Taxanes: old drugs, new oral formulations.

Oral administration of anticancer drugs is most often preferred over intravenous administration, as it is convenient for patients, prevents hospitalisation and reduces costs of the therapy. However, the oral route is often hampered by low oral bioavailability, for instance of the taxanes paclitaxel and docetaxel. Limited oral bioavailability can be due to pharmaceutical as well as pharmacological reasons.

[Concomitant use of proton pump inhibitors and systemic corticosteroids].

Objective: To provide an overview of the incidence of peptic ulcer in patients who use systemic corticosteroids and of the underlying mechanism of action, in order to determine whether there is a need for gastric protection using proton pump inhibitors in these patients.

Design: Systematic literature review of published meta-analyses and case-control studies, supported by relevant literature on the effects of corticosteroids in relation to the development of ulcers.

Method: Analysis of literature was performed using the PubMed database with the search terms 'adrenal cortex hormones', 'peptic ulcer' and their synonyms.

Population pharmacokinetic-pharmacodynamic analysis for eribulin mesilate-associated neutropenia.

Aims: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia.

Severe skin toxicity in pediatric oncology patients treated with voriconazole and concomitant methotrexate.

We report the occurrence of skin toxicities in pediatric oncology patients on concomitant treatment with voriconazole and methotrexate (MTX). Of 23 patients who received this combination, 11 patients suffered from cheilitis and/or photosensitivity. In contrast, only in 1 of 9 patients who received voriconazole without MTX was photosensitivity observed.

Utility and work productivity data for economic evaluation of breast cancer therapies in the Netherlands and Sweden.

Objective: This study aimed to estimate utility values in laypeople and productivity loss for women with breast cancer in Sweden and the Netherlands.

Methods: To capture utilities, validated health state vignettes were used, which were translated into Dutch and Swedish. They described progressive disease, stable disease, and 7 grade 3/4 adverse events.

Liquid chromatography-tandem mass spectrometric assay for the mutated BRAF inhibitor dabrafenib in mouse plasma.

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for the mutated BRAF inhibitor dabrafenib was developed and validated. Plasma samples were pre-treated using protein precipitation with acetonitrile containing PLX4720 as internal standard. The extract was directly injected into the reversed-phase chromatographic system after dilution with water.

Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.

Purpose: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses.

Methods And Materials: Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.

Development of a framework for cohort simulation in cost-effectiveness analyses using a multistep ordinary differential equation solver algorithm in R.

Introduction: Dynamic processes in cost-effectiveness analysis (CEA) are typically described using cohort simulations, which can be implemented as Markov models, or alternatively using systems of ordinary differential equations (ODEs). In the field of CEA, simple and potentially inaccurate single-step algorithms are commonly used for solving ODEs, which can potentially induce bias, especially if an incorrect step size is used. The aims of this project were 1) to implement and demonstrate the use of a modern and well-established hybrid linear multistep ODE solver algorithm (LSODA) in the context of CEA using the statistical scripting language R and 2) to quantify bias in outcome for a case example CEA as generated by a commonly used single-step ODE solver algorithm.

The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase.

Abcc4 together with abcb1 and abcg2 form a robust cooperative drug efflux system that restricts the brain entry of camptothecin analogues.

Purpose: Multidrug resistance-associated protein 4 (ABCC4) shares many features with P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), including broad substrate affinity and expression at the blood-brain barrier (BBB). However, the pharmacologic relevance of ABCC4 at the BBB is difficult to evaluate, as most drugs are also substrates of ABCB1 and/or ABCG2.

Experimental Design: We have created a mouse strain in which all these alleles are inactivated to assess their impact on brain delivery of camptothecin analogues, an important class of antineoplastic agents and substrates of these transporters.

Effect of inhibition of the FGFR-MAPK signaling pathway on the development of ocular toxicities.

By the introduction of molecularly targeted anti-cancer drugs, that are designed to intervene with specific pathways aberrant in cancers with distinct mutations, the type of adverse events encountered has changed greatly compared to the adverse events profile of classical chemotherapeutic agents. Ocular toxicities, such as serous retinal detachment and retinal vein occlusion, are observed in the treatment with several protein kinase inhibitors, such as MEK inhibitors. This review discusses the pathophysiology, diagnosis and advice for clinical management of these toxicities, and focuses on the current understanding of the underlying molecular mechanisms.

Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement.

The use of oral anticancer drugs has increased during the last decade, because of patient preference, lower costs, proven efficacy, lack of infusion-related inconveniences, and the opportunity to develop chronic treatment regimens. Oral administration of anticancer drugs is, however, often hampered by limited bioavailability of the drug, which is associated with a wide variability. Since most anticancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in the bioavailability can have a negative impact on treatment outcome.

Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb-drug interactions in cancer patients.

The use of complementary and alternative medicines (CAM) by cancer patients is increasing. Concomitant use of CAM and anticancer drugs could lead to serious safety issues in patients. CAM have the potential to cause pharmacokinetic interactions with anticancer drugs, leading to either increased or decreased plasma levels of anticancer drugs.

Pharmacokinetics and excretion of 14C-bendamustine in patients with relapsed or refractory malignancy.

Background: Bendamustine is an alkylating agent with clinical activity against a variety of hematologic malignancies and solid tumors. To assess the roles of renal and hepatic drug elimination pathways in the excretion and metabolism of bendamustine, a mass balance study was performed in patients with relapsed or refractory malignancies.

Methods: A single 60-minute intravenous dose of 120 mg/m(2), 80-95 μCi (14)C-bendamustine hydrochloride was administered to six patients, followed by collection of blood, urine, and fecal samples at specified time points up to day 8 or until the radioactivity of the 24-hour urine and fecal collections was below 1% of the administered dose (whichever was longer).

Correction of peripheral blood mononuclear cell cytosolic protein for hemoglobin contamination.

Pharmacodynamic (PD) analysis requires accurate and precise quantification of enzyme activity targeted by anticancer agents in surrogate cells like peripheral blood mononuclear cells (PBMCs). Enzyme activity is normally reported per mass unit of protein input. However, high and fluctuating hemoglobin (Hb) contamination strongly influences the protein content of PBMC cytosolic lysate.

Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA.

We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for P-glycoprotein (Pgp, MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in vitro. Cell survival, drug transport, and competition experiments with barasertib pro-drug and the more active form of the drug (barasertib-hQPA) were performed using MDCKII (wild type, MDR1, BCRP, and MRP2) and LLCPK (wild type and MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. Moreover we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in vivo using Bcrp1(-/-)/Mdr1a/1b (-/-) (triple knockout) and wild type mice.

Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years.

Purpose: The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.

Methods: Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively.

Pharmacodynamic assay of thymidylate synthase activity in peripheral blood mononuclear cells.

A simple, selective, and sensitive method utilizing tritium ((3)H) release from (3)H-deoxyuridine 5'-monophosphate (dUMP) substrate for accurate and precise determination of the low basal thymidylate synthase activity (TSA) in normal healthy peripheral blood mononuclear cells (PBMCs) was developed and validated. The method is based on the removal of the remaining substrate after the TSA reaction by absorption onto activated carbon and measurement of the supernatant fluid by liquid scintillation counting. The method background was substantially decreased by using lyophilized substrate and optimized binding conditions of remaining substrate onto carbon after TSA reaction.

Quantitative determination of capecitabine and its six metabolites in human plasma using liquid chromatography coupled to electrospray tandem mass spectrometry.

Capecitabine is the oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The purpose of this study was to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, dihydro-5-fluorouracil (FUH(2)), α-fluoro-ureidopropionic acid (FUPA) and fluoro-β-alanine (FBAL) in human plasma using liquid chromatography coupled to electrospray tandem mass spectrometry. To this end two individual assays were developed: one for the simultaneous quantification of capecitabine, 5'-dFCR and 5'-dFUR using reversed phase chromatography and gradient elution, and one assay for 5-FU, FUH(2), FUPA and FBAL using hydrophilic interaction chromatography and isocratic elution.

Slow dissolution behaviour of amorphous capecitabine.

In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the "gelling" properties of amorphous capecitabine in an aqueous environment.

Optimizing drug development of anti-cancer drugs in children using modelling and simulation.

Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs.

[Prevention of severe toxicity from capecitabine, 5-fluorouracil and tegafur by screening for DPD-deficiency].

Capecitabine, 5-fluorouracil and tegafur form the group called the fluoropyrimidines, which is one of the most frequently prescribed group of anti-cancer drugs for the treatment of (metastatic) colorectal, gastric and breast cancer. The primary enzyme responsible for the inactivation of the fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD). Consequently, patients with an inborn partial DPD deficiency, induced, for example by the polymorphism DPYD*2A, are highly prone to severe, potentially lethal toxicity following a standard dose of fluoropyrimidines.

P-glycoprotein and cytochrome P450 3A act together in restricting the oral bioavailability of paclitaxel.

Paclitaxel is avidly transported by P-glycoprotein (P-gp/MDR1/ABCB1). This results in low oral bioavailability, which can be boosted by coadministration of P-gp inhibitors. Unlike paclitaxel, docetaxel is extensively metabolized by CYP3A4 and its oral bioavailability can be enhanced in mice and humans by coadministration of the potent CYP3A inhibitor ritonavir.

Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel.

For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel.