A limited sampling schedule to estimate individual pharmacokinetics of pemetrexed in patients with varying renal functions

Purpose: Pemetrexed is a widely used cytostatic agent with an established exposure–response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. Methods: Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE ≤ 20%. Results: For an accurate estimation of clearance, only four samples in a convenient window of 8 h were required for accurate and precise prediction (MPE and NRMSE of 3.6% and 5.7% for dataset 1 and of 15.5% and 16.5% for dataset 2). A single sample at t = 24 h performed also within the criteria with MPE and NRMSE of 5.8% and 8.7% for dataset 1 and of 11.5% and 16.4% for dataset 2. Bias increased when patients had lower creatinine clearance. Conclusions: We presented two limited sampling designs for estimation of pemetrexed pharmacokinetics. Either one can be used based on preference and feasibility

Medicatiescreening met Beers-criteria en STOPP/START-criteria bij de oudere patiënt: associatie tussen potentieel ongewenst geneesmiddelengebruik en geneesmiddelgerelateerde ziekenhuisopnamen

OBJECTIVE To assess the risk of medication-related hospital admissions associated with inappropriate medication use applying the Beers and the STOPP/START criteria. There are multiple screening methods to detect and reduce potentially inappropriate medication [PIM] and prescribing omissions (PPOs). Whether this will result in less medication-related hospitalisations is unknown. DESIGN A nested case-control study was conducted with a subset of patients of the Hospital Admissions Related to Medication (HARM) study. METHODS Cases were defined as patients ≥65 years with a potentially preventable medication-related hospital admission. For each case one control was selected, matched on age and sex. The primary determinant was defined as the presence of one or more PlMs and/or PPOs according to the Beers 2012 and the STOPP/START criteria. The strength of the association between a PIM/PPO and a medication-related hospital admission was evaluated with multivariate logistic regression and expressed as odds ratios with 95% confidence intervals (Cl95). RESULTS PlMs and PPOs detected with the STOPP/START criteria are associated with medication-related hospital admissions [OR 3.47; CI95 1.70-7.09], while for the presence of PIMs according to the Beers 2012 criteria a non-significant trend was visible (ORadj 1.49; CI95 0.90-2.47). CONCLUSION Both the STOPP/START criteria and the Beers 2012 criteria can be used to identify older people at risk for medication-related problems. The choice which set of criteria should be used is more dependent on other factors (e.g. national guidelines, practical considerations) than on the association of each set with ADR-related hospital admission

nfluence of antidepressants on glucose homeostasis : effects and mechanisms

Depression has shown to be a common morbidity in patients with diabetes mellitus and comorbid depression in diabetes mellitus patients is frequently treated with antidepressants. It has been postulated that antidepressants may interfere with glucose homeostasis and that the interference of antidepressants with glucose homeostasis, at least partly, depends on the complex pharmacology of antidepressants. If antidepressants indeed interfere with glucose homeostasis, glycaemic control could be further complicated, which is a limiting factor to prevent, or delay long-term microvascular complications. There are two main objectives in this thesis. The first objective is to investigate the relative risk of hyper- and hypoglycaemia or other metabolic changes associated with antidepressant use. The second objective is to elucidate the mechanism behind antidepressant related disturbances in glucose homeostasis from a pharmacological perspective and to find out which patients are at risk. The first part of this thesis (Chapter 2) focuses on the receptor binding profiles of antidepressants in relation to adverse drug reaction profiles of antidepressants. We presented a novel model to classify antidepressants based on their binding properties of most common receptor- and transporter sites for a better understanding of receptor-mediated pharmacological action of antidepressants. In addition, we evaluated the pharmacological classification with the traditional classification of antidepressants through an analysis of type A and type B adverse drug reaction (ADR) categories. We found that the pharmacological classification of antidepressants may be helpful to predict type A ADR profiles of antidepressants. In Chapter 3, we used this pharmacological classification to elucidate the mechanism of antidepressant-related disturbances in glucose homeostasis from a pharmacological perspective. Chapter 3 focuses on the association between antidepressant use and interference with glucose homeostasis. The studies in Chapter 3 show that antidepressants interfere with glucose homeostasis and that the antidepressants are associated with both hyper- and hypoglycaemia. In several studies, we observed a statistical significant association between antidepressant use and effects on glucose homeostasis. In other studies, we observed a statistically non-significant association. However, direction of effects of antidepressants on glucose homeostasis was consistent in all studies. We showed that antidepressants with common binding affinity for the norepineprine transporter, histamine 1 receptor and serotonin 2C receptor are associated to hyperglycaemic effects and may contribute to deterioration of diabetes mellitus. Antidepressants with selective binding affinity for the serotonin transporter may have hypoglycaemic effects and may have insulin sparing effects in patients with diabetes. In conclusion, the findings from the studies in this thesis justify the conclusion that antidepressants may disturb glucose homeostasis. The risk of severe antidepressant-related disturbances in glucose homeostasis may be small, but even so the fact that depression and diabetes mellitus are common diseases and they often co-occur, even a small risk has major impact on population level. It is important that patients, physicians and pharmacists are informed about the effects of antidepressants on glucose homeostasis so that they can use this information for better prescribing and use of antidepressants

Individualizing Pharmacotherapy in Patients with Renal Impairment: The Validity of the Modification of Diet in Renal Disease Formula in Specific Patient Populations with a Glomerular Filtration Rate below 60 Ml/Min. A Systematic Review

Contains fulltext : 153158.pdf (publisher's version ) (Open Access)BACKGROUND: The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus. METHODS AND FINDINGS: We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73m2), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P30% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used. CONCLUSION: In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity

Fluctuation of the renal function after discharge from hospital and its effects on drug dosing in elderly patients--study protocol

Contains fulltext : 155294.pdf (publisher's version ) (Open Access)BACKGROUND: Chronic kidney disease (CKD) is associated with an increased mortality rate, risk of cardiovascular events and morbidity. Impaired renal function is common in elderly patients, and their glomerular filtration rate (GFR) should be taken into account when prescribing renally excreted drugs. In a hospital care setting the GFR may fluctuate substantially, so that the renal function group and therefore the recommended dose, can change within a few days. The magnitude and prevalence of the fluctuation of renal function in daily clinical practice and its potential effects on appropriateness of drug prescriptions after discharge from the hospital is unknown. METHODS/DESIGN: This is a prospective observational study. Patients >/= 70 years with renal impairment (eGFR < 60 ml/min/1.73 m(2)) admitted to a geriatric ward are eligible to participate. Participants undergo blood sample collection to measure serum creatinine level at three time points: at discharge from hospital, 14 days, and 2 months after discharge. At these time points the actual medication of the participants is assessed and the number of incorrect prescriptions according to the Dutch guidelines in relation to their estimated renal function is measured. In addition, for a hypothetical selection of drugs, the need for drug dose adaptation in relation to renal function is measured. The outcome of interest is the percentage of patients that changes from renal function group after discharge from hospital compared to the renal function at discharge. In addition, the percentages of patients whose actual medications are incorrectly prescribed and for the hypothetical selection of drugs that would have required dose adaptation will be determined at discharge, 14 days and 2 months after discharge. For each outcome, risk factors which may lead to increased risk for fluctuation of renal function and/or incorrect drug prescribing will also be identified and analysed. DISCUSSION: This study will provide data on changes in renal function in elderly patients after discharge from the hospital with a focus on the medications used. The benefits for healthcare professionals comprise of the creation, adjustment or confirmation of recommendations for the monitoring of the renal function after discharge from hospital of elderly patients