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What is known and objective The evaluation of clinical pharmacy services is essential for their further development and establishment. We analysed drug-related problems (DRPs) and subsequent clinical pharmacists' interventions (PIs) at a Swiss university hospital. Method We conducted a retrospective analysis of DRPs and subsequent PIs that were identified and implemented during interdisciplinary ward rounds in internal medicine at the University Hospital Basel, Switzerland, between 2015 and 2017. We estimated the potential clinical and economic impact of PIs using a validated evaluation tool (CLEOde ). Results and discussion Based on medication reviews of 5441 patients, clinical pharmacists identified 5024 DRPs, of which 2892 DRPs (57.6%) were followed by a PI that was directly accepted and implemented by the physician in charge and included in the present analysis. The leading cause and type of PIs were inappropriate dose and dose adjustment, respectively. Overall, 97.8% of DRPs were followed by PIs with an expected clinical benefit for the patients (major: 11.1%; moderate: 27.6%; minor: 59.1%). The drugs most often involved in PIs of major clinical impact were antithrombotics, acid blockers and cardiovascular drugs. With regard to the economic impact, 40.7% of DRPs implied PIs resulting in an increase of immediate therapy costs, whereas 39.3% implied PIs resulting in a decrease of immediate therapy costs. The remaining PIs were cost-neutral. What is new and conclusion This study emphasizes that clinical pharmacists may help improve the effectiveness and safety of pharmacotherapy on acute care medical wards.

Background The correct use of antimicrobial treatment is necessary to ensure their effectiveness, the control of resistance and to avoid the occurrence of adverse reactions. Purpose To analyse the pharmaceutical interventions (PI) in antimicrobial treatment and quantify the degree of their acceptance. Material and methods Descriptive and retrospective study in a 150 bed-hospital was made. PI on antimicrobial treatments were analysed over a period of 16 months (December 2016 – March 2018). The collected data were: age, antimicrobial treatment, type of PI and degree of acceptance of the PI. The reasons for PI were classified into: inadequate dosage, dose adjustment due to renal insufficiency, drug change after antibiogram, therapeutic duplicity, suspension of treatment due to inadequate duration and change of route of administration. The degree of acceptance of the PI was detected based on the medical prescription modifications according to the recommendations. The pharmaceutical recommendations were made through the daily evolutions in the patient’s history in the Ticares computer program. Results Two-hundred and forty-four PI were carried out in 132 patients (1.84 PI per patient). The average age of the patients was 79 years (53% women). The PI, according to classification were: 160 (65.6%) PI due to changes in the antimicrobial administration route (92 were accepted, 57.5%); 70 (28.7%) PI due to suspension of treatment due to inadequate duration (44 were accepted, 62.90%); seven (2.9%) PI for dose adjustment due to renal failure (three were accepted, 42.9%); three (1.2%) PI due to therapeutic duplicity (100% accepted); three (1.2%) PI due to inadequate posology (two were accepted, 66.7%); and one (0.4%) PI due to antimicrobial change after antibiogram (the patient was discharged and it could not be confirmed if there was a change in the prescription). Regarding the degree of acceptance, 144 (59%) IP were accepted and 60 (37,29%) IP were not accepted. Conclusion More than half of the pharmaceutical interventions resulted in a change in the medical prescription according to the recommendation. The pharmaceutical validation adds safety to the hospitalisation process and represents an improvement in the quality of care. References and/or acknowledgements No conflict of interest.

Background A previous research project1 had confirmed that patients with renal impairment and poly-medication had a greater risk of suffering from medication-related problems. Purpose Our objective was to develop a practicable method of monitoring medication which could be permanently integrated into the everyday routines of a team of pharmacists working at a general hospital without the facilities of a university medical centre. Materials and methods Glomerular filtration rates (GFRs) were recorded on a daily basis by staff at the clinic’s laboratory. This list enabled us to monitor the medication of 425 inpatients with GFR Results In about one-third of the cases (154 patients, about six per day) the medication to be administered was changed directly or after joint consultation between the medical and pharmaceutical staff. More than half of the recommendations were immediately applied, and in roughly one-quarter of the remaining cases a decision deferred, pending further risk-benefit assessment. Therapeutic intervention (type A or B) was required for approximately 51% of the inpatients with GFRs of 10–30 ml/min, but, in contrast, only recommended for approximately 17% of inpatients with GFRs of 30–40 ml/min. Furthermore, a drug list was designed to facilitate routine work (with a link towww.dosing.de), as well as an information leaflet listing those drugs used in our hospital that either required dose adjustment or should not be used in cases of renal impairment. Conclusion An increase in patient safety by means of intervention was achieved in 114 of the 154 cases, limiting patient assessment to GFRs of 10–30 ml/min (in accordance with KDIGO classification 4). This would correspond to a work-efficient intervention rate of 51% (about seven medication errors per day). After successfully presenting our results to the board of management and at the chief physicians’ conference meeting, the decision was taken to continue to provide this everyday form of clinical service despite our limited human resources situation. References and/or acknowledgements 1. Schlosser L. Medication management for patients with renal failure. Krankenhauspharm 2017; 02/17:112–

