The influence of body composition on the systemic exposure of paclitaxel in esophageal cancer patients

Changes in body composition are associated with chemotherapy-related toxicities and effectiveness of treatment. It is hypothesized that the pharmacokinetics (PK) of chemotherapeutics may depend on body composition. The effects of body composition on the variability of paclitaxel PK were studied in patients with esophageal cancer. Skeletal muscle index (SMI), visceral adipose tissue (VAT), and skeletal muscle density (SMD) were measured at the third lumbar vertebra on computed tomography (CT) scans performed before treatment. Paclitaxel PK data were collected from a prospective study performed between May 2004 and January 2014. Non-linear mixed-effects modeling was used to fit paclitaxel PK profiles and evaluate the covariates body surface area (BSA), SMI, VAT, and SMD using a significance threshold of p < 0.001. Paclitaxel was administered to 184 patients in a dose range of 50 to 175 mg/m2 . Median BSA was 1.98 m2 (range of 1.4 to 2.8 m2 ). SMI, VAT, and SMD were not superior to BSA in predicting paclitaxel PK. The additive value of SMI, VAT, and SMD to BSA was also negligible. We did not find evidence that paclitaxel dosing could be further optimized by correcting for SMI, VAT, or SMD

Pharmacokinetics of Selected Anticancer Drugs in Elderly Cancer Patients : Focus on Breast Cancer

BACKGROUND: Elderly patients receiving anticancer drugs may have an increased risk to develop treatment-related toxicities compared to their younger peers. However, a potential pharmacokinetic (PK) basis for this increased risk has not consistently been established yet. Therefore, the objective of this study was to systematically review the influence of age on the PK of anticancer agents frequently administered to elderly breast cancer patients. METHODS: A literature search was performed using the PubMed electronic database, Summary of Product Characteristics (SmPC) and available drug approval reviews, as published by EMA and FDA. Publications that describe age-related PK profiles of selected anticancer drugs against breast cancer, excluding endocrine compounds, were selected and included. RESULTS: This review presents an overview of the available data that describe the influence of increasing age on the PK of selected anticancer drugs used for the treatment of breast cancer. CONCLUSIONS: Selected published data revealed differences in the effect and magnitude of increasing age on the PK of several anticancer drugs. There may be clinically-relevant, age-related PK differences for anthracyclines and platina agents. In the majority of cases, age is not a good surrogate marker for anticancer drug PK, and the physiological state of the individual patient may better be approached by looking at organ function, Charlson Comorbidity Score or geriatric functional assessment

Incidence of hematologic toxicity in older adults treated with gemcitabine or a gemcitabine-containing regimen in routine clinical practice : a multicenter retrospective cohort study

PURPOSE: Older adults receiving cytotoxic agents may be more susceptible to hematologic toxicities because of progressive reduction in organ functions and multiple co-morbidities. Because older adults are under-represented in clinical trials, this retrospective study aims to evaluate hematologic toxicity of gemcitabine-based regimens in older patients compared with their younger counterparts in clinical practice. PATIENTS AND METHODS: A total of 494 patients routinely treated with gemcitabine, either alone or in combination with platinum-based drugs, in the Slotervaart Hospital or The Netherlands Cancer Institute between January 2003 and January 2013 were enrolled. Patient characteristics, underlying malignancy, treatment regimen, administered doses of gemcitabine, and laboratory values were retrospectively collected from electronic patient records. The relative dose intensity achieved in older patients and their younger counterparts was evaluated using the Wilcoxon rank sum test. Incidence of hematologic toxicity in older adults (age ≥70 years) and their younger counterparts (age <70 years) was compared using the Fisher's exact test. Predictors of experiencing Grade 3 or 4 hematologic toxicity were evaluated using logistic regression. RESULTS: Patient characteristics and baseline laboratory values were equally distributed among the two age groups, except for the estimated glomerular filtration rate being significantly lower in the older patients. Reduction of the first administered dose of gemcitabine was significantly more frequently applied in the older patients (p = 0.03). However, no significant difference in the gemcitabine relative dose intensity over the median number of four treatment cycles was observed (65 % in the older patients group vs. 67 % in the younger control group). Incidence of severe hematologic toxicity (Grade ≥3) was not significantly higher in the older patients. A subset analysis of nadir blood counts showed a trend towards an increased incidence of Grade ≥3 hematologic toxicity for the older patients in the gemcitabine-cisplatin treatment group. Moreover, the relative risk for developing Grade 3 or 4 leukocytopenia in the older patients was increased fivefold (p = 0.007) for combination therapy with gemcitabine and cisplatin. Blood transfusions were administered nearly twofold more frequently in the older patients, but this difference did not reach statistical significance. CONCLUSION: Treatment with gemcitabine or a gemcitabine-containing regimen appeared to be feasible and well tolerated in the older patients who were selected to receive chemotherapy. Overall, patients ≥70 years of age did not incur a higher incidence of severe or life-threatening hematologic toxicity nor did they undergo more frequent or larger dose adjustments. These data support additional treatment-specific prospective studies and clinical trials in older cancer patients to optimize treatment benefit and risk in this heterogeneous older patient population

