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.
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.
Association of single-nucleotide polymorphisms in UGT1, NR1I2, ABCC2, ABCC5 and ABCG1 with irinotecan-induced toxicity in colorectal cancer
BACKGROUND
Irinotecan is used in the palliative treatment of metastatic colorectal cancer. Its metabolism is complex with many different transporters and enzymes involved. For UGT1A1*28 (rs8175347), an association with irinotecan-induced toxicity has been established. Recent studies suggested that other single-nucleotide polymorphisms (SNPs) within genes encoding irinotecan-related enzymes and transporters can lead to reduced or increased irinotecan-induced toxicity, mainly diarrhoea and neutropenia.
OBJECTIVE
In this study we aim to replicate associations between SNPs related to UGT1 rs11563250; NR1I2 rs10934498, rs2472677, rs3814055 and rs1523127; ABCC5 rs10937158, rs3749438, rs562 and rs2292997; ABCG1 rs225440 and ABCC2 rs717620 and grade 3 to 4 diarrhoea and febrile neutropenia in a population of 221 mCRC patients treated with irinotecan. The well-known UGT1A1*28 variant is also evaluated.
DESIGN
Retrospective clinical association study.
METHODS
DNA samples used for this study were obtained from patients participating in the CAIRO study (NCT00312000). The DNA samples were genotyped for twelve SNPs, selected on the basis of the results of previously published studies. For the main analysis, associations between SNPs and toxicity data were tested with logistic regression.
RESULTS
ABCC2 rs717620T is significantly associated with grade > 3 febrile neutropenia (OR = 2.72; P = 0.025). UGT1A1*28 shows significant associations with an increased risk on grade 3 to 4 diarrhoea (OR = 1.76, P = 0.035) and grade 3 to 4 febrile neutropenia (OR = 3; P = 0.01).
CONCLUSION
The outcomes of previous studies could not be replicated, except for UGT1A1*28. Moreover, we found an association with the opposite direction of effect between ABCC2 rs717620T and severe neutropenia. Based on the outcomes of this study genotyping for the tested variants – with exception of UGT1A1*28 – cannot be recommended.
Therapeutic use of low molecular weight heparins in obese patients: dosing based on body weight without cut-off limit
BACKGROUND
The correct dose of therapeutic low molecular weight heparins (LMWHs) in patients with a body mass index ≥ 30 kg/m2 is uncertain. Literature and guidelines are not clear and consistent about the correct dose.
DESIGN and METHODS
In this review, an overview of the literature on therapeutic use of LMWHs in this population is provided. Sixteen pharmacokinetic and pharmacodynamic or clinical studies were included.
RESULTS
Based on these results, obese patients should receive therapeutic doses of LMWHs, based on their total body weight without a dose cap as recommended in the Summary of Product Characteristics. In patients with morbid obesity, anti-Xa level monitoring and subsequently an adjusted dosage on the base of supratherapeutic anti-Xa levels is recommended.
Can tablets be split in half manually in a reliable manner?
BACKGROUND
Since 2017 the Dutch Health and Youth Care Inspectorate does not allow compounding pharmacies to produce tablets with half dosage strength when the same dosage can also be reached by splitting a marketed tablet – with scoring meant for dividing the tablet into two equal parts – in half.
OBJECTIVE
To determine whether it is possible to manually split tablets in half using a reliable and validated method.
DESIGN and METHODS
In this exploratory study six different tablets were manually split in half and tests for loss of mass and loss of uniformity were performed. The influence of different tablet characteristics on the splitting process was assessed.
RESULTS
All six tablets met the requirements of the test for loss of mass (< 3%). Two of the six tablets met the requirements of the European Pharmacopoeia test for loss of uniformity. Type of scoring and the thickness of the tablet seem to be factors influencing the process of tablet splitting.
CONCLUSION
Tablet splitting by hand in the pharmacy is not feasible because for most tablets it will not be possible to develop a reliable and validated method. It will also be difficult to comply with legislation with regards to working conditions. The possibility of mechanical splitting of tablets should be studied and other alternatives should be considered.