Prevalence of drug-drug interactions in sarcoma patients: key role of the pharmacist integration for toxicity risk management.

BACKGROUND: The risk of drug-drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment. PATIENTS AND METHODS: We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software. RESULTS: One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p < 0.0001), proton pump inhibitor (p = 0.026) and antidepressant (p < 0.001) were identified as risk factors of DDI (p < 0.02). Only marital status (p = 0.003) was associated with complementary medicine use. A pharmacist performed 157 medication reconciliations and made 71 interventions among 59 patients (37%). In multivariate analysis, factors associated with pharmacist intervention were: complementary medicines (p = 0.004), drugs number (p = 0.005) and treatment with TKI (p = 0.0002) CONCLUSIONS: Clinical interventions on DDI are more frequently required among sarcoma patients treated with TKI than CT. Multidisciplinary risk assessment including a medication reconciliation by a pharmacist could be crucial to prevent DDI with TKI.

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management]. / Inhibiteurs de tyrosine kinase ciblant l'angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients.

INTRODUCTION: Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge. AREAS COVERED: Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management. EXPERT OPINION: The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug-drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.

Pharmacokinetic-pharmacodynamic assessment of tacrolimus in liver-transplant recipients during the early post-transplantation period.

During the early post-transplantation period, the limitations of monitoring current tacrolimus dose with classic pharmacokinetics (PK) have been demonstrated in liver-transplant recipients. Evaluation of the pharmacodynamics (PD) using calcineurin activity (CNA) has been proposed to optimize tacrolimus dosing. The aim of the present study was to determine the time of maximal inhibition of CNA, to explore the relation between exposure to tacrolimus and CNA, and to analyze its variability. Blood was drawn from 14 patients 0, 2, 3, 4, 6, and 9 hours after tacrolimus intake on post-transplantation days 8, 21, and 90 to measure blood tacrolimus concentrations using the EMIT 2000 assay and CNA in peripheral blood mononuclear cells. Tacrolimus and CNA data were obtained for 33 blood-sample collection sessions and analyzed using a population approach. Three models were built to describe tacrolimus PK, CNA kinetics, and the relationships between the area under the CNA-time curve (AUC12effCNA) and AUC12Tacrolimus or CminTacrolimus. Coagulation factor V and whole/split liver graft were identified as covariates influencing tacrolimus clearance. Indeed, apparent tacrolimus clearance rose by 14% when factor V increased by 10% and was threefold higher in patients with whole-liver grafts. The median maximal inhibition of CNA was reached 4 hours after tacrolimus intake on days 8, 21, and 90 and represented an 18% drop in CNA compared with activity at drug intake. The variability of the PK-PD relationship was minimal when using AUC12Tacrolimus. The large variability of the PD parameters (coefficient of variation was 89%) that linked AUC12effCNA to AUC12Tacrolimus indicates that monitoring tacrolimus concentrations may not be adequate to control CNA. Measuring CNA in peripheral blood mononuclear cells 4 hours after tacrolimus intake during the first 3 months after liver transplantation could be a means to improve tacrolimus monitoring and thereby avoid acute graft-rejection episodes.

Comparison of the time to extubation after use of remifentanil or sufentanil in combination with propofol as anesthesia in adults undergoing nonemergency intracranial surgery: a prospective, randomized, double-blind trial.

BACKGROUND: Anesthetics with a short context-sensitive half-time (ie, the time required for the effect-site concentration of an IV drug to decrease by 50% at steady state), such as the opioids remifentanil and sufentanil, are suitable for anesthesia when early neurologic assessment is desired to detect postoperative complications. OBJECTIVE: This study compared the efficacy and safety profile of remifentanil and sufentanil in combination with propofol for anesthesia in adult patients undergoing nonemergency intracranial surgery. METHODS: This was a prospective, randomized, double-blind study in adults aged 18 to 75 years who were scheduled to undergo a supratentorial neurosurgical procedure with a maximum anticipated duration of 480 minutes. Eligible patients had no incapacitating severe systemic disease (American Society of Anesthesiologists physical status class 1-3), and only those in whom immediate postoperative extubation was planned were included. Anesthesia was induced with propofol and either remifentanil 1 microg/kg or sufentanil 0.25 microg/kg. Propofol was continued using a target-controlled infusion (TCI) system. Maintenance infusion rates for remifentanil and sufentanil were 0.25 and 0.0025 microg.kg-1.min-1, respectively. The opioid and propofol infusions were adjusted based on hemodynamic parameters (mean arterial blood pressure, heart rate). The primary end point was the time to extubation. Secondary end points were hemodynamic stability (defined as the number of anesthetic adjustments required to maintain intraoperative hemodynamic parameters within 20% of preinduction values), postoperative IV morphine requirement, postoperative nausea/vomiting (PONV), and intraoperative anesthetic costs. RESULTS: Sixty adults (29 remifentanil, 31 sufentanil) were included in the study. The 2 groups were similar with respect to sex, weight, indication for surgery, and duration of anesthesia. The sufentanil group was significantly older than the remifentanil group (55.3 vs 45.7 years, respectively; P=0.001). The median extubation time was similar in the remifentanil and sufentanil groups (10 minutes [interquartile range, 5-19 minutes] and 16 minutes [interquartile range, 10-30 minutes], respectively). Remifentanil was associated with the need for significantly fewer adjustments to maintain hemodynamic stability compared with sufentanil (0.8 vs 2.1; P=0.037), greater use of postoperative morphine (44.8% vs 22.6% of patients, P=0.01; mean IV morphine dose per patient: 4 vs 1.3 mg, P=0.016), and higher intraoperative opioid costs per patient euro vs euro P<0.001). The incidence of PONV did not differ significantly between groups. The total cost of intraoperative anesthetics per patient was similar in the 2 groups euro and euro as was the cost of propofol euro vs euro CONCLUSION: In these adults undergoing nonemergency intracranial surgery, there was no significant difference in extubation time between those receiving remifentanil and sufentanil infusions adjusted based on hemodynamic parameters in combination with propofol administered by TCI.