Background The adjustment of infliximab (IFX) doses is commonly based on subjective data or invasive methods. However, pharmacokinetic monitoring of IFX plasma levels is a currently available tool that has proved to be useful in the optimisation of clinical results.1 Purpose To analyse the clinical course of acute-phase reactants in patients with inflammatory bowel disease (IBD) treated with IFX, and to evaluate if there is a clinical benefit resulting from applying the pharmacokinetic recommendations in the management of these patients. Material and methods Retrospective, cross-sectional study carried out in a general hospital. All the determinations of IFX performed during 2017 in patients with IBD were analysed. After analytical determination, the pharmacy service performed a pharmacokinetic study (Bayesian statistics) and recommended a new dosage to the digestive specialist. Identification data of the patients and analytical results (fecal calprotectin and C-reactive protein (CRP)) measured before the monitoring (pre) and 3 months later (post) were collected. In addition, it was evaluated if the digestive specialist followed the pharmacokinetic recommendation (acceptance/rejection). Results During the study period, the IFX serum levels of 21 patients with IBD were determined. The mean level of fecal calprotectin measured before the extraction of IFX blood levels was 1,257.2 mg/kg and this was reduced to 503.2 mg/kg at 3 months after monitoring (p=0.053). As for CRP, a decrease was also observed, with a CRP value of 7.1 mg/L before monitoring and a CRP value of 3.8 mg/L after 3 months (p=0.035). These data were analysed again, stratifying according to the degree of acceptance of the pharmacist’s recommendations for clinical decision-making (table 1). Conclusion Both PCR and calprotectin were reduced after 3 months of IFX monitoring. The clinical improvement observed was greater in the group of patients in whom the dose drug was adjusted following the recommendation of the pharmacist. These results support the role of therapeutic IFX monitoring in the optimisation of IBD treatment, according to the evidence published by other authors. Reference and/or acknowledgements Kelly OB, Donnell SO, Stempak JM, et al. Therapeutic drug monitoring to guide infliximab dose adjustment is associated with better endoscopic outcomes than clinical decision making alone in active inflammatory bowel disease. Inflamm Bowel Dis 2017;23:1202–9. No conflict of interest.

Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate may have reduced methotrexate clearance (CL) due to renal immaturity, which may predispose them to toxicity. The aim of this study was to develop a population pharmacokinetic (PK) model of methotrexate in infants with ALL. A total of 672 methotrexate plasma concentrations were obtained from 71 infants enrolled in the Children’s Oncology Group (COG) Clinical Trial P9407. Infants received methotrexate 4 g/m2 intravenously for four cycles during weeks 4–12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap and a visual predictive check. Simulations were performed to evaluate methotrexate dose and the utility of a bedside algorithm for dose individualization. Methotrexate was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared with the interindividual variability for CL and central volume of distribution (10.7% and 13.2%, respectively). Simulations identified that 21.1% of simulated infants benefitted from bedside dose adjustment, and adjustment of methotrexate doses during infusions can avoid supratherapeutic concentrations. Infants treated with high-dose methotrexate demonstrated a relatively high degree of IOV in methotrexate CL. The magnitude of IOV in the CL of methotrexate suggests that use of a bedside algorithm may avoid supratherapeutic methotrexate concentrations resulting from high IOV in methotrexate CL.

Background After thyroidectomy, patients require Levothyroxine (LT4). It may take years of dose adjustments to achieve euthyroidism. During this time, patients encounter undesirable symptoms associated with hypo- or hyper-thyroidism. Currently, providers adjust LT4 dose by clinical estimation, and no algorithm exists. The objective of this study was to build a decision tree that could estimate LT4 dose adjustments and reduce the time to euthyroidism. Methods We performed a retrospective cohort analysis on 320 patients who underwent total or completion thyroidectomy at our institution. All patients required one or more LT4 dose adjustments from their initial postoperative dose before attaining euthyroidism. Using the Classification and Regression Tree algorithm, we built various decision trees from patient characteristics, estimating the dose adjustment to reach euthyroidism. Results The most accurate decision tree used thyroid-stimulating hormone values at first dose adjustment (mean absolute error = 13.0 μg). In comparison, the expert provider and naive system had a mean absolute error of 11.7 μg and 17.2 μg, respectively. In the evaluation dataset, the decision tree correctly predicted the dose adjustment within the smallest LT4 dose increment (12.5 μg) 79 of 106 times (75%, confidence interval = 65%-82%). In comparison, expert provider estimation correctly predicted the dose adjustment 76 of 106 times (72%, confidence interval = 62%-80%). Conclusions A decision tree predicts the correct LT4 dose adjustment with an accuracy exceeding that of a completely naive system and comparable to that of an expert provider. It can assist providers inexperienced with LT4 dose adjustment.

BACKGROUND 6-Mercaptopurine (6-MP) is considered the backbone of therapy in the maintenance phase of acute lymphoblastic leukemia (ALL). Gene polymorphisms involved in thiopurine degradation are predictors of toxicity in patients treated with 6-MP. We investigated the effects of nucleoside diphosphate linked moiety X (nudix) type motif 15 (NUDT15) polymorphism NUDT15c.415C>T on neutropenia incidence, dose adjustment for 6-MP, and survival rates in Thai children with ALL. METHODS Children diagnosed with ALL who received 6-MP in the maintenance phase of treatment, in 2005-2016, were retrospectively enrolled. RESULTS The subjects consisted of 102 patients (median age, 5.2 years; 58 boys). On genetic testing 78, 22, and two patients were normal (CC), heterozygous (CT), and homozygous (TT), respectively. The incidence of neutropenia at 3 months was significantly higher in the CT/TT than CC polymorphism groups (OR, 12; 95%CI: 3.781-38.085, P < 0.001). The mean dose of 6-MP at 3, 6, and 12 months was significantly lower in the CT/TT versus the CC group (P < 0.001). The 5 year overall survival (OS) rate for CC was 80.4%, and for CT/TT, 95.5% (P = 0.34). The 5 year event-free survival (EFS) for CC and CT/TT was 75.1% and 85.7%, respectively (P = 0.17). After adjusted risk classification, no significant differences were observed for OS or EFS between the CC and CT/TT groups. CONCLUSION Patients harboring the CT/TT polymorphism of NUDT15 had a significantly higher incidence of neutropenia during the first 3 months of maintenance, resulting in significantly lower doses of 6-MP.

Current precision medicine approaches offer powerful tools to optimize medication regimens; however, the potential impact of these tools in cancer patients with multiple drug treatments has not fully appreciated yet. Here we describe a planning project scheduled to start in the next six months.The overall endpoint of this project is to explore the potential association between the presence of individual genetic profile and severe toxicity rates in so-called "frail" cancer patients, using a nested case-control study design. The pilot study includes the detection of the individual pharmacogenetic profile of 150 (cases), prospect enrolled cancer "frail" patients, and 150 (control) retrospectively paired enrolled individuals. Methods for addressing the primary endpoint include: (a) Evaluation of cost-effectiveness analysis by recording QALY criteria; (b) Data recording by a brief self-administered questionnaire used to evaluate the adherence of a patient's tests and the impact of this genotyping on the patient's adverse drug reactions (ADR); (c) A sample size of paired (for age, gender, education, social status, geriatric syndromes, number of medications and comorbidities) 150 (cases) and 150 (controls); (d) Genotyping method choice by current widely diffuse platforms.The investigators believe that genotype screening and the management of the overall cost of health care personalized therapy has the potential to reduce the health care costs of the Italian national health system (SSN).Finally, the innovative issue of this project is to advocate the creation of a new model of the co-operative team (Physicians, pharmacist, geneticist and lab manager) that join for planning the most appropriated personalized therapy for their patient.

Background: In 2005, the European Medicines Agency (EMA) released guidance on pharmacokinetic studies in patients with hepatic impairment. This guidance describes the design of these studies and what information should be presented in the Summary of Product Characteristics (SmPC). We aim to evaluate the availability and clinical applicability of information on medicine use in patients with hepatic impairment in SmPCs and registrational dossiers of recently approved medicines.Methods: We reviewed SmPC information on use in patients with hepatic impairment of 51 new medicines authorized between 2015 and 2017. Per medicine, we assessed the availability of nine information items derived from the EMA guidance, i.e. type of hepatic disease studied; stratification by severity of hepatic impairment; influence of hepatic impairment on the pharmacokinetics; safety advice in mild, moderate, and severe hepatic impairments; and dosing recommendation in mild, moderate, and severe hepatic impairments. If unavailable, the European Public Assessment Report (EPAR) and study report were consulted consecutively. Of available items, clinical applicability was assessed by labeling information as "clear" or "ambiguous".Results: Of 51 medicines, 15 had no pharmacokinetic study in patients with hepatic impairment described in their SmPC. The other 36 SmPCs contained on average seven of the nine information items (range 4-9). One SmPC contained all 9 items, and after consulting, the study reports, 11 SmPCs were complete. The item "type of hepatic disease studied" was available in one SmPC, though it could be retrieved in 21 study reports. Regarding clinical applicability, there was no medicine with all information items available and clearly formulated in the SmPC. A total of 12 medicines (33%) contained only clearly formulated information, while 24 (67%) contained at least one ambiguously formulated information item (range 0-4). Items often ambiguously formulated were: "definition of mild, moderate, and severe hepatic impairment" (15 ambiguous SmPCs) and "safety advice in severe hepatic impairment" (17 ambiguous SmPCs).Conclusion: While SmPCs contain a large part of information requested by the EMA, clinical applicability seems low, as it is often unclear to which specific type of hepatic disease patient the advice applies. This can negatively influence the practical use by healthcare professionals.

International audience; Background - The hepatotoxicity of acetaminophen is recognised worldwide. Unfavourable prognoses relating to overdose include liver transplantation and/or death. Several hepatotoxicity risk factors (HRFs) should motivate the adjustment of acetaminophen daily intake (to 75 and low weight were associated with the prescriber's choice of dose. Neither chronic alcoholism nor hepatocellular insufficiency influenced the acetaminophen doses prescribed. Conclusion - Considering the widespread use of acetaminophen and its favourable safety profile compared with other analgesic drugs, it appears urgent to remind prescribers of the maximum daily dose recommendations for acetaminophen for patients with HRFs, especially those with chronic alcoholism and hepatocellular insufficiency.

A narrative review from a multidisciplinary task force of experts in critical care medicine and clinical mycology was carried out. The multi drug-resistant species Candida auris has emerged simultaneously on several continents, causing hospital outbreaks, especially in critically ill patients. Although there are not enough data to support the routine use of continuous antibiotic prophylaxis in patients subjected to extracorporeal membrane oxygenator, a clear increase of invasive fungal infection (IFI) has been described with the use of this device. Possible IFI treatment failures could be related with suboptimal antifungal concentrations despite dose adjustment. Invasive aspergillosis has become an important life-threating infection in intensive care unit related with new risk factors described. IFI remain important problem in critical patients due to the appearance of new risk factors, new species, and resistance increase. Multidisciplinary packages of measures designed to reduce IFI incidence and improve diagnostics tools may reduce the high mortality associated.

OBJECTIVES The purposes of this study are to perform a large-scale evaluation of the standardized dosage adjustment nomogram recommended by the American College of Chest Physicians (CHEST) for the management of enoxaparin in hospitalized pediatric patients and to determine the necessity of routine and repeated anti–factor Xa (anti-Xa) levels.METHODS A retrospective cohort study was designed, and charts were reviewed in a single tertiary care institution for all patients who received enoxaparin between October 1, 2010, through September 30, 2016. Patients were included if they were receiving treatment doses of enoxaparin according to the pediatric CHEST guidelines, had a subtherapeutic or supratherapeutic anti-Xa level drawn at 3.5 to 6 hours after a dose, had a dose changed in an attempt to attain a therapeutic anti-Xa level, and had a second anti-Xa level drawn 3.5 to 6 hours after the dose change. Descriptive statistical methods were used to characterize the ability of dose adjustment via a nomogram to attain an anti-Xa of 0.5 to 1 unit/mL.RESULTS A total of 467 patients were identified who received the appropriate initial dose and dosage adjustment and whose levels were drawn according to the CHEST guidelines. In patients who had an initial anti-Xa level of CONCLUSIONS The current dosage adjustment nomogram recommended by the CHEST guidelines does not reliably lead to therapeutic anti-Xa levels when used to adjust enoxaparin doses in pediatric patients.

Background Staphylococcus aureus bacteraemia (SAB) is a serious and often fatal infectious disease. The quality of management of SAB is modifiable and can thus affect the outcome. Quality indicators (QIs) can be used to measure the quality of care of the various aspects of SAB management in hospitals, enabling professionals to identify targets for improvement and stimulating them to take action. Objectives To develop QIs for the management of hospitalized patients with SAB. Methods A RAND-modified Delphi procedure was used to develop a set of QIs for the management of SAB in hospitalized patients. First, available QIs for the management of SAB were extracted from the literature published since 1 January 2000 (MEDLINE and Embase databases). Thereafter, an international multidisciplinary expert panel appraised these QIs during two questionnaire rounds with an intervening face-to-face meeting. Results The literature search resulted in a list of 39 potential QIs. After appraisal by 30 medical specialists, 25 QIs describing recommended care at patient level were selected. These QIs defined appropriate follow-up blood cultures (n=2), echocardiography (n=6), source control (n=4), antibiotic therapy (n=7), antibiotic dose adjustment (n=2), intravenous-to-oral switch (n=2), infectious disease consultation (n=1) and medical discharge report (n=1). Conclusions A set of 25 QIs for the management of SAB for hospitalized patients was developed by using a RAND-modified Delphi procedure among international experts. These QIs can measure the quality of various aspects of SAB management. This information can be fed back to the relevant stakeholders in order to identify improvement targets and optimize care.

Teicoplanin is a glycopeptide antibiotic used for treatment of severe Gram-positive bacterial infection. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of teicoplanin and to review our clinical experience. We established an LC-MS/MS method to analyze serum concentration of teicoplanin using simple protein precipitation with a 5 min run time for each sample. The linearity, lower limit of quantitation, detection accuracy, precision, carryover, matrix effect, and extraction recovery were evaluated. From September 2014 to June 2017, a total of 421 serum teicoplanin concentrations was measured in 223 patients. We collected demographic and clinical data, medication history, and laboratory findings through retrospective review of medical records. The LC-MS/MS method was linear for serum teicoplanin concentrations in the range of 12.0-89.0 μg/mL. The intra- and inter-assay precisions were below CV 7.5%. The accuracy was less than ±10% bias. The lower limit of quantification was 0.2 μg/mL. The extraction recovery ranged from 88.8% to 96.6%. Of 421 measurements, 87 (20.7%) were subtherapeutic (10 μg/mL), and four (0.9%) were above the toxic threshold (≥ 60 μg/mL). Serum teicoplanin concentration was measured once in 140 patients (63%), and multiple measurements were completed for the others (83 patients, 37%). Intra-patient variability in teicoplanin concentration was found (CV 33%, range 2-94%). Our simple and rapid LC-MS/MS method was successfully applied in TDM of teicoplanin in clinical practice. Such TDM of teicoplanin may be useful for individualized dose adjustment.

Most widely used testosterone replacement therapy (TRT) products can be inconvenient and cumbersome topical and invasive injectable requiring dose adjustments to attain efficacy. In a pivotal study, a recently approved oral TRT only 26% of patients did not require any dose adjustment. Typically, patients start on a sub-therapeutic dose with gradual dose increases to attain efficacy resulting in additional visit(s) to clinic and pharmacy. Physician research data (N=402) suggested it typically takes 3-6 months of titrations to reach an efficacious dose for majority of patients, a significant barrier in effecting a switch without a period of “efficacy gap”. The requirement of additional visit(s) presents significant challenges for new and current patients desiring to start and to switch to a convenient TRT option, especially in the current COVID-19 pandemic. Recent reports suggest increase of disease severity/mortality in men with low testosterone is possibly due to underlying co-morbidities commonly associated with male hypogonadism. There remains a need for an effective, safe, and easy to use and prescribe product that does not require dose titration. TLANDO is a “triglyceride-free” oral single strength TRT with single dose designed to lymphatically deliver effective and safe levels of testosterone regardless of meal fat content. Moreover, dose titration is prone to some inherent titration decision errors and requires understanding of often complex titration rules. The objective is to assess whether TLANDO, an oral TRT without requiring dose titration, safely restores effective testosterone (T) levels in hypogonadal men. An open-label, single-arm, multicenter study (NCT03242590) was performed with TLANDO in hypogonadal males (N=95). Subjects received orally 225 mg twice a day testosterone undecanoate (TU) for 24 days without dose adjustment. Efficacy was evaluated by % of subjects who achieved daily T Cavg within the eugonadal range. Using 450mg daily dose without dose adjustment, 80% of subjects (95% CI of 72% to 88%) achieved a T Cavg in the normal range and safely restored with mean T Cavg of 476±184 ng/dL post steady state. T restoration was comparable to other non-oral TRT products. TLANDO was well tolerated with no deaths, no drug-related severe AEs, and no hepatic AEs. In conclusion, effective T restoration using TLANDO, an easy to use and prescribe oral TRT option, was confirmed. Minimal AEs were reported with no hepatic AEs. Upon approval, TLANDO will be the first convenient TRT option without requiring dose adjustments; therefore, enabling selection of an efficacious dose from the start of therapy. TLANDO is well suited for new or existing TRT patients desiring a convenient oral option.

The primary objective of this study is to evaluate the capacity of concentration-guided sorafenib dosing protocols to increase the proportion of patients that achieve a sorafenib maximal concentration (Cmax) within the range 4.78 to 5.78 μg/mL. A full physiologically based pharmacokinetic model was built and validated using Simcyp® (version 19.1). The model was used to simulate sorafenib exposure in 1000 Sim-Cancer subjects over 14 days. The capacity of concentration-guided sorafenib dose adjustment, with/without model-informed dose selection (MIDS), to achieve a sorafenib Cmax within the range 4.78 to 5.78 μg/mL was evaluated in 500 Sim-Cancer subjects. A multivariable linear regression model incorporating hepatic cytochrome P450 (CYP) 3A4 abundance, albumin concentration, body mass index, body surface area, sex and weight provided robust prediction of steady-state sorafenib Cmax (R2 = 0.883, p &lt, 0.001). These covariates identified subjects at risk of failing to achieve a sorafenib Cmax ≥ 4.78 μg/mL with 95.0% specificity and 95.2% sensitivity. Concentration-guided sorafenib dosing with MIDS achieved a sorafenib Cmax within the range 4.78 to 5.78 μg/mL for 38 of 52 patients who failed to achieve a Cmax ≥ 4.78 μg/mL with standard dosing. In a simulation setting, concentration-guided dosing with MIDS was the quickest and most effective approach to achieve a sorafenib Cmax within a designated range.

Background: Recent cell-based and animal experiments have demonstrated an effective reduction in botulinum neurotoxin A (BoNT/A) by copper. Aim: We aimed to analyze whether the successful symptomatic BoNT/A treatment of patients with Wilson’s disease (WD) corresponds with unusually high doses per session. Methods: Among the 156 WD patients regularly seen at the outpatient department of the university hospital in Düsseldorf (Germany), only 6 patients had been treated with BoNT/A during the past 5 years. The laboratory findings, indications for BoNT treatment, preparations, and doses per session were extracted retrospectively from the charts. These parameters were compared with those of 13 other patients described in the literature. Results: BoNT/A injection therapy is a rare (

This review outlines the background and current status of different dose expressions of plant protection products (PPP) applied in three-dimensional (3D) crops that are grown in orchards, groves, berry plantations, vineyards or greenhouses. It describes the course of dose expression harmonization process, and gives an overview of dose adjustment tools. In some EU countries there are used dose expressions that link the recommended amount of PPP with canopy height (CH), leaf wall area (LWA), tree row volume (TRV), or plant row distance (PRD). In the Mediterranean countries, a common way of PPP dosing recommendation is concentration of spray liquid. The advantages and disadvantages of each dose expression are discussed. Harmonization of dose expressions has for long been of great importance for the PPP authorization procedure, which in the EU is performed on a zonal basis. In the Central Zone it was agreed that the LWA model would be a common dose expression that must be used during efficacy trials in pome fruits, vines and high growing vegetables, and then in the subsequent zonal evaluation process. For the crops with wide canopies, such as citruses, olives or nuts, which are mainly grown in the Southern Zone, the TRV model might be a more appropriate dose expression to be agreed for a common use. However, any dose expression method should be corrected based on leaf area density. The crop-specific decision support tools, assisting growers to adjust effective PPP dose in specific circumstances, cover pome and stone fruits, citruses, olives, vines and greenhouse tomatoes.

Advanced age and immunosuppressed states allow for complications of herpes zoster such as encephalitis. In this case report, we describe a patient with encephalopathy two days after initiation of antiviral therapy. After the necessary imaging and cerebrospinal fluid (CSF) analysis, it became evident that the neurological syndrome was due to acyclovir. Despite currently practised renal dose modification, the patient developed acyclovir-induced neurotoxicity and required intensification of his dialysis schedule to eliminate the drug. Acyclovir-induced neurotoxicity is a rare clinical presentation and presents a clinical dilemma to the physician who has to distinguish this entity from herpes zoster encephalitis and posterior circulation stroke.

Immunosuppression in immediate post liver transplantation (LT) setting is crucial to prevent rejection. Most immunosuppressant (IS) drugs have several adverse effects, necessitating dose adjustment, close monitoring of blood levels, and choosing the right drug on a case-to-case basis so as to achieve optimal immunosuppression with minimal side effects. Although guidelines are available for management, the IS regimen differs from center to center, especially with introduction of new agents. The calcineurin inhibitors (CNIs) are the most important class of IS regimen. However, the occurrence of major adverse effects with CNIs has necessitated the need for alternative drugs such as mammalian target of rapamycin inhibitors and antibody induction therapies. Early rejection episode management, especially within the first 3 months after LT, needs special consideration. The present review will highlight the current strategies in induction and maintenance of LT recipients in the immediate post-LT period and in a selective special situation.

Background and aimsIn previous phase III studies, the PCSK9 monoclonal antibody alirocumab was administered at doses of 75 or 150 mg every 2 weeks (Q2W). CHOICE I (NCT01926782) evaluated 300 mg every 4 weeks (Q4W) in patients on either maximally tolerated statin or no statin, both ± other lipid-lowering therapies.MethodsCHOICE I included patients with hypercholesterolemia at moderate-to-very-high cardiovascular risk. Patients were randomized to alirocumab 300 mg Q4W, 75 mg Q2W (calibrator arm), or placebo for 48 weeks, with dose adjustment for either alirocumab arm to 150 mg Q2W at Week (W) 12 if at W8 LDL-C levels were >70/100 mg/dL (1.8/2.6 mmol/L) depending on cardiovascular risk or LDL-C reduction was

In some clinical settings laboratory measurement of direct oral anticoagulants effect is helpful in guiding medical care, such as life-threatening bleeding, need for emergency surgery, renal impairment, severe hepatic failure, extremes of body weight, or in patients with bleeding or thrombosis on therapy. This article reviews approaches to laboratory testing to assess the anticoagulant effect of these drugs. Because of the wide variation in levels measured in patients on therapy and minimal clinical data from dose adjustment, dose adjustment based on levels is not currently advised. In addition, these drugs interfere with many clot-based laboratory tests and caution is advised in interpreting these tests in patients on direct oral anticoagulants.

Tablet splitting is an accepted practice for the administration of drugs for a variety of reasons, including dose adjustment, ease of swallowing and cost savings. The purpose of this study was to evaluate the physical properties of lisinopril tablets as a result of splitting the tablets either by hand or with a splitting device. The impact of the splitting technique of lisinopril (Zestril® tablets, 20 mg) on certain physical parameters such as weight variation, friability, disintegration, dissolution and drug content were studied. Splitting the tablets either by hand or with a splitter resulted in a minute but statistically significant average weight loss of &lt, 0.25% of the tablet to the surrounding environment. The variability in the weight of the hand-split tablet halves was more pronounced (37 out of 40 tablet halves varied by more than 10% from the mean weight) than when using the tablet splitter (3 out of 40 tablet halves). The dissolution and drug content of the hand-split tablets were therefore affected because of weight differences. However, the pharmacopoeia requirements for friability and disintegration time were met. Hand splitting of tablets can result in an inaccurate dose and may present clinical safety issues, especially for drugs with a narrow therapeutic window in which large fluctuations in drug concentrations are undesirable. It is recommended to use tablets with the exact desired dose, but if this is not an option, then a tablet splitter could be used.

Tablet subdivision is a common practice used mainly for dose adjustment. The aim of this study was to investigate how the technical aspects of production as well as the method of tablets subdivision (employing a tablet splitter or a kitchen knife) influence the accuracy of this practice. Five drugs commonly used as subdivided tablets were selected. For each drug, the innovator drug product, a scored-generic and a non-scored generic were investigated totalizing fifteen drug products. Mechanical and physical tests, including image analysis, were performed. Additionally, comparisons were made between tablet subdivision method, score, shape, diluent composition and coating. Image analysis based on surface area was a useful tool as an alternative assay to evaluate the accuracy of tablet subdivision. The tablet splitter demonstrates an advantage relative to a knife as it showed better results in weight loss and friability tests. Oblong, coated and scored tablets had better results after subdivision than round, uncoated and non-scored tablets. The presence of elastic diluents such as starch and dibasic phosphate dehydrate conferred a more appropriate behaviour for the subdivision process than plastic materials such as microcrystalline cellulose and lactose. Finally, differences were observed between generics and their innovator products in all selected drugs with regard the quality control assays in divided tablet, which highlights the necessity of health regulations to consider subdivision performance at least in marketing authorization of generic products.

Nephropharmakologie beschaftigt sich mit allen Aspekten der Arzneimitteltherapie bei Nierenpatienten, insbesondere der Dosisanpassung an die Nierenfunktion. Dosisanpassungen sollen einerseits Nebenwirkungen vermeiden andererseits aber auch den Effekt sichern: Sie sind in der Regel jedoch erst erforderlich, wenn die GFR unter 60 ml/min fallt. Auch braucht es – bei maximal halbmaximaler Dosis – keine Anpassung solange die Halbwertszeit kurzer als das normale Dosierungs-Intervall bleibt. Fur Antibiotika und Chemotherapeutika zahlt der sofortige und kraftige Wirkungseintritt. Bei zeitabhangigen Effekten ware zur Anpassung die Reduktion der Dosis zu empfehlen dagegen bei konzentrationsabhangigen Effekten die Verlangerung des Dosierungsintervalls. Neuere Psychopharmaka, Antikonvulsiva, Antidiabetika und Antikoagulanzien sind haufig ebenfalls nierenabhangig, konnen jedoch einschleichend dosiert werden. Sie sollten deshalb nur mit der halbmaximalen Standarddosis gegeben werden, wenn keine praziseren Vorschlage greifbar sind.

Valproic acid (VA) is used in epileptology for the basic and additional control of simple and complex focal seizures, absences, generalized tonicclonic seizures, and myoclonus. Information has been recently stored on cases of chronic overdosage of VA due to its blood accumulation. These conditions are described in the use of both high and average therapeutic doses of VA preparations in patients with a genetically determined delay in metabolism. The paper presents current methods for clinical and laboratory diagnosis and correction of chronic intoxication when valproic acid preparations are administered during the prehospital, hospital and rehabilitation phases of treatment. The authors note that a personalized approach is of importance for dose adjustment and prediction of unwanted adverse drug reactions associated with the use of VA preparations.

Background: Patient adherence to immunosuppressant regimens after organ transplant is crucial to preserve graft function, and simplifying the regimen improves adherence. In this study, our experience of conversion from twice-daily (b.i.d.) to once-daily (q.d.) tacrolimus (TAC) in stable liver transplant recipients is reviewed and the proper conversion regimen is investigated. Methods: Between November 2011 and August 2012, the regimen was converted in 32 stable liver transplant recipients, and data on the conversions gathered retrospectively from medical records. TAC trough level, dose, and laboratory findings were evaluated at preconversion and 1 to 12 months after conversion. Results: Conversion from b.i.d. to q.d. regimen was based on 1:1 proportion in 16 patients and dose escalation in 16 patients. The mean conversion time after transplant was 56.8 months (range; 21∼94). Reconversion to b.i.d. regimen was needed in nine patients. Among these patients, seven patients needed titration due to elevated liver enzyme. The trough level decreased significantly after conversion (from 4.7 to 3.1 ng/mL) in patients with conversion at 1:1 proportion, while increasing slightly without statistical significance (3.7 to 4.0 ng/mL) in patients with dose escalation. At 1 year after conversion, dose adjustment was required to preserve trough level and graft function in 14 patients. Conclusions: Based on our results, TAC q.d. formulation can be a useful option to improve adherence in stable liver transplant recipients. However, dose titration should be considered for preserving proper trough level in case of low TAC level or TAC single regimen.

Supplemental Digital Content is Available in the Text. Article first published online 7 March 2016., Background: The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation. Methods: Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [≥40 kg, 40 mg EOW

The use of natural products (NPs), including herbal medicines and other dietary supplements, by North Americans continues to increase across all age groups. This population has access to conventional medications, with significant polypharmacy observed in older adults. Thus, the safety of the interactions between multi-ingredient NPs and drugs is a topic of paramount importance. Considerations such as history of safe use, literature data from animal toxicity and human clinical studies, and NP constituent characterization would provide guidance on whether to assess NP-drug interactions experimentally. The literature is replete with reports of various NP extracts and constituents as potent inhibitors of drug metabolizing enzymes, and transporters. However, without standard methods for NP characterization or in vitro testing, extrapolating these reports to clinically-relevant NP-drug interactions is difficult. This lack of a clear definition of risk precludes clinicians and consumers from making informed decisions about the safety of taking NPs with conventional medications. A framework is needed that describes an integrated robust approach for assessing NP-drug interactions; and, translation of the data into formulation alterations, dose adjustment, labelling, and/or post-marketing surveillance strategies. A session was held at the 41st Annual Summer Meeting of the Toxicology Forum in Colorado Springs, CO, to highlight the challenges and critical components that should be included in a framework approach.

In infants aged less than 12 months, there are few data on pharmacokinetics of high-dose methotrexate (MTX) for brain tumors at the dose of 8 g/m2. Consolidated knowledges are present only with the dose of 5 g/m2 in acute lymphoblastic leukemia. We collected data on 8 infants at the time of their first treatment with high-dose MTX, 8 g/m2, to evaluate the pharmacokinetic profile. All children had a dose adjustment with a weight-based prescription (1 m2 = 30 kg). The median age was 4.5 months (range 0–9). The median weight was 5.63 kg (range 3.12–9.0). The median steady-state MTX concentration at the end of 6-hr infusion was 486 µM/L (range 227–790). The median systemic MTX clearance was 4.14 L/h/m2 (range 1.98–9.35). The median MTX concentration after 24 h from the beginning of infusion was 3.29 µM/L (range 1.14–100.44). Three (37.5 %) patients had a delayed elimination of MTX (delayed early, delayed late, or total delayed: one for each). These altered elimination occurred principally in children weighing less than 4 kg (p: 0.0179). Moreover, a systemic MTX clearance at the end of infusion minor than 3 L/h/m2 can predict a delayed elimination (p: 0.0179). Patients with altered elimination underwent rescue measures (leucovorin supplement and/or exchange transfusion). Our data suggest that a higher dose of MTX for the treatment of aggressive brain tumors in early infants had an acceptable pharmacokinetic profile. Greater attention must be used in the treatment of children weighing less than 4 kg.

Aims The aims of the study were to characterize the pharmacokinetics (PK) of alogliptin in healthy and type 2 diabetes mellitus (T2DM) subjects using a population PK approach and to assess the influence of various covariates on alogliptin exposure. Methods Plasma concentration data collected from two phase 1 studies and one phase 3 study following administration of alogliptin (12.5–400 mg) were used for the PK model development. One- and two-compartment models were evaluated as base structural PK models. The impact of selected covariates was assessed using stepwise forward selection and backward elimination procedures. The predictability and robustness of the final model was evaluated using visual predictive check and bootstrap analyses. The final model was used to perform simulations and guide appropriate dose adjustments. Results A two-compartment model with first-order absorption and elimination best described the alogliptin concentration vs. time profiles. Creatinine clearance and weight had a statistically significant effect on the oral clearance (CL/F) of alogliptin. The model predicted a lower CL/F (17%, 35%, 80%) and a higher systemic exposure (56%, 89%, 339%) for subjects with mild, moderate and severe renal impairment, respectively, compared with healthy subjects. Effect of weight on CL/F was not considered clinically relevant. Simulations at different doses of alogliptin support the approved doses of 12.5 mg and 6.25 mg for patients with moderate and severe renal impairment, respectively. Conclusions The PK of alogliptin was well characterized by the model. The analysis suggested an alogliptin dose adjustment for subjects with moderate-to-severe renal impairment and no dose adjustments based on weight.

We implemented a 3-3-1 algorithm in order to provide safe and simple self-titration in patients who newly initiated BOT as well as who were already on BOT and evaluated its utility in clinical setting. A total of 46 patients, 21 patients in the newly-initiated group and 25 patients in the existing BOT group performed dose adjustment using 3-3-1 algorithm. HbA1c was significantly improved 4 weeks after the initiation from 8.5% ± 1.2% at baseline to 7.3% ± 0.7% at the final evaluation (p 0.01, vs. Baseline). The average daily insulin units increased throughout the study period from 10.1 ± 6.7 at baseline to 14.6 ± 8.9 units at the final evaluation. Weight didn’t significantly change throughout the study (p = 0.12). The incidents of hypoglycemia were 0.8/month during the insulin dose self-adjustment period and 0.4/month during the follow-up period. The 3-3-1 algorithm using insulin glargine provided a safe and simple dose adjustment and demonstrated its utility in patients who were newly introduced to insulin treatment as well as who were already on BOT.

Previous study suggested that low body weight was one of the risk factors of thrombocytopenia induced by linezolid in non-hemodialysis patients. However, there have been little investigations for the linezolid-induced thrombocytopenia in hemodialysis patients. This study was to evaluate the association between several factors of body size descriptors and thrombocytopenia in hemodialysis-patients. No factor of body size descriptors showed significant correlation with linezolid-induced thrombocytopenia (patients with thrombocytopenia vs patients without thrombocytopenia: body weight; 60.0 kg vs 55.3 kg, p = 0.82: body mass indices; 21.1 kg/m2 vs 21.2 mg/m2, p = 0.44: ideal body weight; 61.2 kg vs 59.5 kg, p = 0.21: lean body weight; 50.1 kg vs 45.7 kg, p = 0.64: dosage amount; 20.0 mg/kg vs 21.7 mg/kg, p = 0.74: body surface area; 1.65 m2 vs 1.54 m2, p = 0.43). There were not significant differences in the body size descriptors between linezolid therapy for more than 14 days and for less than 13 days (more than 14 days vs less than 13 days: body weight; 53.5 kg vs 56.8 kg, p = 0.75: body mass indices; 20.9 kg/m2 vs 21.1 mg/m2, p = 0.47: ideal body weight; 60.3 kg vs 59.9 kg, p = 0.17: lean body weight; 44.3 kg vs 47.7 kg, p = 0.56: dosage amount; 22.4 mg/kg vs 21.1 mg/kg, p = 0.67: body surface area; 1.51 m2 vs 1.59 m2, p = 0.37). Our data suggested that dosage adjustment of linezolid based on body weight was not recommended in hemodialysis-patients.

SummaryWhat is known and objective The second-generation direct-acting antivirals represented the first major turning point for the eradication of HCV infection in almost all settings of patients. However, no data were available on use in gastro-resected patients. Case description We report on a gastrectomized patient with chronic hepatitis C infection. She was treated with sofosbuvir and ledipasvir (SOF/LDV) for 12 weeks, with measurement of blood levels of the drugs. She obtained sustained virological response at week 12 and 24 without dose adjustment. What is new and conclusion This case report can provide information useful for clinical practice in this set of patients and can open new perspectives in evaluating actual SOF/LDV bioavailability.

The UAB Pediatric Sickle Cell Clinic cares for patients at both an academic center and satellite clinics. One difference in clinics is that CBC results are not available at the time of patient care during satellite clinics, but are available at the academic center. Therefore, hydroxyurea (HU) dosing adjustments are made within seven days through telehealth; after reviewing faxed CBC results, a sickle cell nurse calls families and educates them on any revised HU dosing plans and reinforces adherence to HU. We hypothesized that this type of telehealth HU dosing adjustments would not impact HU laboratory response. Methods: We performed a one-year retrospective review of 172 HbSS and HbSB0 thalassemia patients prescribed HU during 2019 that were cared for in both the academic center (Birmingham) and satellite clinics (Montgomery, Tuscaloosa, Opelika). We excluded patients on HU and a second sickle cell disease modifying therapy. We abstracted from the EMR: age, sex, clinic location, diagnosis, HU dose (mg/kg), WBC, Hb, MCV, Platelets, Absolute Reticulocyte, HbF, and ANC. We recorded the total number of well-clinic visits and categorized clinic visit/year as ≤ 2or >2; satellite clinic visits are fixed either monthly to every three months which limited our ability to reschedule patients with missed visits. We also recorded the number of ED visits and admissions to the hospital for a) pain and b) all sickle cell complications except for scheduled procedures. We collected acute visit data from the EMR at the academic center for onsite participants and from patient report from satellite participants. We evaluated dosing adjustment as whether dosing was increased for ANC > 4000 per institutional standard of care. We categorized correct dosing adjustments if > 65% of visits had a dose adjustment per institutional protocol; we categorized patients as a deviation from protocol if the physician did not increase the dose based on ANC. We performed descriptive statistics, t-test for continuous variables, chi-square for categorical variables, and regression modeling using JMP Pro 14 (Cary, NC). P-values Results: The mean age of the 172 participants was 11±5 years, mean Hb was 8.5±1.1g/dL, mean MCV was 91.3±10.1 fL, mean HbF% was 12.7±6.7, and mean ANC was 4.9±2.3. Fifty two percent of participants were female. We identified 107 participants prescribed HU at the academic center and 65 participants from satellite clinics. We identified no significant differences in HU monitoring laboratory values for Hb (p=0.6), MCV (p=0.7), HbF (p=0.13), ANC (p=0.9) by clinic location. We did not identify a difference in sex of participants by clinic location (p=0.9); also, HbF% (p=0.6) and HU dose (p=0.3) were not associated with sex. We did not identify a difference in all admissions to the hospital (p=0.5) or pain admissions to the hospital (p=0.6) between academic center vs. satellite clinic patients. However, academic center patients did have a higher number of acute pain visits (p=0.03) to either the ED or UAB pediatric pain clinic. As expected, among all participants, non-adherence to HU (HbF 2 clinic visits. HbF response was significantly associated with clinic visits (p=0.03). Finally, HbF response was significantly inversely correlated with age (p=0.003). Adjusting for clinic location, number of clinic visits, and age, HbF % was associated with age (p=0.006) and clinic visits (p=0.006), but not associated with clinic location. Conclusion: Our data demonstrate that telehealth for HU dosing provided a similar level of HU response to in-person HU dosing adjustments. This finding importantly suggests that telehealth for monitoring and adjusting HU in patients with poor access to a Pediatric Hematologist or during a pandemic should not impact HU response. Strategies to improve overall adherence need prospective evaluation at our institution, but are not related to telehealth dosing of HU. Disclosures Lebensburger: Novartis: Consultancy.

not available.

Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)