A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed.

INTRODUCTION: For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed. METHODS: We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute value or in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. RESULTS: The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively. CONCLUSIONS: In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.

Cumulative pemetrexed dose increases the risk of nephrotoxicity.

INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis.

OBJECTIVES: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment. METHODS: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated. RESULTS: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed. CONCLUSION: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.

Influence of antidepressants on glycaemic control in patients with diabetes mellitus.

PURPOSE: Anecdotal evidence suggests that antidepressants (ADs) may complicate glycaemic control. The objective of this longitudinal study was to investigate the influence of ADs on glycaemic control within diabetes patients. METHODS: From the pharmacy registry database PHARMO, we selected insulin users who did not use oral antidiabetics. The study population comprised: 133 patients with at least 12 months insulin use before and 6 months during an AD episode, including 56 patients with an additional 6 months of insulin use after the AD episode; 180 patients with 24 months insulin use without an AD episode. Glycaemic control was measured as the amount of insulin used, which was calculated intra-individually in 3-month periods. We stratified for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). RESULTS: Mean age (s.d.) of the subjects was 53.9 (19) years; 46.9% were men. Overall, the amount of insulin used did not change during or after AD use. No-AD users showed an increase of 16% in amount of insulin used over a period of 2 years (p < 0.001). SSRI users showed a decrease of 13% in amount of insulin used during the AD episode (p = 0.029), while no change was seen in TCA users. Notable was the large intra- and interindividual variation in amount of insulin used across all groups. CONCLUSIONS: Overall, AD use did not influence glycaemic control in diabetes patients. The tendency for a difference between SSRIs and TCAs is suggestive for a pharmacologic effect of ADs rather than a general effect of depression on glycaemic control.

[Serious intoxication after inhaling methanol]. / Ernstige intoxicatie met methanol door inhalatie.

A 38-year-old man presented with severe methanol intoxication after inhaling methanol over a period of 36 hours in a poorly-ventilated laboratory. He complained of visual disturbances, mild photophobia, hyperventilation and nausea. Laboratory results showed severe metabolic acidosis with a toxic serum-methanol level. He was treated by acute haemodialysis and ethanol infusions. After 9 hours of haemodialysis the serum-methanol value fell below toxic levels. Therapy resulted in the complete disappearance of symptoms and he was able to leave the intensive-care unit 24 hours after presentation. Often, late presentation is a cause of serious morbidity and even mortality in severe methanol intoxication, so early recognition is essential. This is the first published case of methanol intoxication due to inhalation, which is as serious and requires the same treatment as ingestion of methanol.

The Association Between Potentially Inappropriate Prescribing and Medication-Related Hospital Admissions in Older Patients: A Nested Case Control Study.

INTRODUCTION: Medication-related problems can cause serious adverse drug events (ADEs) that may lead to hospitalization of the patient. There are multiple screening methods to detect and reduce potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs). Whether this will result in less medication-related hospitalizations is unknown. The study objective was to assess the risk of preventable medication-related hospital admissions associated with potentially inappropriate prescribing, using the Beers 2012 and the Screening Tool of Older Person's Prescriptions and the Screening Tool to Alert doctors to Right Treatment (STOPP & START) 2008 criteria. DESIGN, SETTING AND PARTICIPANTS: A nested case-control study was conducted with a subset of Dutch participants from the Hospital Admissions Related to Medication (HARM) study. Cases were defined as patients aged ≥65 years with a potentially preventable medication-related hospital admission. For each case, one control was selected, matched for age and sex. The primary determinant was the presence of one or more PIMs according to the Beers 2012 and STOPP 2008 criteria. The secondary determinant was the presence of one or more PIMs and PPOs according to the STOPP & START 2008 criteria. The strength of the association between inappropriate prescribing and medication-related hospital admission was evaluated with multivariate logistic regression and expressed as odds ratios (ORs) with 95 % confidence intervals (CIs). RESULTS: The prevalence of Beers 2012 criteria PIMs in the total cohort was 44.4 %. The prevalence of STOPP & START 2008 criteria PIMs and PPOs were, respectively, 34.1 and 57.7 %. STOPP 2008 criteria PIMs were associated with preventable medication-related hospital admissions [OR adjusted for number of drugs and comorbidities (ORadj) 2.30, 95 % CI 1.30-4.07], whereas there was no association with Beers 2012 criteria PIMs (ORadj 1.49, 95 % CI 0.90-2.47). STOPP PIMs and START PPOs together were also associated with preventable medication-related hospital admissions (ORadj 3.47, 95 % CI 1.70-7.09). CONCLUSION: Our study shows that patients with potentially inappropriate prescribing detected with the STOPP & START 2008 criteria are at risk of preventable medication-related hospital admissions. The STOPP & START 2008 criteria can be used to identify older people at risk of medication-related problems.

[Detection of inappropriate medication use in the elderly; will the STOPP and START criteria become the new Dutch standards?]. / Detectie van ongeschikt medicatiegebruik bij ouderen: worden de STOPP- en START-criteria de nieuwe standaard?

Many drugs that can be prescribed safely and effectively to younger patients are potentially inappropriate for the elderly as a result of physiological changes and increased comorbidity. A screening tool can be useful for detecting potentially inappropriate medication use in the elderly. When analysing medication use in the elderly, both overtreatment and undertreatment should be assessed. In Ireland, a screening method called the STOPP and START criteria has been developed; these provide 'handles' for the detection of potential overtreatment and undertreatment. The STOPP and START criteria, therefore, seem to be more fitting to the Dutch situation than the widely used Beers' criteria. In the new Dutch multidisciplinary guideline, 'Polypharmacy in the elderly' the use of the STOPP and START criteria is advised. In this article, we present a translation of the STOPP and START criteria which has been adapted for Dutch practice.