Redispensing of expensive oral anticancer medicines: A practical application.

INTRODUCTION: Increasing use of expensive oral anticancer medicines comes with the downside of a financial and environmental burden, partially caused by unused medication. Returned oral anticancer medicine to the pharmacy could be considered for redispensing providing guaranteed quality. This study aimed to identify and implement quality aspects and criteria for redispensing oral anticancer medicine in daily pharmacy practice. METHODS: A systematic analysis was conducted to determine the eligibility of oral anticancer medicine for redispensing. Over a one-year period, the number of returned oral anticancer medicine accepted for redispensing was quantified, and the reduction in financial waste and environmental burden calculated based on this assessment. RESULTS: Four categories of quality aspects were identified for determining the eligibility of oral anticancer medicine for redispensing: Product presentation suitability (stability characteristics, storage requirements), physical condition (unopened or opened secondary or primary packaging, visual appearance), authentication (Falsified Medicines Directive, confirmation of initial dispense, recall), and additional aspects (remaining shelf life, period of storage in uncontrolled conditions). A standardized procedure for redispensing was implemented in daily pharmacy practice. During the study period, 10,415 oral anticancer medicine dose units out of 13,210 returns (79%) were accepted for redispensing. The total value of oral anticancer medicine accepted for redispensing was €483,301, accounting for 0.9% of the total value dispensed during this period. Furthermore, the potential reduction in environmental burden was estimated at 1132.1 g of potent active pharmaceutical ingredient. CONCLUSIONS: By implementing strict procedures considering all relevant quality aspects, redispensing of oral anticancer medicine can be successfully implemented into daily pharmacy practice, resulting in a significant reduction in financial waste and environmental burden.

An easy, fast, and efficient assay for the quantification of peptide Hepcidin-25 in serum and plasma with LC-MS/MS.

BACKGROUND: The peptide hormone hepcidin-25 plays an important role in iron metabolism. Low or high levels of hepcidin-25 are associated with various iron disorders; therefore, hepcidin-25 is an important biomarker. This study describes an easy and fast analytical assay for the quantification of hepcidin-25 with liquid chromatography-tandem mass spectrometry (LC-MS/MS). METHODS: Sample preparation was performed by protein precipitation with trichloroacetic acid, and injection onto a LC-MS/MS was directly conducted from a LoBind 96-well plate. RESULTS: The concentration range covered by the quality control samples, ranged from 0.25 nmol/L (12.3% CV) to 11.9 nmol/L (CV < 9%). Matrix effect was limited (mean recovery of 99.9% with a CV of 6.4%). The assay was validated for serum, EDTA and heparin plasma. An international secondary reference material was used for calibration. The reference interval (90% CL) was estimated for hepcidin-25 by analysing serum and plasma samples from 156 healthy subjects with a lower limit: 0.12 (0.07-0.19) and upper limit: 11.2 nmol/L (9.5-13.0). CONCLUSIONS: We present a fast and easy assay for the quantification of hepcidin-25 in serum and plasma samples. The assay was successfully used for the detection of various forms of hereditary haemolytic anaemias, to characterize the interplay between erythropoiesis and iron levels.

Bottom-up sample preparation for the LC-MS/MS quantification of anti-cancer monoclonal antibodies in bio matrices.

Therapeutic monoclonal antibodies (mAbs) are rapidly taking over the treatment of many malignancies, and an astonishing number of mAbs is in development. This causes a high demand for quantification of mAbs in biomatrices both for measuring therapeutic mAb concentrations and to support pharmacokinetics and pharmacodynamics studies. Conventionally, ligand-binding assays are used for these purposes, but LC-MS is gaining popularity. Although intact (top-down) and subunit (middle-down) mAb quantification is reported, signature peptide (bottom-up) quantification is currently most advantageous. This review provides an overview of the reported bottom-up mAb quantification methods in biomatrices as well as general recommendations regarding signature peptide and internal standard selection, reagent use and optimization of digestion in bottom-up quantification methods.

Use of leftovers of monoclonal antibody products after partial extraction - A microbiological safety study.

BACKGROUND/PURPOSE: In the absence of thorough microbiological, chemical and physical stability data, high amounts of pharmaceutical products, from which the seal has been broken, are to be discarded after preparation. We performed a generic microbiological validation study for several marketed monoclonal antibody products, in order to define conditions under which leftovers from partially extracted product can be used in order to minimize loss. METHODS: From the daily practice of the Central Preparation Unit of the Netherlands Cancer Institute, used monoclonal antibody product vials were collected. To examine the integrity of the primary packaging, a VDT/S Vacuum Leak tester from Erweka was used. Vials were punctured with different types of spikes or a needle prior to experiments and examined for leakage afterward. In addition, microbiological monitoring was performed by broth simulation of the preparation method. RESULTS: All vials (631 vials, 18 different monoclonal antibody products) showed no leakage after puncturing with a 18 G needle. However, the use of a spike system resulted in leakage in 108 of the 435 tested vials. Results from the broth simulations confirmed a higher risk of contamination after puncturing with a spike as compared to needle-punctured vials (0.5% vs. 0.05%). CONCLUSION: When working under aseptic preparation conditions and making use of appropriate needle, the risk of contamination is acceptably low to justify storage and reuse of leftover monoclonal antibody product from a microbiological perspective. The spikes tested lead to an unacceptably high level of loss of integrity and subsequent risk of microbiological contamination if stored in a non-classified environment. We concluded that these results could be applied generically to all monoclonal antibody products with a primary packaging composed of a glass vial and rubber stopper.

Treatment of Peritoneal Dissemination in Stomach Cancer Patients With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Rationale and Design of the PERISCOPE Study.

BACKGROUND: Patients with gastric cancer and peritoneal carcinomatosis have a very poor prognosis; median survival is 3 to 4 months. Palliative systemic chemotherapy is currently the only treatment available in the Netherlands. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has an established role in the treatment of peritoneal carcinomatosis originating from colorectal cancer, appendiceal cancer, and pseudomyxoma peritonei; its role in gastric cancer is uncertain. Currently, there is no consensus on the choice of chemotherapeutic agents used in HIPEC for gastric cancer. OBJECTIVE: The main objectives of this study are (1) to investigate the safety, tolerability, and feasibility of gastrectomy combined with cytoreductive surgery and HIPEC after systemic chemotherapy, as a primary treatment option for patients with advanced gastric cancer with tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis; and (2) to determine the maximum tolerated dose (MTD) of intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin. METHODS: The PERISCOPE study is a multicenter, open label, phase I-II dose-escalation study. The MTD of docetaxel will be studied using a 3+3 design. Patients with locally advanced (cT3-cT4) gastric adenocarcinoma are eligible for inclusion if the primary gastric tumor is considered resectable, tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis is confirmed by diagnostic laparoscopy/ laparotomy, and prior systemic chemotherapy was without disease progression. At laparotomy, cytoreductive surgery (complete removal of all macroscopically visible tumor deposits) and a total or partial gastrectomy with a D2 lymph node dissection is performed. An open HIPEC technique is used with 460mg/m2 hyperthermic oxaliplatin for 30 minutes (41°C to 42°C) followed by normothermic docetaxel for 90 minutes (37°C) in a dose that will be escalated per 3 patients (0, 50, 75, 100, 125, 150 mg/m2). The primary endpoint is treatment related toxicity. RESULTS: Patient accrual is ongoing and the first results are expected in 2017. CONCLUSIONS: The PERISCOPE study will determine the safety, tolerability, and feasibility of gastrectomy combined with cytoreduction and HIPEC using oxaliplatin in combination with docetaxel after systemic chemotherapy as primary treatment option for gastric cancer patients with tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis. This study will provide pharmacokinetic data on the intraperitoneal administration of oxaliplatin and docetaxel, including the MTD of intraperitoneal-administered docetaxel. These data are a prerequisite for the safe conduct of future HIPEC studies in patients with gastric cancer. TRIAL REGISTRATION: Netherlands Trial Registration (NTR): NTR4250; http://www.trialregister.nl/trialreg/admin/ rctview.asp?TC=4250 (Archived by WebCite at http://www.webcitation.org/6rWJONgkt).

Therapeutic drug monitoring of antiretroviral drugs at home using dried blood spots: a proof-of-concept study.

