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

Zandvliet, Anthe S.
Schellens, Jan H. M.
Dittrich, Christian
Wanders, Jantien
Beijnen, Jos H.
Huitema, Alwin D. R.

¹Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, ²Beta Faculty, Department of Pharmaceutical Sciences, Division of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht and ³Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands, ⁴LBI-ACR Vienna and ACR–ITR Vienna, Centre for Oncology and Haematology, KFJ-Spital, Vienna, Austria and ⁵Eisai Ltd, London, UK

Correspondence Dr Anthe S Zandvliet, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Tel: +31 20 5124657; E-mail: [email protected]

This research was supported by a grant from the Eisai network of companies.

Received 28 Jan 2008; Accepted 16 May 2008; PUBLISHEDOnlineEarly 16 July 2008

British Journal of Clinical Pharmacology 66(4):p 485-497, October 2008.

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.