at multiple time points. In vitro plasma protein binding was described by a Langmuir model with a maximal binding capacity (Bmax = 767 μM) and an equilibrium dissociation constant (KD = 1.02 μM). The maximal capacity of plasma protein binding in vivo corresponded to albumin levels. The bound concentration in erythrocytes was described by a two-site model, comprising a saturable and a nonspecific binding component. The saturable component (Bmax = 174 μM) may correspond to binding to carbonic anhydrase. The physiological model adequately described the nonlinear disposition of indisulam in whole blood. Indisulam was bound to plasma proteins and distributed to erythrocytes in a saturable manner. These saturable processes may be attributed to binding to albumin (in plasma) and to carbonic anhydrase (in erythrocytes).

A dose-escalation study of indisulam in combination with capecitabine (Xeloda) in patients with solid tumours.

This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m−2 and capecitabine 1250 mg m−2 BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m−2) in combination with capecitabine (1250 mg m−2 BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m−2 and capecitabine 1250 mg m−2 BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction.