Case Report: Lymphodepletion followed by CAR-T cell therapy with Idecabtagen vicleucel in a patient with severe renal impairment.

Acute kidney injury and chronic kidney disease is common in multiple myeloma. Fludarabine which is part of lymphodepletion before CAR-T cell therapy is renally eliminated and its use is not recommended for patients with severe renal impairment defined as a glomerular filtration rate below 30ml/min/1.73m2. We administered fludarabine to a 58-year-old female patient with myeloma-associated severe renal impairment as part of lymphodepletion before Idecabtagen vicleucel infusion. Fludarabine was administered in reduced dose (15mg/m2) and cyclophosphamide with a dose of 300mg/m2 followed by hemodialysis over six hours using a larger filter (FX-100). The therapy was well tolerated with excellent CAR-T cell expansion and complete remission which is ongoing now beyond 12 months.

A Unified Data Architecture for Assessing Motor Symptoms in Parkinson's Disease.

INTRODUCTION: The diagnosis and treatment of Parkinson's disease depend on the assessment of motor symptoms. Wearables and machine learning algorithms have emerged to collect large amounts of data and potentially support clinicians in clinical and ambulant settings. STATE OF THE ART: However, a systematical and reusable data architecture for storage, processing, and analysis of inertial sensor data is not available. Consequently, datasets vary significantly between studies and prevent comparability. CONCEPT: To simplify research on the neurodegenerative disorder, we propose an efficient and real-time-optimized architecture compatible with HL7 FHIR backed by a relational database schema. LESSONS LEARNED: We can verify the adequate performance of the system on an experimental benchmark and in a clinical experiment. However, existing standards need to be further optimized to be fully sufficient for data with high temporal resolution.

Implementation and operational management of marketed chimeric antigen receptor T cell (CAR-T Cell) therapy-a guidance by the GoCART Coalition Pharmacist Working Group.

Chimeric Antigen Receptor T cells (CAR-T cells) are a type of Advanced Therapy Medicinal Product (ATMP) classified as ex-vivo (cell-based) gene therapy. CAR-T cells constitute an immunotherapy that works by enabling T cells to specifically recognise cancer cells and destroy them [1]. CAR-T cells are currently licensed to treat certain blood cancers including relapsed or refractory lymphomas, B-cell acute lymphoblastic leukaemia or multiple myeloma [2]. The indications for their use are expanding and are expected to encompass other therapeutic areas. CAR-T cells are used both in children and adults [2]. CAR-T cells are biologic drugs and are therefore more complex than traditional medicinal products. T cells collected from the patient (or donor) are sent to a Good manufacturing Practice (GMP) manufacturing facility where they are genetically modified to contain a chimeric antigen receptor (CAR). This receptor is designed to recognise and target a specific protein on cancer cells. Once manufactured, they are delivered to the hospital where they are administered to the designated patient. Hospital pharmacies are central in the process of ensuring appropriate organisational governance, operational handling, clinical suitability, and pharmacovigilance [1, 3]. The GoCART Coalition Pharmacist working group's mission was to develop standards of care to advance the field of cellular therapies in Europe. The purpose of this document is to provide practical guidance on the implementation and safe operational use of marketed CAR-T cell products within hospital pharmacies primarily throughout Europe. This document outlines the key areas where pharmaceutical expertise should focus and the key considerations for the hospital pharmacy. Countries may have different requirements and there may be variation in practice between hospitals. This document is intended as a guide and the recommendations should be adapted to meet local requirements. This document does not provide clinical information relating to the use of CAR-T cell products. The Summary of medicinal Product Characteristics (SmPC) [4, 5], and national and international clinical guidelines (where in place) should be followed for the most up-to-date clinical management of CAR-T cell patients. An example is the UK "institutional readiness documents" for pharmacy which includes detailed checklists for each stage of the pathway [6]. Spain developed the Plan of Advanced Therapies in the National Health System: CAR medicines published in November 2018 [7], the CAR-T Medicines Management Procedure of the Spanish Society of Hospital Pharmacy [8] or the Hospital pharmacist's roles and responsibilities with CAR-T medicines article published also by the Spanish Oncology group of the Spanish Society of Pharmacy [9]. This guide has been designed to support the implementation of marketed CAR-T products; however, the principles may also be applicable to clinical trials. For CAR-T cell products being used in clinical trials, additional trial regulation and clinical trial protocols must be followed. This document is divided into two sections. Section 1 outlines considerations for hospital pharmacies during the implementation of a CAR-T cell service. Section 2 outlines the key operational considerations for hospital pharmacies in the patient and product pathway.

Development of an immediate release excipient composition for 3D printing via direct powder extrusion in a hospital.

3D printing offers the possibility to prepare personalized tablets on demand, making it an intriguing technology for hospital pharmacies. For the implementation of 3D-printed tablets into the digital Closed Loop Medication Management system, the required tablet formulation and development of the manufacturing process as well as the pharmaceutical validation were conducted. The goal of the formulation development was to enable an optimal printing process and rapid dissolution of the printed tablets for the selected model drugs Levodopa/Carbidopa. The 3D printed tablets were prepared by direct powder extrusion. Printability, thermal properties, disintegration, dissolution, physical properties and storage stability were investigated by employing analytical methods such as HPLC-UV, DSC and TGA. The developed formulation shows a high dose accuracy and an immediate drug release for Levodopa. In addition, the tablets exhibit high crushing strength and very low friability. Unfortunately, Carbidopa did not tolerate the printing process. This is the first study to develop an immediate release excipient composition via direct powder extrusion in a hospital pharmacy setting. The developed process is suitable for the implementation in Closed-Loop Medication Management systems in hospital pharmacies and could therefore contribute to medication safety.

Clinical pharmacy services in critical care: results of an observational study comparing ward-based with remote pharmacy services.

BACKGROUND: Pharmacists are essential team members in critical care and contribute to the safety of pharmacotherapy for this vulnerable group of patients, but little is known about remote pharmacy services in intensive care units (ICU). AIM: We compared the acceptance of pharmacist interventions (PI) in ICU patients working remotely with ward-based service. We evaluated both pharmacy services, including further information on PI, including reasons, actions and impact. METHOD: Over 5 months, a prospective single-centre observational study divided into two sequential phases (remote and ward-based) was performed on two ICU wards at a university hospital. After a structured medication review, PI identified were addressed to healthcare professionals. For documentation, the national database (ADKA-DokuPIK) was used. Acceptance was used as the primary endpoint. All data were analysed using descriptive methods. RESULTS: In total, 605 PI resulted from 1023 medication reviews. Acceptance was 75% (228/304) for remote and 88% (265/301; p < 0.001) for ward-based services. Non-inferiority was not demonstrated. Most commonly, drug- (44% and 36%) and dose-related (36% and 35%) reasons were documented. Frequently, drugs were stopped/paused (31% and 29%) and dosage changed (31% and 30%). PI were classified as "error, no harm" (National Coordinating Council for Medication Error Reporting and Prevention [NCC MERP] categories B to D; 83% and 81%). The severity and clinical relevance were at least ranked as "significant" (68% and 66%) and at least as "important" for patients (77% and 83%). CONCLUSION: The way pharmacy services are provided influences the acceptance of PI. Remote pharmacy services may be seen as an addition, but acceptance rates in remote services failed to show non-inferiority.

Iron Chelation with Deferasirox Suppresses the Appearance of Labile Plasma Iron During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT), non-transferrin-bound iron and its chelatable form, labile plasma iron (LPI), regularly appear in the blood of patients at high levels of transferrin saturation (TfS). As these free iron species potentially favor infection and mediate transplantation-associated toxicities, chelation therapy could be an approach to improve outcome after transplantation. However, data addressing iron chelation in the immediate peritransplantation period are sparse. In this study, we investigated the influence of iron chelation with deferasirox during conditioning chemotherapy on the appearance of LPI, the incidence of infection and toxicities, and the tolerability of this treatment in the peritransplantation period. We conducted this single-center prospective observational study in 25 adults with iron overload (serum ferritin >1000 µg/L) undergoing allogeneic HSCT after myeloablative busulfan-based conditioning chemotherapy. Patients received iron chelation with deferasirox (14 mg/kg) from the start of conditioning until day 3 post-transplantation. Iron parameters, including LPI, were obtained at the chelator's trough level daily until day 0 and then on days 4, 7, and 14. Data on infection (bacteremia or invasive fungal disease) and toxicity, as well as the tolerability of deferasirox, were collected until the end of the follow-up period on day 28. Data were analyzed descriptively. TfS levels exceeded 70% in median on 6 days (range, 4 to 10 days) and in 63.6% (range, 36.4% to 90.9%) of the samples per patient, although in 19 of 25 patients (76%), no elevated LPI values were detected during the intake of deferasirox despite high TfS levels. Only 6 patients (24%) showed mildly increased LPI values (≤0.5 units) during the intake of deferasirox, 3 of whom had presented with elevated LPI values before the start of conditioning. Deferasirox was well tolerated, and no aggravation of toxicities was observed. Infection occurred in 5 patients (20%), including 3 of the 6 patients with elevated LPI values despite chelation therapy. In the present study, we demonstrate that iron chelation with deferasirox safely suppresses the appearance of LPI and might decrease the incidence of infection, whereas the impact on transplantation-associated toxicities remains to be elucidated.

Medication errors in cancer therapy: Reports from German hospital pharmacists between 2008 and 2019.

OBJECTIVE: Since medication errors can have severe consequences, the development of methods to improve patient safety is becoming increasingly important. The aim of this evaluation was to identify frequent medication errors in oncology as well as characteristic correlations in the various error patterns. In addition, the implementation rate of the proposed pharmaceutical intervention was determined in order to assess the benefit of a clinical pharmacist in the field of oncology. METHODS: The evaluation was based on a data-set from a national documentation system for medication errors and interventions (DokuPIK) used by hospital pharmacists in the field of oncology from 2008 to 2019, namely 6684 reported cases in oncology, representing about 5% of all reports in DokuPIK. RESULTS: The most frequently reported errors were incorrect doses (22% of reported errors), followed by interactions (14%); in 10% of errors the prescription/documentation was incomplete/incorrect. The intervention suggested by the pharmacist was implemented in 97% of the cases. Based on the respective Anatomical Therapeutical Chemical Classification (ATC codes), drugs (or groups of drugs) were identified that were reported frequently in connection with medication errors, namely carboplatin and cyclophosphamide as anticancer drugs pantoprazole as non-anticancer drug. CONCLUSION: Frequently occurring medication errors in the field of oncology were identified, facilitating the development of specific recommendations for action and prevention strategies. The implementation of an electronic prescription software is particularly recommended for the avoidance of dosage errors in chemotherapy.

Individualized busulfan dosing improves outcomes compared to fixed-dose administration in pre-transplant minimal residual disease-positive acute myeloid leukemia patients with intermediate-risk undergoing allogeneic stem cell transplantation in CR.

Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. Eighty-seven patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. Thirty-two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n = 18/25 (72%); decreased: n = 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2%-19% vs. 35%, 23%-49% p = 0.02), improved 3-year leukemia-free survival (LFS) (78%, 54%-91% vs. 55%, 40%-70% p = 0.009) and - overall survival (OS) (82%, 60%-93% vs. 69%, 54%-81% p = 0.05) after individualized compared to fixed Bu. Non-relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p = 0.044), LFS (HR 3.6, p = 0.018) and relapses (HR 3.6, p = 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p = 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity.

Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer.

Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.

The impact of pharmacists' interventions within the Closed Loop Medication Management process on medication safety: An analysis in a German university hospital.

Background: Single elements of the Closed Loop Medication Management process (CLMM), including electronic prescribing, involvement of clinical pharmacists (CPs), patient individual logistics and digital administration/documentation, have shown to improve medication safety and patient health outcomes. The impact of the complete CLMM on patient safety, as reflected in pharmacists' interventions (PIs), is largely unknown. Aim: To evaluate the extent and characterization of routine PIs performed by hospital-wide CPs at a university hospital with an implemented CLMM. Methods: This single-center study included all interventions documented by CPs on five self-chosen working days within 1 month using the validated online-database DokuPIK (Documentation of Pharmacists' Interventions in the Hospital). Based on different workflows, two groups of CPs were compared. One group operated as a part of the CLMM, the "Closed Loop Clinical Pharmacists" (CL-CPs), while the other group worked less dependent of the CLMM, the "Process Detached Clinical Pharmacists" (PD-CPs). The professional experience and the number of medication reviews were entered in an online survey. Combined pseudonymized datasets were analyzed descriptively after anonymization. Results: A total of 1,329 PIs were documented by nine CPs. Overall CPs intervened in every fifth medication review. The acceptance rate of PIs was 91.9%. The most common reasons were the categories "drugs" (e.g., indication, choice of formulation/drug and documentation/transcription) with 42.7%, followed by "dose" with 29.6%. One-quarter of PIs referred to the therapeutic subgroup "J01 antibacterials for systemic use." Of the 1,329 underlying PIs, 1,295 were classified as medication errors (MEs) and their vast majority (81.5%) was rated as "error, no harm" (NCC MERP categories B-D). Among PIs performed by CL-CPs (n = 1,125), the highest proportion of errors was categorized as B (56.5%), while in the group of PIs from PD-CPs (n = 170) errors categorized as C (68.2%) dominated (p < 0.001). Conclusion: Our study shows that a structured CLMM enables CPs to perform a high number of medication reviews while detecting and solving MEs at an early stage before they can cause harm to the patient. Based on key quality indicators for medication safety, the complete CLMM provides a suitable framework for the efficient medication management of inpatients.

Population Pharmacokinetics of Busulfan and Its Metabolite Sulfolane in Patients with Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation.

For patients with myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment to date. Busulfan-based conditioning regimens are commonly used, although high inter-individual variability (IIV) in busulfan drug exposure makes individual dose selection challenging. Since data regarding the IIV in patients with myelofibrosis are sparse, this study aimed to develop a population pharmacokinetic (PopPK) model of busulfan and its metabolite sulfolane in patients with myelofibrosis. The influence of patient-specific covariates on the pharmacokinetics of drug and metabolite was assessed using non-linear mixed effects modeling in NONMEM®. We obtained 523 plasma concentrations of busulfan and its metabolite sulfolane from 37 patients with myelofibrosis. The final model showed a population clearance (CL) and volume of distribution (Vd) of 0.217 L/h/kg and 0.82 L/kg for busulfan and 0.021 L/h/kg and 0.65 L/kg for its metabolite. Total body weight (TBW) and a single-nucleotide polymorphism of glutathione-S-transferase A1 (GSTA1 SNP) displayed a significant impact on volume of distribution and metabolite clearance, respectively. This is the first PopPK-model developed to describe busulfan's pharmacokinetics in patients with myelofibrosis. Incorporating its metabolite sulfolane into the model not only allowed the characterization of the covariate relationship between GSTA1 and the clearance of the metabolite but also improved the understanding of busulfan's metabolic pathway.

Ciprofloxacin in Patients Undergoing Extracorporeal Membrane Oxygenation (ECMO): A Population Pharmacokinetic Study.

Extracorporeal membrane oxygenation (ECMO) is utilized to temporarily sustain respiratory and/or cardiac function in critically ill patients. Ciprofloxacin is used to treat nosocomial infections, but data describing the effect of ECMO on its pharmacokinetics is lacking. Therefore, a prospective, observational trial including critically ill adults (n = 17), treated with ciprofloxacin (400 mg 8-12 hourly) during ECMO, was performed. Serial blood samples were collected to determine ciprofloxacin concentrations to assess their pharmacokinetics. The pharmacometric modeling was performed (NONMEM®) and utilized for simulations to evaluate the probability of target attainment (PTA) to achieve an AUC0-24/MIC of 125 mg·h/L for ciprofloxacin. A two-compartment model most adequately described the concentration-time data of ciprofloxacin. Significant covariates on ciprofloxacin clearance (CL) were plasma bicarbonate and the estimated glomerular filtration rate (eGFR). For pathogens with an MIC of ≤0.25 mg/L, a PTA of ≥90% was attained. However, for pathogens with an MIC of ≥0.5 mg/L, plasma bicarbonate ≥ 22 mmol/L or eGFR ≥ 10 mL/min PTA decreased below 90%, steadily declining to 7.3% (plasma bicarbonate 39 mmol/L) and 21.4% (eGFR 150 mL/min), respectively. To reach PTAs of ≥90% for pathogens with MICs ≥ 0.5 mg/L, optimized dosing regimens may be required.

Detection of human herpesvirus 6 DNA and chromosomal integration after allogeneic hematopoietic stem cell transplantation: A retrospective single center analysis.

INTRODUCTION: Human herpesvirus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant morbidity and mortality. METHODS: The epidemiology of HHV-6 infections and their impact on outcome after allo-HSCT were retrospectively analyzed in 689 adult allo-HSCT recipients (January 2015-December 2018). Chromosomal integration of HHV-6 (ciHHV-6) in the donor was retrospectively investigated to critically evaluate antiviral treatment strategies. RESULTS: HHV-6 DNA in any specimen was found in 89 patients. HHV-6 infections (encephalitis (one), gastroenteritis (44), dermatitis (two), hepatitis (one), or pneumonitis (five)) were diagnosed in 53/689 patients (7.7%). Elevated levels of HHV-6 DNA were found in 38 patients (5.5%). ciHHV-6, analyzed in patients with HHV-6 viral loads ≥104  copies/ml, was identified in four patients (10/38 patients; 10.5%). Two of those displayed copy numbers of HHV-6 ranging from ≥2 × 105 to 2.5 × 106  copies/ml (HHV-6A). Here, ciHHV-6 was integrated into donor and not into the patients' cells. In this series of allo-HSCT recipients, 10.5% of patients with blood viral loads of HHV-6 showed ciHHV-6. CONCLUSION: Screening of the donor for ciHHV-6 before initiation of antiviral therapy is recommended.

