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Pharmaceutics of Oral Anticancer Agents and Stimulants

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Pharmaceutics of Oral Anticancer Agents and Stimulants Pharmaceutics of oral anticancer agents and stimulants Maikel Herbrink The research in this thesis was performed at the Departments of Pharmacy & Pharma- cology and Medical Oncology & Clinical Pharmacology of the Netherlands Cancer Insti- tute – Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands. Printing of this thesis was financially supported by: Netherlands Cancer Institute Chipsoft BV Pfizer BV ISBN: 978-90-393-6997-5 Design, lay-out and print Gildeprint, Enschede © Maikel Herbrink, 2018 Pharmaceutics of oral anticancer agents and stimulants Farmaceutisch onderzoek naar oraal toegediende antikankermiddelen en stimulantia (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. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 27 juni 2018 des middags te 4.15 uur door Maikel Herbrink geboren op 2 februari 1990 te Groningen Promotoren: Prof. dr. J.H. Beijnen Prof. dr. J.H.M. Schellens Copromotor: Dr. B. Nuijen Contents Preface 9 Chapter 1: Introduction 15 1.1 Variability in bioavailability of small molecular tyrosine 17 kinase inhibitors Cancer Treat Rev. 2015 May;41(5):412-422 1.2 Inherent formulation issues of kinase inhibitors 51 J Control Release. 2016 Oct;239:118-127 1.3 High-tech drugs in creaky formulations 81 Pharm Res. 2017 Sep;34(9):1751-1753 Chapter 2: Pharmaceutical analysis of oral anticancer drug substances 89 2.1. Thermal study of pazopanib hydrochloride 91 J Therm Anal Calorim. 2017 Dec;130(3):1491-1499 2.2. Thermal stability study of crystalline and novel spray- 111 dried amorphous nilotinib hydrochloride J Pharm Biomed Anal. 2018 Jan;148:182-188 Chapter 3: Formulation improvement of oral anticancer agents 131 3.1 Solubility and bioavailability improvement of pazopanib 133 hydrochloride Accepted for publication in Int J Pharm. 3.2 Improving the solubility of nilotinib through novel spray- 159 dried solid dispersions Int J Pharm. 2017 Aug;529(1-2):294-302 Chapter 4: Bioanalysis of oral anticancer agents 183 4.1 Quantification of 11 therapeutic kinase inhibitors in 185 human plasma for therapeutic drug monitoring using liquid chromatography coupled with tandem mass spectrometry Ther Drug Monit. 2016 Dec;38(6):649-656 4.2 Development and validation of a liquid chromatography- 205 tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs Biomed Chromatogr. 2018 Apr;32(4) Chapter 5: Dexamphetamine 227 5.1 Development and validation of a high-performance liquid 229 chromatography-tandem mass spectrometry assay for the quantification of dexamphetamine in human plasma J Pharm Biomed Anal. 2018 Jan;148:259-264 5.2. Pharmacokinetics of sustained-release oral 245 dexamphetamine sulphate in cocaine and heroin dependent patients Accepted for publication in J Clin Psychopharmacol. Chapter 6: Conclusion & Perspectives 261 Appendix Summary 275 Nederlandse samenvatting 283 Dankwoord 291 List of publications 297 Curriculum vitae 303 Molecular structures 307 Preface For the past 20 years, the pharmacological therapy of cancer has been undergoing a meta- morphosis, rapidly changing from treatment with broad and unspecific cytotoxic agents to personalized and highly specific targeted agents. This new class of drugs largely consists of small molecular compounds that mostly inhibit kinases. Through their disruption of the ki- nase function, the targeted agents interfere with multiple cancer signaling pathways which are essential to tumor development, survival, growth, and metastasis [1]. Alongside the advancing targeted therapy came the so-called ‘intravenous-to-oral-switch’. This is illustrated by the fact that an increasing number of marketed targeted anticancer drugs are administered orally. Additionally, most of the targeted agents that are being investigated are intended for oral ingestion. Part I of this thesis addresses the issues that originate from the oral administration of targeted anticancer agents. Chapter 1 introduces the physicochemical and related pharmacokinetic properties of the orally administered kinase inhibitors. Chapter 1.1 presents the variability in the pharma- cokinetics of this class of drugs. Furthermore, it addresses the therapeutic consequenc- es that are associated with this generally unfavorable behavior. Chapter 1.2 discusses the inherent link between the targeted nature of kinase inhibitors and their suboptimal biopharmaceutical properties. Additionally, it shows through literature and patent data that the currently marketed drug formulations are mostly inadequate in overcoming the physicochemical challenges. Chapter 1.3 elaborates on both the previous chapters and takes a strong stance in favor of investing more effort in pharmaceutical formulation development of future oral drugs. In the process towards a well-designed pharmaceutical formulation, the characteriza- tion of the drug substance plays a pivotal role. Chapter 2 describes the thermal prefor- mulation studies of pazopanib hydrochloride and nilotinib hydrochloride. Chapter 2.1 focusses on the thermal degradation profile of crystalline pazopanib hydrochloride and examines future processing possibilities. In Chapter 2.2 we describe the thermal and thermodynamic properties of crystalline and amorphous nilotinib hydrochloride and the stability thereof. Chapter 3 describes the development of improved pharmaceutical formulations of both pazopanib hydrochloride and nilotinib hydrochloride.Chapter 3.1 reports on the solubil- ity and bioavailability improvement of pazopanib hydrochloride through the formulation of a physical powder mixture formulation. It presents data from in vitro and human in vivo studies. Chapter 3.2 describes the design and development process of a spray-dried formulation that contains amorphous nilotinib hydrochloride. Suboptimal pharmaceutical formulations that have already been marketed and are routinely used in the clinic often require therapeutic drug monitoring (TDM) to timely detect under- or overdosing. Chapter 4 provides two fully validated LC-MS/MS assays for the quantification of a broad collection of targeted anti-cancer agents in patient plasma for TDM purposes. The bioanalytical assay described in Chapter 4.1 focusses on the quantification in patient plasma of dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, and vemurafenib and the active metabolite, N-desethyl-sunitinib. Chapter 4.2 presents a method for the quantification of afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib, and trametinib in patient plasma. Part II of this thesis focusses on the manufacturing and pharmacokinetic analysis of dexamphetamine SR tablets that were specifically developed for use in cocaine addic- tion therapy. Cocaine dependence is a harmful mental disease for which there currently is no phar- macotherapy available. Substitution with the safer and regulated dexamphetamine sus- tained-release (SR) has been shown in several studies to be a feasible option for patients with this type of addiction [2]. A Dutch study has demonstrated that dexamfetamine SR is an effective and safe pharmacotherapy for comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment [3]. Chapter 5 describes the preparation and execution of a descriptive pharmacokinetic- ex ploration study of dexamphetamine SR tablets. Chapter 5.1 presents a fully validated LC-MS/MS assay for the quantification of dexamphetamine in patient plasma samples which was used in the pharmacokinetic study.Chapter 5.2 describes the results and the discussion of the pharmacokinetic study itself. References [1] Zhang J, Yang PL, Gray NS. Targeting cancer [3] Nuijten M, Blanken P, van de Wetering B, et al.. with small molecule kinase inhibitors. Nat. Rev. Sustained-release dexamfetamine in the treat- Cancer. 2009;9:28–39. ment of chronic cocaine-dependent patients [2] Castells X, Cunill R, Pérez-Mañá C, et al. Psy- on heroin-assisted treatment: a randomised, chostimulant drugs for cocaine dependence. double-blind, placebo-controlled trial. Lancet. In: Castells X. Cochrane Database Syst. Rev. 2016;387:2226–34. Chichester, UK: John Wiley & Sons, Ltd; 2016. Chapter 1 Introduction Chapter 1.1 Variability in bioavailability of small molecular tyrosine kinase inhibitors M. Herbrink1, B. Nuijen1, J.H.M. Schellens2,3, J.H. Beijnen1,3 1Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, The Netherlands. 2Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek, Amsterdam, The Netherlands. 3Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 18 | Chapter 1.1 Abstract Small molecular tyrosine kinase inhibitors (smTKIs) are in the centre of the very quickly expanding area of personalized chemotherapy and oral applicability thereof. The num- ber of drugs in this class is rapidly growing, with twenty current approvals by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). The drugs are, however, generally characterized by a poor oral, and thus variable, bioavail- ability. This results in significant variation in plasma levels and exposure. The cause is a complex interplay of factors, including poor aqueous solubility, issued permeability, membrane transport
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