Effects of methimazole on the elimination of irinotecan

Purpose: To study the possible pharmacokinetic and pharmacodynamic interactions between irinotecan and methimazole. Methods: A patient treated for colorectal cancer with single agent irinotecan received methimazole co-medication for Graves' disease. Irinotecan pharmacokinetics and side effects were followed during a total of four courses (two courses with and two courses without methimazole). Results: Plasma concentrations of the active irinotecan metabolite SN-38 and its inactive metabolite SN-38-Glucuronide were both higher (a mean increase of 14 and 67%, respectively) with methimazole co-medication, compared to irinotecan monotherapy. As a result, the mean SN-38 glucuronidation rate increased with 47% during concurrent treatment. Other possible confounding factors did not change over time. Specific adverse events due to methimazole co-treatment were not seen. Conclusions: Additional in vitro experiments suggest that these results can be explained by induction of UGT1A1 by methimazole, leading to higher SN-38G concentrations. The prescribed combination of these drugs may lead to highly toxic intestinal SN-38 levels. We therefore advise physicians to be very careful in combining methimazole with regular irinotecan doses, especially in patients who are prone to irinotecan toxicity

Delirium in older COVID-19 patients:Evaluating risk factors and outcomes

Objectives: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. Methods: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. Results: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3–33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1–22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40–1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71–4.72] p < 0.001), but not in multivariable analyses. Conclusions: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty

Characteristics and outcomes of older patients hospitalised for COVID-19 in the first and second wave of the pandemic in The Netherlands:the COVID-OLD study

BACKGROUND: as the coronavirus disease of 2019 (COVID-19) pandemic progressed diagnostics and treatment changed. OBJECTIVE: to investigate differences in characteristics, disease presentation and outcomes of older hospitalised COVID-19 patients between the first and second pandemic wave in The Netherlands. METHODS: this was a multicentre retrospective cohort study in 16 hospitals in The Netherlands including patients aged ≥ 70 years, hospitalised for COVID-19 in Spring 2020 (first wave) and Autumn 2020 (second wave). Data included Charlson comorbidity index (CCI), disease severity and Clinical Frailty Scale (CFS). Main outcome was in-hospital mortality. RESULTS: a total of 1,376 patients in the first wave (median age 78 years, 60% male) and 946 patients in the second wave (median age 79 years, 61% male) were included. There was no relevant difference in presence of comorbidity (median CCI 2) or frailty (median CFS 4). Patients in the second wave were admitted earlier in the disease course (median 6 versus 7 symptomatic days; P < 0.001). In-hospital mortality was lower in the second wave (38.1% first wave versus 27.0% second wave; P < 0.001). Mortality risk was 40% lower in the second wave compared with the first wave (95% confidence interval: 28–51%) after adjustment for differences in patient characteristics, comorbidity, symptomatic days until admission, disease severity and frailty. CONCLUSIONS: compared with older patients hospitalised in the first COVID-19 wave, patients in the second wave had lower in-hospital mortality, independent of risk factors for mortality. The better prognosis likely reflects earlier diagnosis, the effect of improvement in treatment and is relevant for future guidelines and treatment decisions

Frailty is associated with in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands:the COVID-OLD study

BACKGROUND: During the first wave of the coronavirus disease 2019 (COVID-19) pandemic, older patients had an increased risk of hospitalisation and death. Reports on the association of frailty with poor outcome have been conflicting. OBJECTIVE: The aim of the present study was to investigate the independent association between frailty and in-hospital mortality in older hospitalised COVID-19 patients in the Netherlands. METHODS: This was a multicentre retrospective cohort study in 15 hospitals in the Netherlands, including all patients aged ≥70 years, who were hospitalised with clinically confirmed COVID-19 between February and May 2020. Data were collected on demographics, co-morbidity, disease severity and Clinical Frailty Scale (CFS). Primary outcome was in-hospital mortality. RESULTS: A total of 1,376 patients were included (median age 78 years (interquartile range 74-84), 60% male). In total, 499 (38%) patients died during hospital admission. Parameters indicating presence of frailty (CFS 6-9) were associated with more co-morbidities, shorter symptom duration upon presentation (median 4 versus 7 days), lower oxygen demand and lower levels of C-reactive protein. In multivariable analyses, the CFS was independently associated with in-hospital mortality: compared with patients with CFS 1-3, patients with CFS 4-5 had a two times higher risk (odds ratio (OR) 2.0 (95% confidence interval (CI) 1.3-3.0)) and patients with CFS 6-9 had a three times higher risk of in-hospital mortality (OR 2.8 (95% CI 1.8-4.3)). CONCLUSIONS: The in-hospital mortality of older hospitalised COVID-19 patients in the Netherlands was 38%. Frailty was independently associated with higher in-hospital mortality, even though COVID-19 patients with frailty presented earlier to the hospital with less severe symptoms

Influence of smoking on the pharmacokinetics and toxicity profiles of taxane therapy

OBJECTIVE: To examine the effects of smoking on the pharmacokinetics and toxicities of patients treated with docetaxel or paclitaxel. Cigarette smoke is known to interact with the metabolism of several anticancer drugs. It may also affect the incidence and severity of adverse events and the efficacy of chemotherapy. METHODS: Smoking status, toxicity profiles, and pharmacokinetic parameters (calculated by nonlinear mixed-effect modelling population analysis) were determined in 566 patients (429 non-smokers and 137 smokers) treated with docetaxel or paclitaxel. RESULTS: Smokers treated with docetaxel showed less grade 4 neutropenia (35% vs. 52%; P = 0.01) than non-smokers. Smokers treated with paclitaxel had less grade 3/4 leukopenia than non-smokers (12% vs. 25%; P = 0.03), and the white blood cell (WBC) nadir was lower in non-smokers (median 2.7 × 109/L, range 0.05 × 109/L-11.6 × 109/L) than in smokers (median 3.3 × 109/L, range 0.8 × 109/L-10.2 × 109/L; P = 0.02). Of interest, significantly lower WBC counts and absolute neutrophil counts at baseline were seen in non-smoking patients treated with paclitaxel (P = 0.0001). Pharmacokinetic parameters were similar in smokers and non-smokers for both taxanes. CONCLUSION: Cigarette smoking does not alter the pharmacokinetic determinants of docetaxel and paclitaxel. Smokers treated with docetaxel and paclitaxel have less neutropenia and leukopenia, but further research is warranted to elucidate this potential protective effect.</p

Therapeutic drug monitoring for the individualization of docetaxel dosing: a randomized pharmacokinetic study

Docetaxel pharmacokinetic (PK) parameters, notably clearance and exposure (AUC), are characterized by large interindividual variability. The purpose of this study was to evaluate the effect of PK-guided [area under the plasma concentration versus time curve (AUC) targeted], individualized docetaxel dosing on interindividual variability in exposure. A limited sampling strategy in combination with a validated population PK model, Bayesian analysis, and a predefined target AUC was used. Fifteen patients were treated for at least 2 courses with body surface area-based docetaxel and 15 with at least 1 course of PK-guided docetaxel dosing. Interindividual variability (SD of ln AUC) was decreased by 35% (N = 15) after 1 PK-guided course; when all courses were evaluated, variability was decreased by 39% (P = 0.055). PK-guided dosing also decreased the interindividual variability of percentage decrease in white blood cell and absolute neutrophil counts by approximately 50%. Further research is required to determine whether the decrease in PK variability can contribute to a reduction in interindividual variability in efficacy and toxicit

Irinotecan chemotherapy during valproic acid treatment: pharmacokinetic interaction and hepatotoxicity

Because of its supposed inhibiting capacities of uridine-diphosphate glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation in rats, the antiepileptic drug valproic acid has been investigated as modulator of irinotecan-induced delayed-type diarrhea in rats. Here, we report on the pharmacokinetic and pharmacodynamic effects of this combination in a cancer patient. A patient who used valproic acid was administered irinotecan (600 mg). To investigate dose-limiting hepatotoxicity encountered during the first course, which was clinically attributed to a supposed higher exposure to the active irinotecan metabolite SN-38, valproic acid was tapered off. Blood samples for pharmacokinetic purposes were drawn during a course with and a course without concomitant valproic acid. Plasma-levels of irinotecan, SN-38, and SN-38G were determined using HPLC-assays. When irinotecan was combined with valproic acid, the exposure to SN-38 was 41% lower. Additionally, reversible elevations of the liver enzyme tests were noted. In particular, seven days after irinotecan administration gammaGT and transaminase levels raised up to 5.3-11.3 times the ULN (CTCAE grade 3). Valproic acid-induced plasma protein binding displacement and/or metabolic modulation of enzymes and drug transporters involved in irinotecan disposition may explain the reduced exposure to SN-38 in the presence of valproic acid. Given the herewith-coupled potential undertreatment, patients should firstly switch to another antiepileptic drug not known to interfere with irinotecan treatment. Additionally, this particular combination should not be implemented in clinical studies without simultaneously adjusting the irinotecan dose, and the risk of (severe) hepatotoxicity should be considered when designing protocols studying valproic acid (as histone deacetylase-inhibitor) in combination with other (anticancer) drug