Clinical pharmacists' interventions across German hospitals: results from a repetitive cross-sectional study.

Background Pharmacists' interventions (PI) are suitable to improve medication safety and optimise patient outcome. However, in Germany, clinical pharmacy services are not yet available nationwide. Aim To gain prospective data on the extent and the composition of routine PI with special focus on intervention rates among German hospital pharmacists during two intervention weeks. Methods Within a repetitive cross-sectional study, clinical pharmacists documented all PIs on five days during a one-month period (intervention week) in 2017 and 2019 using the validated online-database ADKA-DokuPIK. Additionally, data regarding the supply structure/level of medical care, the extent of clinical pharmacy services and their professional experience were collected. All data were anonymised before analysis. Results In total, 2,282 PI from 62 pharmacists (2017) and 2578 PI from 52 pharmacists (2019) were entered. Intervention rate increased from 27.5 PI/100 patient days in 2017 to 38.5 PI/100 patient days in 2019 (p = 0.0097). Frequency of clinical pharmacy services on a daily basis significantly increased from 60% (2017) to 83% (2019). Reasons for PIs from the categories "drugs" (e.g. indication, choice, documentation/transcription) and "dose" were most common in both intervention weeks. The vast majority of underlying medication errors in both intervention weeks were categorised as "error, no harm" (80.3 vs. 78.6%), while the proportion of errors which did not reach the patient, doubled to 39.8% in IW-2019. Conclusion Regular and daily clinical pharmacy services become more established in Germany and clinical pharmacists are increasingly involved in solving drug related problems proactively and early during the medication management process.

Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), chelation therapy is often postponed until the late post-transplantation period because of potential drug interactions. Therefore we systematically investigated the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) before HSCT. We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily (based on adjusted ideal body weight [AIBW] in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg · h/L. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until day 3 after transplantation. Model-based calculation of the busulfan AUC was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan, and dose adjustments were performed accordingly. Calculated median cumulative AUC before dose adjustment was 93.7 mg · h/L (65.1-151.4 mg · h/L), which was considerably above the target AUC of 80 mg · h/L ± 10%. Median dose adjustment was -17.1% (-50.0% to 18.2%), and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62) mg/kg. A busulfan dose reduction was necessary in 19 patients (76%) whereas a dose increase was only needed in 1 patient. After dose adjustment the median AUC was 79.7 mg/L · h (62.5 - 84.2 mg/L · h). Median busulfan clearance was 0.134 L/h/kg (0.084 - 0.203 L/h/kg), which is significantly lower than the average clearance of 0.2 L/h/kg reported in the literature, whereas volume of distribution was not altered. We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, because the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35% to 40%. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third; therefore a lower initial dose of busulfan followed by TDM could be considered in patients with comedication with deferasirox.

Evaluation of the Robustness of Therapeutic Drug Monitoring Coupled with Bayesian Forecasting of Busulfan with Regard to Inaccurate Documentation.

BACKGROUND: Inaccurate documentation of sampling and infusion times is a potential source of error in personalizing busulfan doses using therapeutic drug monitoring (TDM). Planned times rather than the actual times for sampling and infusion time are often documented. Therefore, this study aimed to evaluate the robustness of a limited sampling TDM of busulfan with regard to inaccurate documentation. METHODS: A pharmacometric analysis was conducted in NONMEM® 7.4.3 and "R" by performing stochastic simulation and estimation with four, two and one sample(s) per patient on the basis of a one-compartment- (1CMT) and two-compartment (2CMT) population pharmacokinetic model. The dosing regimens consisted of i.v. busulfan (0.8 mg/kg) every 6 h (Q6H) or 3.2 mg/kg every 24 h (Q24H) with a 2 h- and 3 h infusion time, respectively. The relative prediction error (rPE) and relative root-mean-square error (rRmse) were calculated in order to determine the accuracy and precision of the individual AUC estimation. RESULTS: A noticeable impact on the estimated AUC based on a 1CMT-model was only observed if uncertain documentation reached ± 30 min (1.60% for Q24H and 2.19% for Q6H). Calculated rPEs and rRmse for Q6H indicate a slightly lower level of accuracy and precision when compared to Q24H. Spread of rPE's and rRmse for the 2CMT-model were wider and higher compared to estimations based on a 1CMT-model. CONCLUSIONS: The estimated AUC was not affected substantially by inaccurate documentation of sampling and infusion time. The calculated rPEs and rRmses of estimated AUC indicate robustness and reliability for TDM of busulfan, even in presence of erroneous records.

Clinical pharmacy services in Germany: a national survey.

OBJECTIVES: Clinical pharmacy services in German hospitals appear to be underdeveloped compared with other European countries. However, recent developments have increased the interest in expanding these services. Detailed data about the current state of clinical pharmacy services in Germany are lacking. This survey establishes the current level of pharmacy services in Germany and the barriers to implementation. METHODS: An online survey conducted in 2017 was distributed to directors of all 389 German hospital pharmacies. The survey contained 26 questions addressing hospital and pharmacy characteristics, clinical pharmacy services provided, the number of clinical pharmacists and the frequency as well as the quality assurance of these services. RESULTS: There were 133 responses (34%). Of these, 84 (63%) pharmacies provided some form of clinical pharmacy services. Based on the 389 contacted pharmacies, a clinical pharmacy service is available in at least 22% of hospital pharmacies in Germany. On average there are 2.4 full-time equivalent (FTE) clinical pharmacists per hospital employed, although there is a wide variation in numbers (0.3-22 FTE) and service provision between hospitals. Clinical pharmacy services are generally provided on a daily or weekly basis, with a principal focus on general surgery, critical care and general medicine wards. CONCLUSIONS: This is the first survey providing a detailed picture of clinical pharmacy services in Germany. There is wide variation in clinical service provision among hospitals, with some hospitals having developed a comprehensive range of clinical services. Compared with other countries, particularly the UK where the focus has shifted to provision of 7-day clinical services, the gap in clinical pharmacy services remains large. The focus should be turned to refining clinical pharmacy services in hospital admissions and discharge planning while also improving Health IT, the opportunities for specialisation and aligning education in accordance with the EAHP common training framework.

Comparison of FORTA, PRISCUS and EU(7)-PIM lists on identifying potentially inappropriate medication and its impact on cognitive function in multimorbid elderly German people in primary care: a multicentre observational study.

OBJECTIVES: Our study aimed to assess the frequency of potentially inappropriate medication (PIM) use (according to three PIM lists) and to examine the association between PIM use and cognitive function among participants in the MultiCare cohort. DESIGN: MultiCare is conducted as a longitudinal, multicentre, observational cohort study. SETTING: The MultiCare study is located in eight different study centres in Germany. PARTICIPANTS: 3189 patients (59.3% female). PRIMARY AND SECONDARY OUTCOME MEASURES: The study had a cross-sectional design using baseline data from the German MultiCare study. Prescribed and over-the-counter drugs were classified using FORTA (Fit fOR The Aged), PRISCUS (Latin for 'time-honoured') and EU(7)-PIM lists. A mixed-effect multivariate linear regression was performed to calculate the association between PIM use patients' cognitive function (measured with (LDST)). RESULTS: Patients (3189) used 2152 FORTA PIM (mean 0.9±1.03 per patient), 936 PRISCUS PIM (0.3±0.58) and 4311 EU(7)-PIM (1.4±1.29). The most common FORTA PIM was phenprocoumon (13.8%); the most prevalent PRISCUS PIM was amitriptyline (2.8%); the most common EU(7)-PIM was omeprazole (14.0%). The lists rate PIM differently, with an overall overlap of 6.6%. Increasing use of PIM is significantly associated with reduced cognitive function that was detected with a correlation coefficient of -0.60 for FORTA PIM (p=0.002), -0.72 for PRISCUS PIM (p=0.025) and -0.44 for EU(7)-PIM (p=0.005). CONCLUSION: We identified PIM using FORTA, PRISCUS and EU(7)-PIM lists differently and found that PIM use is associated with cognitive impairment according to LDST, whereby the FORTA list best explained cognitive decline for the German population. These findings are consistent with a negative impact of PIM use on multimorbid elderly patient outcomes. TRIAL REGISTRATION NUMBER: ISRCTN89818205.