BACKGROUND: In HIV-infected patients, therapeutic drug monitoring (TDM) of antiretroviral drugs is recommended in special populations and in specific situations to optimize therapy. Currently, TDM is performed via measurement of drug plasma concentrations; however, dried blood spots (DBS) may offer a patient friendly and cost-effective alternative. Therefore, this proof-of-concept study assessed the feasibility of TDM of antiretroviral drugs using DBS with sampling at home. METHODS: Included patients were instructed to sample three DBS just before drug intake at three consecutive days at home and one DBS sample together with their routine venous sampling. All samples were analysed using liquid chromatography coupled to tandem mass spectrometry. Feasibility was investigated with a questionnaire and via determination of the calculated plasma trough concentrations. RESULTS: In total, 50 patients (48 male, mean age 50 years [range 29-69]) have been included, of whom most were virologically and immunologically well-controlled. In total, 200 DBS were collected, of which 87.5% were suitable for analysis. The questionnaire showed that most patients (68%) successfully obtained their first DBS and 51% preferred DBS over plasma sampling. Plasma trough concentrations could adequately be determined from DBS. CONCLUSIONS: This proof-of-concept study confirms the feasibility of TDM of antiretroviral drugs using DBS with sampling at home, thereby opening the possibility to obtain trough concentrations at home in populations where venous sampling is difficult.

Clinical evaluation of the determination of plasma concentrations of darunavir, etravirine, raltegravir and ritonavir in dried blood spot samples.

BACKGROUND: Measurement of drug levels in plasma is currently the gold standard for pharmacological studies. However, venous sampling is not feasible in some populations (e.g., neonates) or may be difficult in certain situations, such as nonhospital-based settings. Dried blood spots (DBS) can be obtained by a simple fingerprick and the subsequent collection of blood on a filter card, allowing patient-friendly sample collection in non-hospital-based settings. Despite these advantages, thus far no clinical evaluation has been performed for the use of DBS concentrations as surrogates for plasma levels. Our purpose was to clinically evaluate DBS sampling for the determination of plasma concentrations for the novel antiretroviral drugs etravirine, darunavir/ritonavir and raltegravir. RESULTS: DBS concentrations were measured in 11 HIV-infected patients using LC-MS/MS. DBS concentrations were proportional to plasma concentrations. All drug concentrations were higher in DBS than in plasma samples. The plasma:DBS ratio and the respective relative standard error of estimate (RSE) of darunavir, etravirine, raltegravir and ritonavir were 0.632 (4.97% RSE), 0.523 (4.84% RSE), 0.617 (14.9% RSE) and 0.592 (2.99% RSE), respectively. Hematocrit did not explain variability in our study. CONCLUSIONS: DBS are reproducibly correlated to plasma levels and can be used for monitoring antiretroviral drug exposure in HIV-infected patients.

Prolonged exposure to tenofovir monotherapy 1 month after treatment discontinuation because of tenofovir-related renal failure.

In this study, we present a case of renal failure in a patient who was on a tenofovir-containing regimen, resulting in extremely high tenofovir exposure and prolonged tenofovir monotherapy. We considered this case report important because exposure to tenofovir monotherapy might have consequences for future discontinuation strategies in cases of renal failure.

Population pharmacokinetics of orally administered paclitaxel formulated in Cremophor EL.

AIM: The vehicle Cremophor EL (CrEL) has been shown to impair the absorption of paclitaxel by micellar entrapment of the drug in the gastrointestinal tract. The goal of this study was to develop a semimechanistic population pharmacokinetic model to study the influence of CrEL on the oral absorption of paclitaxel. METHOD: Paclitaxel plasma-concentration time profiles were available from 55 patients (M:F, 17 : 38; total 67 courses; 797 samples), receiving paclitaxel orally once or twice daily (dose range 60-360 mg m(-2)) together with 12-15 mg kg(-1) cyclosporin A. A population pharmacokinetic model was developed using the nonlinear mixed effect modelling program NONMEM. RESULTS: After absorption, paclitaxel pharmacokinetics were best described using a two-compartment model with linear distribution from the central compartment into a peripheral compartment and first-order elimination. Paclitaxel in the gastrointestinal tract was modelled as free fraction or bound to CrEL, with only the free fraction available for absorption into the central compartment. The equilibrium between free and bound paclitaxel was influenced by the concentration of CrEL present in the gastrointestinal tract. The concentration of CrEL in the gastrointestinal tract decreased with time with a first order rate constant of 1.73 h(-1). The bioavailability of paclitaxel was independent of the dose and of CrEL. Estimated apparent paclitaxel clearance and volume of distribution were 127 l h(-1) and 409 l, respectively. Large interpatient variability was observed. Covariate analysis did not reveal significant relationships with any of the pharmacokinetic parameters. CONCLUSION: A pharmacokinetic model was developed that described the pharmacokinetics of orally administered paclitaxel. CrEL strongly influenced paclitaxel absorption from the gastrointestinal tract resulting in time-dependent but no significant dose-dependent absorption over the examined dose range studied.