Het Nederlands Platform voor Farmaceutisch Onderzoek (NPFO) presenteert onderzoek in de farmaceutische wetenschappen. De nadruk ligt op klinische toepassing zoals medicatieveiligheid, patiëntenzorg, formulering, analyse, farmacologie en casuïstiek.
Increased risk of methotrexate intoxication in the elderly
INTRODUCTION
Over two decades, low dose methotrexate (MTX) has been used as a therapy for rheumatoid arthritis and psoriasis [1,2]. The biggest risk of MTX therapy is the development of toxicity with associated side effects and ultimately mortality. Low dose methotrexate use in elderly patients more often leads to MTX intoxication with serious consequences. For atypical complaints in frail older people using methotrexate, the MTX intoxication should be in the differential diagnosis. In this article we describe a patient presenting with atypical complaints as a result of an MTX intoxication.
DESCRIPTION
A 76-year-old female presents with severe dyspnea, during rehabilitation therapy of a recently experienced stroke. She has heart failure NYHA class II and rheumatoid arthritis. She is treated with a low dose schedule of methotrexate, 10 mg per week combined with folic acid 5 mg three times per week and hydroxychloroquine (Plaquenil) 200 mg once daily.
Additional laboratory tests show abnormal values including increased liver values, impaired renal function and bone marrow suppression. Because of known MTX use in combination with the laboratory abnormalities found with unclear underlying cause, an MTX blood level is determined. This appears to be largely increased. Calcium folinate is started intravenously, despite improving blood results the patient does not improve and a palliative policy is followed.
DISCUSSION
For atypical complaints in frail older people using methotrexate, the MTX intoxication should be in the differential diagnosis. Measuring methotrexate levels is unusual in Dutch rheumatology, partly due to the short half-life of MTX. Literature study shows several cases in which inadequate intake of MTX – as well as adequate intake – leads to an MTX intoxication. Decreased kidney function leads to an increased risk of MTX intoxication. Therefore it is, especially in elderly patients with MTX therapy, advisable to frequently check renal function. Dose adjustment should be made in case of impaired renal function and measurement of MTX levels should be considered. Elderly presenting atypical complaints is a common sight. Doctors should ensure that MTX therapy is adequately followed and MTX intoxication must be in the differential diagnosis in elderly with atypical complaint presentation.
CONCLUSION
The risk of developing MTX intoxication in frail elderly is increased despite prescription MTX use. In this category of patients, this often leads to an atypical complaint presentation. For atypical complaints in frail older people using methotrexate, the MTX intoxication should be in the differential diagnosis. Especially with a reduced kidney function, the risk of an MTX-intoxication is higher. In addition, with MTX use the dose regime and actual intake must be extensively requested to prevent fatal consequences.
Development of novel zero-order release budesonide tablets for the treatment of ileo-colonic inflammatory bowel disease and comparison with formulations currently used in clinical practice
BACKGROUND
In patients with inflammatory bowel disease, the terminal ileum and colon is the most affected region. Oral budesonide is an effective treatment but in vitro as well as clinical data suggest that the formulations currently used in clinical practice are suboptimal to treat the entire ileo-colonic region.
OBJECTIVE and DESIGN
The aim of this in vitro study was to develop ileo-colonic-targeted zero-order sustained-release tablets containing 3 mg or 9 mg budesonide (ColoPulse 3 mg and 9 mg, respectively).
METHODS
Tablets were tested in a 10 hour gastrointestinal simulation system for site-specific release, zero-order release kinetics (R2 ≥ 0.95), release rate, and completeness of release (≥ 80%). Release profiles of the novel formulations were compared with Entocort, Budenofalk, and Cortiment (budesonide MMX).
RESULTS
None of these formulations currently used in clinical practice targeted the entire ileo-colonic region. However, ColoPulse 3 mg and 9 mg were targeted to the ileum, released the entire dose with zero-order release kinetics in the ileo-colonic region, and complied with a 6-month accelerated stability study.
CONCLUSION
Therefore, ColoPulse 3 mg and 9 mg are novel, interesting formulations for the treatment of the entire ileo-colonic region in inflammatory bowel disease.
The effect of a customized medication verification tool on the amount of unintended clinically relevant medication discrepancies at hospital admission of psychiatric patients
BACKGROUND
Unintended medication discrepancies (UMDs) at admission is common in hospitalized patients. Studies have shown that medication verification at admission resulted in fewer UMDs. Medication reconciliation studies in psychiatric patients are scarce. At the time of this study, medication verification in the medical psychiatric unit (MPU) of the Elisabeth-Tweesteden Hospital was done by the attending physician. After evaluating this process a customized verification tool was developed.
OBJECTIVE
The effect of using a customized medication verification tool by a pharmacy technician on the prevention of clinically relevant UMDs in psychiatric patients admitted to the MPU of the Elisabeth-Tweesteden Hospital.
DESIGN
A randomized prospective intervention study.
METHODS
Patients admitted to the MPU – who met the inclusion criteria – were randomized in group A, B or C. In group A medication was verified by the attending physician. In group B and C medication was verified by a pharmacy technician using a standardized or customized verification tool, respectively. UMDs were assessed within 24 hours of admission. A panel determined clinical relevancy of the UMDs using the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) index. Categories E till I were considered clinically relevant.
RESULTS
The interim analysis showed 33 UMDs in group A (n = 31), 59 in group B (n = 44), and 88 in group C (n = 42). The amount of clinically relevant UMDs per patient in group A, B, and C was 0.32, 0.27, and 0.57, respectively. The majority of the UMDs were omissions and included mostly non-psychiatric medication.
CONCLUSION
The interim analysis shows relatively more clinically relevant UMDs per patient when medication was verified by a pharmacy technician using a customized verification tool. It is possible that medication verification with a customized verification tool by a pharmacy technician results in the prevention of clinically relevant unintended medication discrepancies.
Variability in pharmacokinetics of intravenous paracetamol in healthy older people
BACKGROUND and OBJECTIVE
Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration (Css-mean) of 10 mg/L as target for effective analgesia.
DESIGN and METHODS
A population pharmacokinetic-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age = 77.3 years [61.8- 88.5], body weight = 79 kg [60-107]). All had received an intravenous paracetamol dose of 1000 mg – over 15 min – after elective knee surgery.
RESULTS
A two-compartment pharmacokinetic-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css-mean of 9.2 mg/L (q6h) and 7.2 mg/L (q8h). Variability in paracetamol pharmacokinetics resulted in a Css-mean above 5.4 (q6h) and 4.1 mg/L (q8h) in 90%, and above 15.5 (q6h) and 11.7 mg/L (q8h) in 10% of the population.
CONCLUSION
The target concentration was achieved in the average patient with 1000 mg q6h, while q8h resulted in underdosing for the majority of the population. Due to large unexplained inter-individual variability in paracetamol pharmacokinetics a relevant proportion of the fit older people remained either under- or overexposed.