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.

The Effect of Intracellular Tacrolimus Exposure on Calcineurin Inhibition in Immediate- and Extended-Release Tacrolimus Formulations.

Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinetic (PK) profile following different tacrolimus formulations (immediate-release (TAC-IR) and extended-release (TAC-LCP)) remains unclear. Therefore, the aim was to study intracellular tacrolimus PK of TAC-IR and TAC-LCP and its correlation with whole blood (WhB) PK and PD. A post-hoc analysis of a prospective, open-label, crossover investigator-driven clinical trial (NCT02961608) was performed. Intracellular and WhB tacrolimus 24 h time-concentration curves were measured in 23 stable kidney transplant recipients. PD analysis was evaluated measuring calcineurin activity (CNA) and simultaneous intracellular PK/PD modelling analysis was conducted. Higher dose-adjusted pre-dose intracellular concentrations (C0 and C24) and total exposure (AUC0-24) values were found for TAC-LCP than TAC-IR. Lower intracellular peak concentration (Cmax) was found after TAC-LCP. Correlations between C0, C24 and AUC0-24 were observed within both formulations. Intracellular kinetics seems to be limited by WhB disposition, in turn, limited by tacrolimus release/absorption processes from both formulations. The faster intracellular elimination after TAC-IR was translated into a more rapid recovery of CNA. An Emax model relating % inhibition and intracellular concentrations, including both formulations, showed an IC50, a concentration to achieve 50% CNA inhibition, of 43.9 pg/million cells.

The potential for deprescribing in a palliative oncology patient population: a cross-sectional study.

OBJECTIVES: The use of preventive medication in palliative oncology patients may be inappropriate due to limited life expectancy. Deprescribing tools are available but time-consuming and not always tailored to this specific population. Our primary goal was to identify potentially inappropriate medications (PIMs) in palliative oncology patients with a life expectancy of up to 2 years using an adapted deprescribing tool. Our secondary aim was to identify patient characteristics associated with the presence of PIMs. METHODS: Oncology patients with a life expectancy of up to 2 years were included cross-sectionally. An adapted deprescribing tool was developed to identify PIMs. Logistic regression was used to identify factors associated with having PIMs. RESULTS: A total of 218 patients were included in this study of which 56% had at least one PIM with a population mean of 1.1 PIM per patient. Most frequently defined PIMs were antihypertensive drugs and gastric acid inhibitors. Identification of PIMs by review took an estimated 5-10 min per patient. Polypharmacy, age >65 years and inpatient/outpatient status were found to be associated with having at least one PIM. CONCLUSIONS: Deprescribing is possible in more than half of palliative oncology patients with a life expectancy of up to 2 years. The adapted deprescribing tool used is non-time consuming and suitable for palliative oncology patients, regardless of age.

Deprescribing in palliative patients with cancer: a concise review of tools and guidelines.

PURPOSE: Palliative cancer patients can benefit from deprescribing of potentially inappropriate medications (PIMs). Tools and guidelines developed for the geriatric population are mainly available. This systematic review gives an overview of available guidelines and tools to deprescribe for palliative cancer patients. METHODS: A systematic search was carried out using the databases SCOPUS and PubMed. Studies focused on palliative cancer patients were included. RESULTS: The search identified 137 studies of which 15 studies were included in this systematic review. Six of the included tools were developed specifically for cancer patients. One of these tools was externally validated and applied in several studies and settings. Guidelines or tools that were not specifically developed for cancer patients but that were applied on cohorts of palliative cancer patients were also included. CONCLUSION: Tools developed for geriatric patients contain drugs that are not inappropriate when used in the palliative cancer care setting. Tools developed for cancer patients are more suitable and can be applied in combination with stepwise methods to individualize deprescribing per patient. The tools and guidelines described in this systematic review can be used to further implement deprescribing in the clinical routine for palliative cancer patients.

Peripheral infiltration of remdesivir in 3 patients with COVID-19: Case series and discussion.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic resulted in accelerated market access to remdesivir worldwide. Therefore, data about complications experienced during use of the drug are limited. This is the first published case series (1 case report exists) to describe remdesivir infiltration in 3 patients with COVID-19. SUMMARY: In the first case, a 91-year-old woman experienced remdesivir infiltration resulting in edema, hematoma at the area of infiltration; on palpation, the affected area felt cooler than the surrounding areas. Swelling was still present after 6 weeks. In the second case, remdesivir infiltration occurred in a 72-year-old male, resulting in edema, hematoma, and pain at the area of infiltration. The hematoma lasted for 7 days. The third case concerned a 67-year-old woman, in whom remdesivir infiltration led to edema and a small hematoma. The hematoma regressed to a negligible size within 3 days. However, a week after infiltration, redness had reappeared. In 2 cases, the patient was immediately treated with hyaluronidase injections, but no specific treatments were provided in the other case. CONCLUSION: Based on the product information provided by remdesivir's manufacturer, we believe symptoms and signs observed in the 3 cases may have resulted from the low pH (~4) of the nonbuffered remdesivir solution, although the patients were not formally assessed for caustic injury. Previous experience with other noncytotoxic medications suggests that infusion-specific factors (eg, volume of leaked fluid) and patient-specific factors (eg, advanced age) may have a role in the outcome of remdesivir infiltration. The possibility of symptoms caused by cyclodextrins in the formulation or by intrinsic toxicity of remdesivir warrants exploration.

Influence of the Circadian Timing System on Tacrolimus Pharmacokinetics and Pharmacodynamics After Kidney Transplantation.

Introduction: Tacrolimus is the backbone immunosuppressant after solid organ transplantation. Tacrolimus has a narrow therapeutic window with large intra- and inter-patient pharmacokinetic variability leading to frequent over- and under-immunosuppression. While routine therapeutic drug monitoring (TDM) remains the standard of care, tacrolimus pharmacokinetic variability may be influenced by circadian rhythms. Our aim was to analyze tacrolimus pharmacokinetic/pharmacodynamic profiles on circadian rhythms comparing morning and night doses of a twice-daily tacrolimus formulation. Methods: This is a post-hoc analysis from a clinical trial to study the area under curve (AUC) and the area under effect (AUE) profiles of calcineurin inhibition after tacrolimus administration in twenty-five renal transplant patients. Over a period of 24 h, an intensive sampling (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 20, and 24 h) was carried out. Whole blood and intracellular tacrolimus concentrations and calcineurin activity were measured by UHPLC-MS/MS. Results: Whole blood and intracellular AUC12-24 h and Cmax achieved after tacrolimus night dose was significantly lower than after morning dose administration (AUC0-12 h) (p < 0.001 for both compartments). AUE0-12 h and AUE12-24 h were not statistically different after morning and night doses. Total tacrolimus daily exposure (AUC0-24 h), in whole blood and intracellular compartments, was over-estimated when assessed by doubling the morning AUC0-12 h data. Conclusion: The lower whole blood and intracellular tacrolimus concentrations after night dose might be influenced by a distinct circadian clock. This significantly lower tacrolimus exposure after night dose was not translated into a significant reduction of the pharmacodynamic effect. Our study may provide conceptual bases for better understanding the TDM of twice-daily tacrolimus formulation.

Sustained Inhibition of Calcineurin Activity With a Melt-Dose Once-daily Tacrolimus Formulation in Renal Transplant Recipients.

Tacrolimus (Tac) is the cornerstone calcineurin inhibitor in transplantation. Extended-release Meltdose formulation (Tac-LCP) offers better bioavailability compared with immediate-release formulation (Tac-IR). We postulated that the less fluctuating pharmacokinetic (PK) profile of Tac-LCP might maintain a sustained inhibition of calcineurin activity (CNA) between dose intervals. Higher concentrations (peak plasma concentration (Cmax )) after Tac-IR may not result in a more potent CNA inhibition due to a capacity-limited effect. This study was aimed at evaluating the pharmacodynamic (PD)/PK profiles of Tac-IR compared with Tac-LCP. An open-label, prospective, nonrandomized, investigator-driven study was conducted. Twenty-five kidney transplant recipients receiving Tac-IR were switched to Tac-LCP. Before and 28 days after conversion, intensive CNA-PD and PK sampling were conducted using ultra-high-performance liquid chromatography-tandem accurate mass spectrometry. PD nonlinear mixed effects model was performed in Phoenix-WinNonlin. Statistically significant higher Cmax (P < 0.001) after Tac-IR did not result in lower CNA as compared with after Tac-LCP (P = 0.860). Tac-LCP showed a statistically more maintained CNA inhibition between dose intervals (area under the effect-time curve from 0 to 24 hours (AUE0-24h )) compared with Tac-IR, in which CNA returned to predose levels after 4 hours of drug intake (373.8 vs. 290.5 pmol RII·h/min·mg prot, Tac-LCP vs. Tac-IR; P = 0.039). No correlation was achieved between any PD and PK parameters in any formulations. Moreover, Tac concentration to elicit a 50% of the maximum response (half-maximal inhibitory concentration) was 9.24 ng/mL. The higher Cmax after Tac-IR does not result in an additional CNA inhibition compared with Tac-LCP attributable to a capacity-limited effect. Tac-LCP may represent an improvement of the PD of Tac due to the more sustained CNA inhibition during dose intervals.

Validation and evaluation of four sample preparation methods for the quantification of intracellular tacrolimus in peripheral blood mononuclear cells by UHPLC-MS/MS.

Rejection and toxicity occur despite monitoring of tacrolimus blood levels during clinical routine. The intracellular concentration in lymphocytes could be a better reflection of the tacrolimus exposure. Four extraction methods for tacrolimus in peripheral blood mononuclear cells were validated and evaluated with UHPLC-MS/MS. Methods based on protein precipitation (method 1), solid phase extraction (method 2), phospholipids and proteins removal (method 3) and liquid-liquid extraction (method 4) were evaluated on linearity, lower limit of quantification (LLOQ), imprecision and bias. Validation was completed for the methods within these requirements, adding matrix effect and recovery. Linearity was 0.126 (LLOQ)-15 µg/L, 0.504 (LLOQ)-15 µg/L and 0.298 (LLOQ)-15 µg/L with method 1, 2 and 3, respectively. With method 4 non-linearity and a LLOQ higher than 0.504 µg/L were observed. Inter-day imprecision and bias were ≤4.6%, ≤10.9%; ≤6.8%, ≤-11.2%; ≤9.4%, ≤10.3% and ≤44.6%, ≤23.1%, respectively, with methods 1, 2, 3 and 4. Validation was completed for method 1 and 3 adding matrix effect (7.6%; 15.0%) and recovery (8.9%; 10.8%), respectively. The most suitable UHPLC-MS/MS method for quantification of intracellular tacrolimus was protein precipitation due to the best performance characteristics and the least time-consuming rate and complexity.

Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: A matched pair analysis.

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression-free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p < 0.001). Our study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety.