B. Gourieux

Pharmacokinetic drug–drug interactions with methotrexate in oncology

Methotrexate is an antifolate agent used in the treatment of various cancers and some autoimmune diseases. In oncology, methotrexate is frequently administered at a high dose (>1 g/m2) and comes with various procedures to reduce the occurrence of toxicity and particularly to ensure optimal renal elimination. Drug–drug interactions involving methotrexate are the origin of severe side effects owing to delayed elimination of the antifolate and, more rarely, of decreased efficacy in relation to suboptimal exposure. Most of these interactions are driven by membrane drug transporters whose activity/expression can be inhibited by the interacting medication. In the last 10 years, research on drug transporters has permitted retrospective identification of the molecular mechanisms underlying drug–drug interactions with methotrexate. This article summarizes reported drug–drug interactions involving methotrexate in clinical oncology with reference to the role of drug transporters that control the disposition of the antifolate agent.

Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature.

Abstract: Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non–small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK–pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

Clinical usefulness of oral immunoglobulins in lung transplant recipients with norovirus gastroenteritis: a case series.

Viral gastroenteritis causing diarrhea is a common complication observed in lung transplant recipients. Differently from the mild and typically self-limited disease seen in immunocompetent subjects, immunocompromised patients frequently have a more severe course. Norovirus and rotavirus are among the leading causes of severe gastroenteritis in transplant recipients. Specific treatment is unavailable, although good supportive treatment can significantly reduce morbidity. Previous studies have suggested that oral immunoglobulins may be used for the treatment of acute viral gastroenteritis after solid-organ transplantation. Herein, we conducted a retrospective chart review of 12 lung transplant recipients with norovirus-induced gastroenteritis who were treated with oral immunoglobulins for 2 days. Eleven patients were successfully treated, whereas 1 subject was only mildly improved. Four patients had at least 1 recurrence. No significant adverse effects were observed. We conclude that oral immunoglobulins may be clinically useful for lung transplant recipients with norovirus-induced gastroenteritis.

Development and multi-centre evaluation of a method for assessing the severity of potential harm of medication reconciliation errors at hospital admission in elderly

BACKGROUND Medication reconciliation is a powerful process to correct medication errors (ME) resulting from miscommunicated information at transitions of care. This study aims to develop and evaluate a scoring method for assessing the severity of potential harm of ME intercepted by medication reconciliation at hospital admission in elderly. METHODS The development of the scoring method was based on a literature search and the creation of a list of high-risk drugs used in outpatient care. The evaluation of the method was carried out in 7 French hospitals and was based on two criteria: the inter-rater reliability and acceptability. The assessment of the inter-rater reliability was based on intra-class correlation coefficient (ICC) calculations. Each hospital prospectively enrolled the 10 first patients aged 65 or older presenting with at least one ME. Seven blocks of 10 patients were formed. After randomization, each block was rated by practitioners from 3 hospitals. The assessment of the acceptability was based on a satisfaction questionnaire. RESULTS A clinical algorithm was developed. The inter-rater reliability of the method was validated by the overall agreement of the 7 hospitals ratings. The agreement was at least substantial (ICC>0.60) and in most of cases almost perfect (ICC>0.80). The acceptability of the method was judged as satisfactory. CONCLUSION This multi-centre project has validated an instrument for assessing the severity of potential harm of ME intercepted by medication reconciliation. This will allow studies to be conducted with large cohorts of patients in order to develop epidemiological databases of ME of potential clinical significance.

SynthèseMécanismes des interactions pharmacocinétiques impliquant les agents anticancéreux orauxMecanisms of pharmacokinetic interactions involving oral anticancer agents

Oral anticancer agents and particularly kinase inhibitors are subject to pharmacokinetic drug interactions in relation to absorption and elimination phases. Interacting factors are food, fruit juices, cigarette smoke, acid-reducing agents and inducers/inhibitors. Some anticancer agents are inducers and/or inhibitors and can also perpetrate drug interactions. This review emphasizes the mechanisms of pharmacokinetic drug interactions involving oral anticancer agents.

Mécanismes des interactions pharmacocinétiques impliquant les agents anticancéreux oraux

Oral anticancer agents and particularly kinase inhibitors are subject to pharmacokinetic drug interactions in relation to absorption and elimination phases. Interacting factors are food, fruit juices, cigarette smoke, acid-reducing agents and inducers/inhibitors. Some anticancer agents are inducers and/or inhibitors and can also perpetrate drug interactions. This review emphasizes the mechanisms of pharmacokinetic drug interactions involving oral anticancer agents.

Gastrointestinal perforations in patients treated with erlotinib: A report of two cases with fatal outcome and literature review

Erlotinib has been approved as second-line treatment in patients with non-small cell lung cancer (NSCLC) experiencing relapse after first-line platinum-based chemotherapy. Herein, we report two occurrences of erlotinib-associated gastrointestinal perforation (GIP) in NSCLC patients. Two patients aged 60 and 79 years received erlotinib as third- and second-line NSCLC treatment, respectively. GIP occurred following 3 weeks and 6 months of erlotinib treatment, leading to death a few days later in both patients, neither of whom had any intestinal metastasis. Risk factors related to erlotinib-induced GIP were concomitant oral corticosteroid therapy and ciprofloxacin administration, which may result in erlotinib overexposure. GIP is a severe adverse drug reaction of erlotinib, infrequently described in the literature, compared to other targeted therapies. The lethal risk of erlotinib-associated GIP should be taken into account when evaluating the benefit-risk balance of erlotinib in patients without epidermal growth factor receptor activating mutations.

Anticoagulant and antiplatelet combined therapy in patients 75 years and over with atrial fibrillation: a prospective observational study assessing adherence to clinical guidelines

Objective According to current guidelines on atrial fibrillation (AF), the addition of an antiplatelet therapy to an anticoagulant for a stable vascular disease does not decrease the ischaemic hazard but increases the risk of bleeding. The aim of the study was to assess compliance of practices with existing clinical guidelines concerning the use of anticoagulant-antiplatelet combined therapy in patients 75 years and over with AF. Methods This prospective observational study was carried out at the University Hospital of Strasbourg (France) between August 2016 and January 2017 with data collection on 1 day of every month. To be included, the patient had to be 75 years and over with AF and treated with anticoagulant-antiplatelet therapy. The population included all the patients admitted at the hospital excluding those from the Gynaecology-Obstetrics and Paediatrics departments. With regard to clinical ongoing guidelines (French, European, American and Canadian), the patients were sorted into three groups. Group 1: combined therapy in compliance with recommendations; Group 2: combined therapy debatable as to benefit-risk ratio; and Group 3: combined therapy not compliant with recommendations. Result Ninety-three out of 3307 patients 75 years and over received anticoagulant-antiplatelet combined therapy prior to their hospital admission. Thirty-two patients (34.4% – Group 1) had experienced an acute event and/or revascularisation within the past year. Twenty-four patients (25.8% – Group 2) had not experienced recent revascularisation and had stable coronary disease but were suffering from peripheral artery disease. Group 3 consisted of 37 patients (39.8%), none of which had experienced recent revascularisation or had unstable coronary disease. For all groups, the main dual therapy was acetylsalicylic acid + fluindione (59.1%). Conclusion In our study, 37 antiplatelet (39.8%) treatments could have been stopped. These results should spur prescribers into regular reassessment of combination antithrombotic therapy since it contributes to polypharmacy and increases the risk of adverse events.

PP-004 Quality control assessment of cytotoxic bags by UV-Raman spectrometry

Background About 6,000 cytotoxic bags per year are produced in the compounding unit of a University Hospital Pharmacy. Each bag is checked by UV-Raman spectrometry. This analytical technique presents many advantages for better efficiency: identification and quantification of results, short time of analyses (2 min) and a minimal volume sample (1 mL). Purpose To evaluate the quality of cytotoxic bags prepared and analysed over 11 months by this spectrometry tool. Material and methods All the drugs and solvents were identified and a calibration curve was constructed. Each drug is subject to quality control every week. For eleven months, cytotoxic bags were routinely produced and then checked by UV-Raman spectrometry. Criteria for acceptance was ±10% error. Tolerance occurred when error was between 10% and 15%. If ±15% error was found status was rejected. Results 4838 cytotoxic bags were produced and checked in 11 months. 14 cytotoxic drugs were analysed by UV-Raman: carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, etoposide, ganciclovir, gemcitabine, ifosfamide, oxaliplatin, paclitaxel, pemetrexed, vinorelbine. 92.1% of cytotoxic bags were in the concentration range of ±10%; 5.2% in the range ±15% and 2.0% with a difference of more ±15%. The preparations presenting most non-compliance were doxorubicin (18.8%), cyclophosphamide (14.3%) and ifosfamide (11.1%). 0.6% of analyses were a misidentification of the molecule. Conclusion This study makes an assessment of the quality of production of our cytotoxic bags and shows that UV-Raman is a suitable technique for the analysis of drugs. These results highlight defects of preparation of some cytotoxic bags. Awareness-raising activities were undertaken in order that the team be more watchful during the preparation and some protocols have been improved. This approach is subject to a process of continuous improvement of the quality of drug preparations, in our laboratory which was recently ISO900 certified. References and/or acknowledgements No conflict of interest.

Stability of an oral ranitidine suspension (15 mg/ml)

Purpose The aim of this study was to evaluate the microbiological and physicochemical stability of 15 mg/ml ranitidine hydrochloride suspension. Methods 15 mg/ml ranitidine hydrochloride suspensions were prepared in commercial vehicle (ORA-BLEND). Suspensions were kept for 90 days at 4 °C and 25 °C. The microbiological stability was assessed by microbial enumeration tests and specific search for Escherichia coli The physical stability was assessed by colour change, pH and chromatogram peaks. Ranitidine was assayed using high-performance liquid chromatography. Each series of three batches at each storage condition was combined into one representative exponential curve for the evolution of degradation of ranitidine suspension. Stability was defined as a remaining concentration of at least 95 % of the initial concentration (ie, 5% degradation). Results Culture of the different suspension samples resulted in no bacterial or fungal growth. Specific search for E coli was negative. There was colour change for each batch. No change from the initial pH (4·2) occurred in samples stored at 4°C but, for samples stored at 25°C, the pH increased from 4·2 to 4·9. Unidentified peaks corresponding to degradation products appeared on the chromatogram at day 30 for suspensions stored at 25°C and at day 60 for suspensions stored at 4°C. Conclusions Ranitidine hydrochloride suspension in amber glass was stable for up to 27 days when stored at 4°C and up to 5 days at 25°C. It is recommended that nurses should allow ranitidine suspension to reach room temperature before use and administration to patients.