Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature.

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

Evaluation of a collaborative care program for pulmonary hypertension patients: a multicenter randomized trial.

Background Pulmonary hypertension is a rare, chronic and life-threatening group of diseases. Recent advances in pulmonary hypertension management prolong survival and improve quality-of-life. However, highly complex drug therapy enhances the risk of drug-related problems. Objective To assess the impact of involving clinical pharmacists in the collaborative care of pulmonary hypertension patients. Setting Ten French University Hospital Pneumology departments, all members of the French Network for Pulmonary Hypertension. Methods This prospective multicenter randomized controlled trial included incident pulmonary hypertension patients who were followed-up for 18 months. Randomization using an adapted Zelen method allocated patients to collaborative care (n = 41) or usual care groups (n = 51). A collaborative care program involving clinical pharmacists was developed through a close partnership between with physicians, nurses and pharmacists. Besides usual care, the program includes regular one-to-one interviews between the pharmacist and the patient. These interviews had following objectives: to perform an exhaustive medication history review; to identify the patient' needs, knowledge and skills; to define educational objectives and to provide patients with relevant information when needed. Following each interview, a standardized report form containing the pharmacist's recommendations was provided to physicians and nurses and discussed collaboratively. An ancillary economic analysis was performed. Main outcome measure Number of drug-related problems and their outcomes. Results The number of drug-related problems was not significantly different between groups (1.6 ± 1.5 vs. 1.9 ± 2.4; p = 0.41). More problems were resolved in the collaborative care group than in the usual care group (86.5% vs. 66.7%, p = 0.01). Time to clinical worsening, therapeutic adherence, satisfaction or quality-of-life were not statistically different between groups. Collaborative care decreased costs of drug-related hospitalizations. Conclusion Including clinical pharmacists in the multidisciplinary care of hospitalized patients with pulmonary hypertension improved the outcome of drug-related problems and reduced the costs of related hospitalization. However, we observed no efficacy on medication errors, clinical outcomes or medication adherence. Clinical Trial Registration ClinicalTrials.gov Identifier NCT01038284.

Gastrointestinal perforations in patients treated with erlotinib: A report of two cases with fatal outcome and literature review.

Erlotinib has been approved as second-line treatment in patients with non-small cell lung cancer (NSCLC) experiencing relapse after first-line platinum-based chemotherapy. Herein, we report two occurrences of erlotinib-associated gastrointestinal perforation (GIP) in NSCLC patients. Two patients aged 60 and 79 years received erlotinib as third- and second-line NSCLC treatment, respectively. GIP occurred following 3 weeks and 6 months of erlotinib treatment, leading to death a few days later in both patients, neither of whom had any intestinal metastasis. Risk factors related to erlotinib-induced GIP were concomitant oral corticosteroid therapy and ciprofloxacin administration, which may result in erlotinib overexposure. GIP is a severe adverse drug reaction of erlotinib, infrequently described in the literature, compared to other targeted therapies. The lethal risk of erlotinib-associated GIP should be taken into account when evaluating the benefit-risk balance of erlotinib in patients without epidermal growth factor receptor activating mutations.

A UV-Raman spectrometry method for quality control of anticancer preparations: Results after 18 months of implementation in hospital pharmacy.

In France, chemotherapy preparation units of hospital pharmacy compound cytotoxic infusion bags adapted to each patient. The narrow therapeutic index of these preparations led us to implement qualitative and quantitative control for patients' safety. To this aim, we calibrated an equipment combining UV-vis spectrometry and Raman spectroscopy (QC Prep+) and monitored 14 different molecule-solvent combinations over a 18 months period. This rapid and specific method allowed the qualitative and quantitative analysis of 1 mL sample tests in less than 2 min. On 5742 anticancer preparations, we obtained accepted results with more than 99.4% solvent identification, 99.6% drug identification and only 1.52% of preparations not matching quantitative specifications (±15% of theoretical concentration). This quantitative control enabled us to pinpoint some critical points of production for two of the most common preparations. We thus updated the procedures of reconstitution and preparation, increasing the quality of final product. UV-Raman spectrometry is thus an effective tool to control chemotherapy infusions and to improve good practices of preparation.