Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents Farmacokinetisch gestuurde toediening van (hooggedoseerde) chemotherapie (met een samenvatting in het Nederlands) PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. Dr W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op vrijdag 17 december 2004 des middags te 12.45 uur door Milly Ellen Attema-de Jonge geboren op 17 juni 1976 te Harderwijk Promotores: Prof. Dr J.H. Beijnen The Netherlands Cancer Institute / Slotervaart Hospital, Amsterdam; Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands Prof. Dr S. Rodenhuis The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital, Amsterdam; Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands Co-promotor: Dr A.D.R. Huitema The Netherlands Cancer Institute / Slotervaart Hospital, Amsterdam, The Netherlands CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DEN HAAG De Jonge, Milly Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents / Milly de Jonge. Utrecht: Universiteit Utrecht, Faculteit Farmacie. Thesis University Utrecht. With a summary in Dutch. ISBN 90-9018807-X 2004 Milly de Jonge, Weesp Cover design: Martin & Maartje Arkes: “tailor-made pharmacy” Printed by: Ponsen & Looijen B.V., Wageningen, The Netherlands The studies described in this thesis were performed at the Department of Pharmacy and Pharmacology of The Netherlands Cancer Institute / Slotervaart Hospital and the Department of Medical Oncology of The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. This work was supported with a grant from the Dutch Cancer Society (project NKI 2001- 2420). Publication of this thesis was financially supported by: Dutch Cancer Society, Amsterdam, The Netherlands Baxter Deutschland GmbH, Heidelberg, Germany Stichting KNMP fondsen, Den Haag, The Netherlands J.E. Jurriaanse Stichting, Rotterdam, The Netherlands Merck Sharp and Dohme B.V., Haarlem, The Netherlands Bristol-Myers Squibb B.V., Woerden, The Netherlands Pfizer B.V., Capelle aan den IJssel, The Netherlands Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands Stichting Netherlands Laboratory for Anticancer Drug Formulation, Amsterdam, The Netherlands Voor Jan Wijbrand Contents Preface 11 Chapter 1: Introduction 1.1 Individualized cancer chemotherapy: Strategies and performance of 15 prospective studies on therapeutic drug monitoring with dose adaptation. Clin Pharmacokinet (in press) 1.2 Clinical pharmacokinetics of cyclophosphamide. 45 Clin Pharmacokinet (in press) Chapter 2: Sampling and bioanalysis 2.1 Simultaneous quantification of cyclophosphamide, 4-hydroxycyclo- 83 phosphamide, N,N’,N’’-triethylenethiophosphoramide (thiotepa) and N,N’,N’’-triethylenephosphoramide (tepa) in human plasma by high- performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-MS/MS). J Mass Spectrom 2004; 39: 262-271 2.2 Sorption of thiotepa to polyurethane catheter causes falsely elevated plasma 101 levels. Ther Drug Monit 2003; 25: 261-263 Chapter 3: Population pharmacokinetics 3.1 Integrated population pharmacokinetic model of both cyclophosphamide and 109 thiotepa suggesting a mutual drug-drug interaction. J Pharmacokinet Pharmacodyn 2004; 31: 135-156 3.2 Sparse sampling design for therapeutic drug monitoring of sequentially 129 administered cyclophosphamide, thiotepa and carboplatin (CTC). Submitted 3.3 Population pharmacokinetics of cyclophosphamide and its metabolites 149 4-hydroxycyclophosphamide, 2-dechloroethylcyclophosphamide and phosphoramide mustard in a high-dose combination with thiotepa and carboplatin. Submitted 3.4 Population pharmacokinetics of orally administered paclitaxel formulated in 167 Cremophor EL. Br J Clin Pharmacol (in press) Chapter 4: Pharmacokinetic determinants 4.1 Significant induction of cyclophosphamide and thiotepa metabolism by 183 phenytoin. Cancer Chemother Pharmacol (in press) 4.2 Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. 191 Submitted 4.3 Effects of co-medicated drugs on cyclophosphamide bioactivation in human 203 liver microsomes. Submitted 4.4 Extremely high exposures in an obese patient receiving high-dose 213 cyclophosphamide, thiotepa and carboplatin. Cancer Chemother Pharmacol 2002; 50: 251-255 4.5 Flat dosing of carboplatin is justified in patients with normal renal function. 223 Submitted Chapter 5: Pharmacokinetic-pharmacodynamic relationships 5.1 Relationship between irreversible alopecia and exposure to cyclophos- 237 phamide, thiotepa and carboplatin (CTC) in high-dose chemotherapy. Bone Marrow Transplant 2002; 30: 593-597 5.2 High exposures to bioactivated cyclophosphamide are related to the 247 occurrence of veno-occlusive disease of the liver (VOD) following high-dose chemotherapy. Submitted Chapter 6: Pharmacokinetically guided dosing 6.1 Accuracy, feasibility and clinical impact of prospective Bayesian 261 pharmacokinetically guided dosing of cyclophosphamide, thiotepa and carboplatin in high-dose chemotherapy. Clin Cancer Res (in press) 6.2 Bayesian pharmacokinetically guided dosing of paclitaxel in patients with 281 non-small cell lung cancer. Clin Cancer Res 2004; 10: 2237-2244 Summary and conclusions 299 Samenvatting en conclusies 307 Dankwoord 313 Curriculum vitae 315 List of publications 316 Preface Preface Large interpatient variability in the pharmacokinetic disposition of anticancer drugs is an important determinant of the differences observed between patients in response to chemotherapeutic treatment, in terms of antitumor activity and side effects. When a drug is administered in the same, standardized dosage, those patients who metabolise and excrete the active drug rapidly experience low systemic exposures. Since, for many anticancer agents, exposure to the agent is correlated to both efficacy and toxicity, pharmacokinetic variability may cause drug therapy to fail in some patients while being effective in others, and may cause significant toxicity in one patient while others tolerate the therapy without adverse events. A significant therapeutic gain may therefore be achievable in anticancer treatment when variability in drug exposure can be minimized. A way to decrease interpatient variability in drug exposure is to monitor plasma levels of these agents. These plasma levels are a source of information of the pharmacokinetic disposition of a compound in an individual patient. Guided by these pharmacokinetic data, the drug dosage may be individually adjusted in order to achieve predefined plasma levels (pharmacokinetically guided dosing, PKGD). Although many anticancer agents have a narrow therapeutic window, PKGD is not routine practice in oncology. Only the importance of monitoring methotrexate levels in plasma has been well established and pharmacokinetic data are routinely used to predict which patient will require folinic acid rescue. The aim of this thesis was to develop, to apply and to study the performance of PKGD in the dosing of the four anticancer agents cyclophosphamide, thiotepa, carboplatin and paclitaxel. Cyclophosphamide, thiotepa and carboplatin (CTC) are alkylating agents often administered in combination in high-dose chemotherapy regimens followed by peripheral blood progenitor cell transplantation. The CTC regimen may be complicated by the occurrence of severe and sometimes life-threatening toxicities, such as mucositis, veno- occlusive disease of the liver, oto-, neuro-, cardio, hepato-, renal and pulmonary toxicity. Since relationships between the occurrence of these toxicities and exposure to the three compounds and their metabolites have been established [1-4], PKGD may be very useful in optimizing the CTC regimen. Because of established relationships between exposure to paclitaxel and both survival and haematological toxicity, PKGD may also be beneficial for this compound [5-7]. Chapter 1.1 of this thesis gives an overview of previously reported studies on PKGD of anticancer agents. It summarizes the prerequisites, techniques for, and difficulties encountered in PKGD in clinical oncology. Because the primary requirement for PKGD is exact knowledge on the pharmacokinetics of a compound, chapter 1.2 deals with the complex pharmacokinetics of cyclophosphamide. A prerequisite for both accurately describing the pharmacokinetics of a compound and application of PKGD is correct sample collection as well as precise, accurate, fast and robust quantification of plasma concentrations in the collected samples. In chapter 2, 11 Preface these methods are described for the agents included in the high-dose CTC regimen. To be able to perform PKGD, the pharmacokinetics of the compound (or combination of compounds) of interest should be accurately described and variability in pharmacokinetics between patients must be quantified. The population pharmacokinetic approach is a powerful tool to obtain profound insight into the, often complex, pharmacokinetics of a compound within a defined patient population. Chapter 3 deals with the development of population pharmacokinetic models describing the pharmacokinetics of cyclophosphamide and thiotepa and their metabolites (chapter 3.1 and 3.3), and of paclitaxel (chapter 3.4). These models form the basis for the Bayesian adaptive dosing strategies described in