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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Chemotherapy with indisulam in combination with a standard dose of carboplatin was not well tolerated in a 3‐weekly regimen in a Phase I dose escalation study. • Myelosuppression was the dose limiting toxicity. • This pharmacokinetic–pharmacodynamic (PK–PD) study was performed to suggest a dosing regimen for the combination therapy indisulam–carboplatin that is well tolerated in patients. WHAT THIS STUDY ADDS • 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. 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.