Incidence of hematologic toxicity in older adults treated with gemcitabine or a gemcitabine-containing regimen in routine clinical practice: a multicenter retrospective cohort study

PURPOSE: Older adults receiving cytotoxic agents may be more susceptible to hematologic toxicities because of progressive reduction in organ functions and multiple co-morbidities. Because older adults are under-represented in clinical trials, this retrospective study aims to evaluate hematologic toxicity of gemcitabine-based regimens in older patients compared with their younger counterparts in clinical practice. PATIENTS AND METHODS: A total of 494 patients routinely treated with gemcitabine, either alone or in combination with platinum-based drugs, in the Slotervaart Hospital or The Netherlands Cancer Institute between January 2003 and January 2013 were enrolled. Patient characteristics, underlying malignancy, treatment regimen, administered doses of gemcitabine, and laboratory values were retrospectively collected from electronic patient records. The relative dose intensity achieved in older patients and their younger counterparts was evaluated using the Wilcoxon rank sum test. Incidence of hematologic toxicity in older adults (age ≥70 years) and their younger counterparts (age <70 years) was compared using the Fisher's exact test. Predictors of experiencing Grade 3 or 4 hematologic toxicity were evaluated using logistic regression. RESULTS: Patient characteristics and baseline laboratory values were equally distributed among the two age groups, except for the estimated glomerular filtration rate being significantly lower in the older patients. Reduction of the first administered dose of gemcitabine was significantly more frequently applied in the older patients (p = 0.03). However, no significant difference in the gemcitabine relative dose intensity over the median number of four treatment cycles was observed (65 % in the older patients group vs. 67 % in the younger control group). Incidence of severe hematologic toxicity (Grade ≥3) was not significantly higher in the older patients. A subset analysis of nadir blood counts showed a trend towards an increased incidence of Grade ≥3 hematologic toxicity for the older patients in the gemcitabine-cisplatin treatment group. Moreover, the relative risk for developing Grade 3 or 4 leukocytopenia in the older patients was increased fivefold (p = 0.007) for combination therapy with gemcitabine and cisplatin. Blood transfusions were administered nearly twofold more frequently in the older patients, but this difference did not reach statistical significance. CONCLUSION: Treatment with gemcitabine or a gemcitabine-containing regimen appeared to be feasible and well tolerated in the older patients who were selected to receive chemotherapy. Overall, patients ≥70 years of age did not incur a higher incidence of severe or life-threatening hematologic toxicity nor did they undergo more frequent or larger dose adjustments. These data support additional treatment-specific prospective studies and clinical trials in older cancer patients to optimize treatment benefit and risk in this heterogeneous older patient population

Combating pan-coronavirus infection by indomethacin through simultaneously inhibiting viral replication and inflammatory response

Severe infections with coronaviruses are often accompanied with hyperinflammation, requiring therapeutic strategies to simultaneously tackle the virus and inflammation. By screening a safe-in-human broadspectrum antiviral agents library, we identified that indomethacin can inhibit pan-coronavirus infection in human cell and airway organoids models. Combining indomethacin with oral antiviral drugs authorized for treating COVID-19 results in synergistic anti-coronavirus activity. Coincidentally, screening a library of FDA-approved drugs identified indomethacin as the most potent potentiator of interferon response through increasing STAT1 phosphorylation. Combining indomethacin with interferon-alpha exerted synergistic antiviral effects against multiple coronaviruses. The anti-coronavirus activity of indomethacin is associated with activating interferon response. In a co-culture system of lung epithelial cells with macrophages, indomethacin inhibited both viral replication and inflammatory response. Collectively, indomethacin is a pan-coronavirus inhibitor that can simultaneously inhibit virus-triggered inflammatory response. The therapeutic potential of indomethacin can be further augmented by combining it with oral antiviral drugs or interferon-alpha.Peer reviewe

Therapeutic drug monitoring of small molecule kinase inhibitors in oncology in a real-world cohort study : does age matter?

AIM: Pharmacokinetics of small molecule kinase inhibitors (KIs) used in cancer treatment may alter with increasing age, but results are conflicting. This study aims to compare exposure to KIs between older and younger patients (≥70 and <70 years) in clinical practice. METHODS: KI plasma concentrations of routinely treated patients were measured using validated assays. Calculated trough concentrations were compared in both age groups. For KIs with a clinically meaningful target concentration (erlotinib, imatinib, pazopanib, sunitinib and vemurafenib), influence of older age on target attainment was assessed. RESULTS: We analysed 616 samples from 454 patients (median age: 61; range 20-93 years), treated with dabrafenib (n = 105), erlotinib (n = 49), imatinib (n = 165), pazopanib (n = 63), sunitinib (n = 87), trametinib (n = 95) and vemurafenib (n = 52). Older age did not significantly influence exposure to erlotinib, imatinib, pazopanib, sunitinib, trametinib and vemurafenib. Elderly patients had significantly higher dabrafenib trough concentrations than younger patients (P = 0.02; 62 ng ml-1 (coefficient of variation [CV] 41%), vs. 53 ng ml-1 (CV 46%), respectively). For KIs with a predefined target concentration, 68% of older and 61% of younger patients reached target. CONCLUSIONS: In this real-world study, exposure to most included KIs was comparable in older and younger patients, except for dabrafenib, which showed higher exposure in older patients. In the absence of an absolute target for this KI, clinical relevance remains unclear. For all other included KIs, our data suggest no clinically relevant influence of older age on KI exposure

Therapeutic drug monitoring of small molecule kinase inhibitors in oncology in a real-world cohort study : does age matter?

AIM: Pharmacokinetics of small molecule kinase inhibitors (KIs) used in cancer treatment may alter with increasing age, but results are conflicting. This study aims to compare exposure to KIs between older and younger patients (≥70 and <70 years) in clinical practice. METHODS: KI plasma concentrations of routinely treated patients were measured using validated assays. Calculated trough concentrations were compared in both age groups. For KIs with a clinically meaningful target concentration (erlotinib, imatinib, pazopanib, sunitinib and vemurafenib), influence of older age on target attainment was assessed. RESULTS: We analysed 616 samples from 454 patients (median age: 61; range 20-93 years), treated with dabrafenib (n = 105), erlotinib (n = 49), imatinib (n = 165), pazopanib (n = 63), sunitinib (n = 87), trametinib (n = 95) and vemurafenib (n = 52). Older age did not significantly influence exposure to erlotinib, imatinib, pazopanib, sunitinib, trametinib and vemurafenib. Elderly patients had significantly higher dabrafenib trough concentrations than younger patients (P = 0.02; 62 ng ml-1 (coefficient of variation [CV] 41%), vs. 53 ng ml-1 (CV 46%), respectively). For KIs with a predefined target concentration, 68% of older and 61% of younger patients reached target. CONCLUSIONS: In this real-world study, exposure to most included KIs was comparable in older and younger patients, except for dabrafenib, which showed higher exposure in older patients. In the absence of an absolute target for this KI, clinical relevance remains unclear. For all other included KIs, our data suggest no clinically relevant influence of older age on KI exposure

Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients : A meta-analysis and evaluation of a clinical cohort

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel

Exposure to Docetaxel in the Elderly Patient Population: a Population Pharmacokinetic Study

BACKGROUND: Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK. METHODS: Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005. RESULTS: Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67 years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively. CONCLUSION: In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors

Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients : A meta-analysis and evaluation of a clinical cohort

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel