Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors.

Background And Objectives: MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate.

Methods: MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial.

A Phase I Dose Escalation Study of Once-Weekly Oral Administration of Docetaxel as ModraDoc001 Capsule or ModraDoc006 Tablet in Combination with Ritonavir.

Purpose: Oral bioavailability of docetaxel is poor. Absorption could be improved by development of pharmaceutical formulations based on docetaxel solid dispersions, denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg) and coadministration of ritonavir, an inhibitor of CYP3A4 and P-glycoprotein. In this study, the safety, MTD, recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of oral docetaxel combined with ritonavir in a once-weekly continuous schedule was investigated.

Age-Associated Hematological Toxicity in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Docetaxel in Clinical Practice.

Background: Older patients with metastatic castration-resistant prostate cancer (mCRPC) may be more prone to chemotherapy-induced hematological toxicity, but tailored docetaxel dosing guidelines in older patients are lacking because of conflicting data.

Objective: This study aims to evaluate the impact of older age on the incidence of hematological toxicity in patients with mCRPC treated with docetaxel in daily clinical practice.

Methods: This study included patients with mCRPC treated with docetaxel between January 2006 and January 2016 at the Netherlands Cancer Institute and Medical Center Slotervaart for whom dosing and hematological toxicity data were available from electronic patient records.

Development and validation of an UPLC-MS/MS method for the therapeutic drug monitoring of oral anti-hormonal drugs in oncology.

A liquid chromatography-mass spectrometry assay was developed and validated for simultaneous quantification of anti-hormonal compounds abiraterone, anastrozole, bicalutamide, Δ(4)-abiraterone (D4A), N-desmethyl enzalutamide, enzalutamide, Z-endoxifen, exemestane and letrozole for the purpose of therapeutic drug monitoring (TDM). Plasma samples were prepared with protein precipitation. Analyses were performed with a triple quadrupole mass spectrometer operating in the positive and negative ion-mode.

Development and validation of a quantitative method for thymidine phosphorylase activity in peripheral blood mononuclear cells.

The enzyme thymidine phosphorylase (TP) is important for activation of capecitabine and 5-fluorouracil. Assessment of TP phenotype might be suitable for identification of patients at risk of fluoropyrimidine-induced toxicity. In this paper, we describe the development and validation an assay for TP activity in peripheral blood mononuclear cells (PBMCs).

Impact of age on exposure to oral antiandrogen therapies in clinical practice.

Background: Oral antiandrogen therapies are predominantly used in older men, but real-life studies evaluating the impact of age on pharmacokinetic exposure are lacking. This study aims to evaluate the impact of age on the pharmacokinetic profiles of abiraterone acetate and enzalutamide in clinical practice.

Patients And Methods: Retrospective observational study to evaluate the impact of age on the first steady-state sample of patients treated with abiraterone acetate or enzalutamide in routine daily clinical practice.

Therapeutic Drug Monitoring of endoxifen as an alternative for CYP2D6 genotyping in individualizing tamoxifen therapy.

Different strategies have been proposed to individualize tamoxifen treatment in order to improve recurrence-free survival in estrogen receptor (ER)-positive breast cancer. To date, the debate remains on which strategy should be used. The objective of this viewpoint is to highlight Therapeutic Drug Monitoring of endoxifen, the active tamoxifen metabolite, as the preferred methodology compared to CYP2D6 genotyping for individualizing tamoxifen therapy for ER-positive breast cancer patients treated in the adjuvant setting.

Review of Chromatographic Bioanalytical Assays for the Quantitative Determination of Marine-Derived Drugs for Cancer Treatment.

The discovery of marine-derived compounds for the treatment of cancer has seen a vast increase over the last few decades. Bioanalytical assays are pivotal for the quantification of drug levels in various matrices to construct pharmacokinetic profiles and to link drug concentrations to clinical outcomes. This review outlines the different analytical methods that have been described for marine-derived drugs in cancer treatment hitherto.

Cost-effectiveness of monitoring endoxifen levels in breast cancer patients adjuvantly treated with tamoxifen.

Purpose: Breast cancer is the most common malignancy in women worldwide. Recurrence rates in breast cancer are considered to be dependent on the serum concentration of endoxifen, the active metabolite of tamoxifen. The goal of this study is to investigate the cost-effectiveness of periodically monitoring serum concentrations of endoxifen in adjuvant estrogen receptor alfa (ERα) positive breast cancer patients treated with tamoxifen in the Netherlands.

Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of C-plitidepsin.

Purpose: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg C-plitidepsin with a maximum radioactivity of 100 µCi.

Methods: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites.

Development and validation of a liquid chromatography-tandem mass spectrometry assay for the quantification of lurbinectedin in human plasma and urine.

Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. This article describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify lurbinectedin in human plasma and urine. Plasma samples were pre-treated with 1 M aqueous ammonia after which they were brought onto supported liquid extraction (SLE) columns.

Translational PK-PD modeling analysis of MCLA-128, a HER2/HER3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose.

Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study.

Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2',2'-difluorodeoxyuridine and their nucleotides.

Aims: Gemcitabine (2',2'-difluoro-2'-deoxycytidine; dFdC) is a prodrug that has to be phosphorylated within the tumour cell to become active. Intracellularly formed gemcitabine diphosphate (dFdCDP) and triphosphate (dFdCTP) are considered responsible for the antineoplastic effects of gemcitabine. However, a major part of gemcitabine is converted into 2',2'-difluoro-2'-deoxyuridine (dFdU) by deamination.

The impact of liver resection on the dihydrouracil:uracil plasma ratio in patients with colorectal liver metastases.

Purpose: The dihydrouracil (DHU):uracil (U) plasma ratio is a promising marker for identification of dihydropyrimidine dehydrogenase (DPD)-deficient patients. The objective of this study was to determine the effect of liver resection on the DHU:U plasma ratio in patients with colorectal liver metastases (CRLM).

Methods: An observational study was performed in which DHU:U plasma ratios in patients with CRLM were analyzed prior to and 1 day after liver resection.

Ultra-sensitive LC-MS/MS method for the quantification of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine in human plasma for a microdose clinical trial.

In microdose clinical trials a maximum of 100 μg of drug substance is administered to participants, in order to determine the pharmacokinetic properties of the agents. Measuring low plasma concentrations after administration of a microdose is challenging and requires the use of ulta-sensitive equipment. Novel liquid chromatography-mass spectrometry (LC-MS/MS) platforms can be used for quantification of low drug plasma levels.

Correction to: Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a C-microtracer and therapeutic dose in cancer patients.

The article ''Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a C-microtracer and therapeutic dose in cancer patients'', written by L. van Andel, H. Rosing, Z.

An LC-MS/MS method for quantification of the active abiraterone metabolite Δ(4)-abiraterone (D4A) in human plasma.

Δ(4)-Abiraterone (D4A) is a recently discovered active metabolite of the oral anti-androgen drug abiraterone acetate. For quantification of this metabolite in human plasma, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated. Human plasma samples of patients treated with abiraterone acetate were prepared by protein precipitation with acetonitrile.

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a C-microtracer and therapeutic dose in cancer patients.

Introduction: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.

Purpose: Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F ) of this novel compound, which is the aim of this study.

A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir.

Introduction: Two solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.

Methods: Adult patients with metastatic solid tumours were included in two dose-escalation arms.

Fixed Dosing of Monoclonal Antibodies in Oncology.

Unlabelled: Most monoclonal antibodies in oncology are administered in body-size-based dosing schedules. This is believed to correct for variability in both drug distribution and elimination between patients. However, monoclonal antibodies typically distribute to the blood plasma and extracellular fluids only, which increase less than proportionally with the increase in body weight.

Liquid chromatography-tandem mass spectrometry assay to quantify plitidepsin in human plasma, whole blood and urine.

Plitidepsin is an anti-cancer drug currently evaluated in phase I/II/III clinical trials. This article describes the development and validation of a bioanalytical assay to quantify plitidepsin in human plasma, urine and whole blood using HPLC-MS/MS. The analyte was extracted from the matrix by liquid-liquid extraction using tert-butyl methyl ether.

Development and Validation of an LC-MS/MS Method for the Simultaneous Quantification of Abiraterone, Enzalutamide, and Their Major Metabolites in Human Plasma.

Background: Abiraterone acetate and enzalutamide are 2 novel drugs for the treatment of metastatic castration-resistant prostate cancer. The metabolism of these drugs is extensive. Major metabolites are N-desmethyl enzalutamide, enzalutamide carboxylic acid, abiraterone N-oxide sulfate, and abiraterone sulfate; of which N-desmethyl enzalutamide is reported to possess antiandrogen capacities.

Human mass balance study and metabolite profiling of C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer.

Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status.

Metabolism and disposition of the anticancer quinolone derivative vosaroxin, a novel inhibitor of topoisomerase II.

Background Vosaroxin is a first-in-class anticancer quinolone derivative that is being investigated for patients with relapsed or refractory acute myeloid leukemia (AML). The primary objective of this study was to quantitatively determine the pharmacokinetics of vosaroxin and its metabolites in patients with advanced solid tumors. Methods This mass balance study investigated the pharmacokinetics (distribution, metabolism, and excretion) of vosaroxin in cancer patients after a single dose of 60 mg/mC-vosaroxin, administered as short intravenous injection.

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome.

Purpose: Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites.