Developing an innovative 3D printing platform for production of personalised medicines in a hospital for the OPERA clinical trial.

Breast cancer is the most frequently diagnosed cancer in women worldwide, and non-adherence to adjuvant hormonotherapy can negatively impact cancer recurrence and relapse. Non-adherence is associated with side effects of hormonotherapy. Pharmacological strategies to mitigate the side effects include coadministration of antidepressants, however patients remain non-adherent. The aim of this work was to develop medicines containing both hormonotherapy, tamoxifen (20 mg), along with anti-depressants, either venlafaxine (37.5 or 75 mg) or duloxetine (30 or 60 mg), to assess the acceptability and efficacy of this personalised approach for mitigating tamoxifen side effects in a clinical trial. A major criterion for the developed medicines was the production rate, specified at minimum 200 dosage units per hour to produce more than 40,000 units required for the clinical trial. A novel capsule filling approach enabled by the pharmaceutical 3D printer M3DIMAKER 2 was developed for this purpose. Firstly, semi-solid extrusion 3D printing enabled the filling of tamoxifen pharma-ink prepared according to French compounding regulation, followed by filling of commercial venlafaxine or duloxetine pellets enabled by the development of an innovative pellet dispensing printhead. The medicines were successfully developed and produced in the clinical pharmacy department of the cancer hospital Gustave Roussy, located in Paris, France. The developed medicines satisfied quality and production rate requirements and were stable for storage up to one year to cover the duration of the trial. This work demonstrates the feasibility of developing and producing combined tamoxifen medicines in a hospital setting through a pharmaceutical 3D printer to enable a clinical trial with a high medicines production rate requirement.

Breast cancer survivors' opinion on personalizing endocrine therapy and developing informative tools.

Understanding breast cancer survivors' perspectives is critical to personalizing endocrine therapy (ET) in the adjuvant setting. A nationwide survey among breast cancer survivors was proposed in France, in collaboration with patient advocacy organizations, to assess their perspectives on personalizing ET and developing dedicated informative tools. This survey explored patients' preferences regarding ET intake schedule, formulation, presentation (color, taste, shape, size, design, and packaging), combination with agents targeting ET-related adverse events, and a mobile application to support them during ET. Of the 1103 individuals who started the survey, 939 (85.1%) were eligible for enrollment and completed the survey. The majority of the participants considered that a personalized ET should take into consideration the intake schedule (n = 974, 90.7%) and swallowable tablet formulation (n = 606, 64.5%), without a preference for ET presentation (n = 619; 65.9%). The majority of the participants expressed a willingness to participate in a potential clinical trial evaluating the combination of ET with agents targeting ET-related adverse events at the start of ET (n = 752, 80.1%) or in the case of major ET-related adverse events (n = 778, 82.8%). The primary considerations were to have an uncompromised ET efficacy and a guaranteed reduction of adverse events. Last, a dedicated mobile application was considered helpful by 665 participants (70.8%). Informative tools should focus on the recommendations for dealing with adverse events (n = 593, 63.2%), the impact on the patient's daily life (n = 515, 54.9%), benefits (n = 504, 53.7%), and adverse events (n = 494, 52.6%) of ET. This survey paves the way for multimodal strategies that can include a personalized ET (e.g., ET in combination with agents targeting ET-related adverse events) and dedicated mobile applications to ultimately improve adherence.

[Patient-partnership in a comprehensive cancer centre: Establishment and roles of a patients and caregivers committee]. / Partenariat patient dans un centre de lutte contre le cancer : mise en place et rôles d'un comité de patients et aidants.

In oncology, the place of patients has a natural and strong legitimacy. Cancer is a common disease, with many singularities but also common features between pathologies, with issues ranging from prevention to possible palliative phases or post-cancer, and conducive to both individual and collective decision-making processes. Patient engagement is now essential at all levels of the healthcare system, from simple information to real involvement (co-construction). For 20 years, Gustave-Roussy, a comprehensive cancer centre in Villejuif, has implemented specific reflection and actions, embodied by the creation of a patients and caregivers committee and complemented by an institutional steering body that illustrates the transformation of "working for" into "working with". At the level of direct care, the main works promoted concern shared-decision-making between patient and professional and accompanying patients. At the institutional level, we find the expertise of hospital projects or services, the development of institutional documents (information and advance directives form, etc.), and internal evaluation (audit). At the political level, participation in Unicancer's patient-experience working group has allowed for a better coordinated deployment with other centers. Unicancer has developed a lexical guide defining patient resources, peer helpers, trainers, evaluators and coordinators. This partnership approach is beneficial for patients, their loved ones, caregivers, and must be amplified and give rise to new research work.

Dispensing Oral Temozolomide in Children: Precision and Stability of a Novel and Ready to Use Liquid Formulation in Comparison with Capsule Derived Mixtures.

Temozolomide (TMZ) is part of the therapeutic armamentarium used in managing pediatric cancers; however, available oral forms (capsules) are not adapted for use in children. Our aim was to assess the dose accuracy and stability of TMZ using capsule contents mixed with food compared with a novel, ready-to-use liquid formulation specifically developed for children (Ped-TMZ, brand name KIZFIZO). Dose accuracy and TMZ stability testing were performed with TMZ capsule contents (90 mg) mixed with food vehicles (apple juice, apple sauce, cream, milk, and mashed potatoes) and compared to an equivalent dose of Ped-TMZ. Acceptance criteria were predefined for TMZ (95.0-105.0%) and its degradation product amino-imidazole-carboxamide (AIC; <1%) content. The delivered dose was significantly higher using Ped-TMZ (96.6 ± 1.2%) and within the predefined criteria for TMZ content, whereas it was systematically under the lower specifications of 95% using capsule-derived preparations with apple juice (91.0 ± 1.5%) and apple sauce (91.6 ± 1.4%), respectively (p < 0.0001). In chemical stability tests, the four food vehicles (apple sauce, cream, milk, mashed potatoes) had a significant effect on TMZ stability (p = 0.0042), and the AIC significantly increased with time in three of the four vehicles (p < 0.0001). Only 1/72 of preparations from capsules met the predefined acceptance criteria, whereas Ped-TMZ showed no TMZ loss, and the AIC remained within specifications. In conclusion, mixing TMZ capsule content with food may result in significant underexposure, possibly even greater in routine practice, as complete food intake by the child is unlikely.

Molecular Mechanisms Involved in the Chemical Instability of ONC201 and Methods to Counter Its Degradation in Solution.

Glioblastoma is one of the most common and aggressive forms of brain tumor, a rare disease for which there is a great need for innovative therapies. ONC201, a new drug substance, has been used in a compassionate treatment program where the choice of dosage form and regimen have yet to be justified. The prior knowledge needed to anticipate ONC201 stability problems has recently been partially addressed, by (i) showing that ONC201 is sensitive to light and oxidation and (ii) identifying the molecular structures of the main degradation products formed. The aim of the work presented here was to improve our understanding of the degradation pathways of ONC201 using data from ab initio calculations and experimental work to supplement the structural information we already published. The C-H bonds located αto the amine of the tetrahydropyridine group and those located alpha to the imine function of the dihydroimidazole group exhibit the lowest bond dissociation energies (BDEs) within the ONC201 molecule. Moreover, these values drop well below 90 kcal.mol-1 when ONC201 is in an excited state (S1; T1). The structures of the photoproducts we had previously identified are consistent with these data, showing that they would have resulted from radical processes following the abstraction of alpha hydrogens. Concerning ONC201's sensitivity to oxidation, the structures of the oxidation products matched the critical points revealed through mapped electrostatic potential (MEP) and average local ionization energy (ALIE). The data obtained from ab initio calculations and experimental work showed that the reactivity of ONC201 to light and oxidation conditions is highly dependent on pH. While an acidic environment (pH < 6) contributes to making ONC201 quantitatively more stable in solution in the face of oxidation and photo-oxidation, it nevertheless seems that certain chemical groups in the molecule are more exposed to nucleophilic attacks, which explains the variation observed in the profile of degradation products formed in the presence of certain antioxidants tested. This information is crucial to better understand the stability results in the presence of antioxidant agents and to determine the right conditions for them to act.

[Robotic production of injectable anticancer drugs in hospital pharmacies]. / Production robotisée des préparations d'anticancéreux injectables en pharmacie hospitalière.

INTRODUCTION: Following the 2005 decree on securing the medicine supply chain, the production of "chemotherapies", anticancer drugs (cytotoxic, cytostatic, immunotherapy), was centralised within hospital pharmacies. To cope with increasingly growing activities, pharmacies are moving towards robotisation. This work offers feedback from four French sites pioneers in robotic production. MATERIAL AND METHOD: A review of the literature was carried out on the PubMed and Google Scholar scientific databases and GERPAC publications relating to the robotic production of chemotherapy preparations. This review allowed to select 25 articles. RESULTS: The robotisation of the production of "chemotherapies" requires infrastructural prerequisites, a reengineering of the manufacturing process and the patient journey. This impacts all the parties involved in this complex process. The "cobotisation" concept or collaborative robotics must be anticipated by the teams. Robotisation is an institutional decision, which must be owned by the pharmaceutical team and endorsed by the medical team and management. DISCUSSION/CONCLUSION: For reasons of optimisation, safeguarding and management of human resources, a large number of centres get equipped with robotic systems. Robotic preparation should extend to other non-hazardous preparation, as it is already the case in other countries. This strategic view should be carried out today to anticipate problems, ensure safety and improve the healthcare quality.

Safety of direct oral anticoagulants in patients with advanced solid tumors receiving anti-VEGF agents: a retrospective study.

PURPOSE: Kinase inhibitors (KI) and antibodies targeting the VEGF pathway are approved in a broad spectrum of cancers and associated with an increased risk of bleeding and thromboembolic events (TE). The use of direct oral anticoagulants (DOACs) apixaban and rivaroxaban is increasing in cancer patients, but limited data are available for patients receiving anti-VEGF agents. METHODS: To assess safety of DOAC with concomitant anti-VEGF agents, a retrospective chart review of all patients receiving concomitantly DOAC and anti-VEGF agents was performed from 2013 to 2020 in our center. Data on demographics, safety, and time on treatment were collected. Main outcome was safety (bleeding and thromboembolic events). RESULTS: Of 92 patients (median age 66 years (IQR: 59-72)), 40 were treated with KI and 52 with bevacizumab. The most frequent primary tumor sites were colon/rectum (24%), kidney (21%), ovary (13%), lung (11%), soft tissue sarcoma (10%), and thyroid (9%); 2% had brain metastases. Apixaban 5 mg bid (n = 41) or rivaroxaban 20 mg daily (n = 51) were given for TE (65%), atrial fibrillation (32%), or other indications (3%). The median duration of concomitant treatment was 4.8 months (95%CI: 0.7-50.0) with bevacizumab and 11.7 months (95%CI: 0.1-53.8) with KI. Grade ≥ 3 bleeding events occurred in 5 patients (5%): 4 patients receiving bevacizumab (one grade 5 upper digestive tract bleeding and three grade 3 rectal or vaginal hemorrhages) and 1 patient under cabozantinib for kidney cancer with endobronchial metastasis (grade 3 hemoptysis). Grade ≥ 3 TE occurred in 8 patients (9%): 7 patients receiving bevacizumab (including one grade 5 pulmonary embolism), and one patient receiving sunitinib (grade 3 pulmonary embolism). Median time-to-event (bleeding or thrombotic event) was not reached (NR) (95%CI: 76.9-NR) for KI and 86.9 months (95%CI: 42.9-148.0) for bevacizumab. CONCLUSIONS AND RELEVANCE: In our experience, the use of DOAC was safe in selected patients treated with KI, but unclear with bevacizumab. More data are needed to endorse guidelines in this specific group of patients.

Ethical issues related to the COVID-19 pandemic in patients with cancer: experience and organisations in a French comprehensive cancer centre.

BACKGROUND: The COVID-19 pandemic has aggressively reached the most vulnerable, not only the elderly but also patients with chronic conditions such as cancer. In this study, we present the outlines of ethical thinking and the measures implemented to try to respect our basic values of care, in the specific environment of an oncology hospital. METHODS: Our ethics committee created an ethical watch system based on 24/7 shifts to assist practitioners in their daily decisions. We discuss the challenges faced by patients with cancer during the pandemic, such as access to critical care and ethical dilemmas in the context of resource scarcity, as well as the issue of isolation of patients. We also debate the restrictions in access to oncology care in a health context strongly 'prioritised' against COVID-19. RESULTS: In all areas of an ethical dilemma, either for sorting out access to critical care or for the dramatic consequences of prolonged isolation of patients, our common thread was our attempt to protect, whenever possible, the principles of deontological ethics by strictly resisting utilitarian pressure. Respecting democratic health decision-making processes is a cornerstone of ethically relevant decisions, including in the context of a sanitary crisis. CONCLUSION: The role of an ethics committee related to real-life situations includes not only a reflexive perspective in respect of fundamental principles, but also the help to enlighten and resolve ethical dilemmas in complex clinical situations. This ethical watch team assists physicians in decision-making, promoting the supportive and palliative dimension of care with a holistic approach.

Design and stability of pediatric oral formulation of imatinib.

BACKGROUND: Imatinib is a protein-tyrosine kinase inhibitor which is currently only commercially available as a tablet dosage form in the strength of 100mg and 400mg. The elaboration of new oral liquid formulations is suitable in pediatrics and for patients who have difficulties to swallow, notably in the absence of commercial forms. This enables the adaptation of dosage and secure the administration. OBJECTIVES: The formulation of an oral pediatric solution of imatinib at a concentration of 30 mg/mL and the evaluation of its stability for the treatment of pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia. METHODS: The physicochemical stability parameters: appearance, pH, osmolality, and drug content of formulation were evaluated for 30 days when stored at 2-8°C. Concentration of solution was measured with a validated method using high performance liquid chromatography (HPLC) coupled with an absorbance UV detector. Equally, microbiological stability was performed. RESULTS: The remaining imatinib concentration was at least 95% of the initial concentration after 30 days stored in fridge temperature. No changes were observed regarding the physical properties of the formulation during the study period. CONCLUSIONS: The stability study showed that the imatinib oral solution at a concentration of 30 mg/mL provides an alternative option at the commercial tablet dosage forms for pediatric patients and patients who have difficulties to swallow.

COVID-19 management in a cancer center: the ICU storm.

A novel coronavirus, SARS-CoV-2, was first reported as a respiratory illness in December 2019 in Wuhan, China. Since then, the World Health Organization (WHO) Emergency Committee declared a global health. COVID-19 has now spread worldwide and is responsible of more than 472,216 persons, out of 9,100,090 officially diagnosed worldwide since 23 of June. In the context of cancer patients, COVID-19 has a severe impact, regarding pulmonary infection but also cancer treatments in this fragile and immunocompromised population, and ICU admission for cancer patients in the context of COVID-19 requires ethical and clinical consideration. In our cancer center, intensivists, oncologists, pharmacists, and hospital administrators had to prepare for a substantial increase in critical care bed capacity (from 10 ICU beds, 6 medical intensive care beds, and 12 surgical intensive care beds, bed capacity was increased to 28 medical intensive care beds with ventilating capacity) and to adapt infrastructure (i.e., ICU beds), supplies (i.e., drugs, ventilators, protective materials), and staff (i.e., nurses and medical staff). Overall, thirty-three COVID-19 patients were admitted in our ICU, 17 cancer-free and 16 with cancer, and 23 required mechanical ventilation, resulting in 4 deaths (of them two patients with cancer). We report here management of a dedicated intensive care unit of a cancer center during the COVID-19 infection pandemic, considering resource allocation and redistribution of healthcare workers.

Medication at discharge in an orthopaedic surgical ward: quality of information transmission and implementation of a medication reconciliation form.

Background Medication reconciliation (MedRec) at discharge is a cumbersome but necessary process to reduce the risk of medication errors at transitions of care. The main barriers to implementing such a process are the large number of professionals involved and a lack of collaboration among caregivers. Objective This study was designed to assess the need for a medication reconciliation form at discharge in an orthopaedic surgical ward. Setting The study was conducted in the orthopaedic surgery ward among inpatients at a 407-bed French teaching hospital. Method We first performed a retrospective audit to evaluate the quality of discharge medication information in the medical record, after which a 5-week prospective study was conducted in 2013. All patients admitted to the orthopaedic surgery unit who had at least two chronic diseases and three medications underwent MedRec at discharge. We designed a Best Possible Medication at Discharge List (BPMDL) to be completed by hospital staff and transmitted to community caregivers. Mean outcome measures We assessed the completeness of medication information in the medical records, discrepancies between medications noted on the BPMDL and those prescribed on the discharge order, and the value of the BPMDL for stakeholders. Results Thirty patients were included in the study. Only 4 % of medical records contained a discharge summary with complete medication information. In 67 % of cases, treatment discontinuations at admission were justified, and medications were reintroduced before discharge, while 107 treatments (45 %) were added but not prescribed on discharge orders. Discontinuations prior to discharge were justified in 60 % of cases (treatments were ended or supportive treatment was required during hospitalization). An average of 2.1 treatments were prescribed on discharge orders (vs. 9.4 prescribed on the BPMDL). Patients, general practitioners (GP), and physicians in long-term care settings (PLTCS) rated the format, content, and readability of the BPMDL as satisfactory, and it was found to be of value for patients and PLTCS to support medication information. Because of the very low response rate among GP (10 %), we were unable to determine their satisfaction with the MedRec discharge process. Conclusion The transmission of patient medication information at discharge is often lacking. As such, the BPMDL appears to have value to both patients and community health providers. Because this study was conducted within a single surgical unit, further study in other surgical wards is needed to assess generalizability.

Patterns and factors associated with low adherence to psychotropic medications during pregnancy--a cross-sectional, multinational web-based study.

BACKGROUND: No previous studies have explored how closely women follow their psychotropic drug regimens during pregnancy. This study aimed to explore patterns of and factors associated with low adherence to psychotropic medication during pregnancy. METHODS: Multinational web-based study was performed in 18 countries in Europe, North America, and Australia. Uniform data collection was ensured via an electronic questionnaire. Pregnant women were eligible to participate. Adherence was measured via the 8-item Morisky Medication Adherence Scale (MMAS-8). The Beliefs about Prescribed Medicines Questionnaire (BMQ-specific), the Edinburgh Postnatal Depression Scale (EPDS), and a numeric rating scale were utilized to measure women's beliefs, depressive symptoms, and antidepressant risk perception, respectively. Participants reporting use of psychotropic medication during pregnancy (n = 160) were included in the analysis. RESULTS: On the basis of the MMAS-8, 78 of 160 women (48.8%, 95% CI: 41.1-56.4%) demonstrated low adherence during pregnancy. The rates of low adherence were 51.3% for medication for anxiety, 47.2% for depression, and 42.9% for other psychiatric disorders. Smoking during pregnancy, elevated antidepressant risk perception (risk≥6), and depressive symptoms were associated with a significant 3.9-, 2.3-, and 2.5-fold increased likelihood of low medication adherence, respectively. Women on psychotropic polytherapy were less likely to demonstrate low adherence. The belief that the benefit of pharmacotherapy outweighed the risks positively correlated (r = .282) with higher medication adherence. CONCLUSIONS: Approximately one of two pregnant women using psychotropic medication demonstrated low adherence in pregnancy. Life-style factors, risk perception, depressive symptoms, and individual beliefs are important factors related to adherence to psychotropic medication in pregnancy.

Reducing medication errors at admission: 3 cycles to implement, improve and sustain medication reconciliation.

BACKGROUND: In France, medication errors are the third leading cause of serious adverse events. Many studies have shown the positive impact of medication reconciliation (MR) on reducing medication errors at admission but this practice is still rarely implemented in French hospitals. OBJECTIVE: Implement and sustain a MR process at admission in two surgery units. The quality improvement approach used to meet this objective is described. SETTING: The gastrointestinal surgery and orthopedic surgery departments of a 407 inpatient bed French teaching hospital. METHODS: A step by step collaborative approach based on plan-do-study-act (PDSA) cycles. Three cycles were successively performed with regular feedback during multidisciplinary meetings. MAIN OUTCOME MEASURE: mean unintended medication discrepancies (UMDs) per patients at admission. RESULTS: The three PDSA cycles and the monitoring phase allowed to implement, optimize and sustain a MR process in the two surgery units. Cycle 1, by showing a rate of 0.65 UMDs at admission (95 % CI 0.39-0.91), underlined the need for a MR process; cycle 2 showed how the close-collaboration between pharmacy and surgery units could help to reduce mean UMDs per patients at admission (0.18; 95 % CI 0.09-0.27) (p < 0.001); finally, cycle 3 allowed the optimization of the MR process by reducing the delays of the best possible medication history availability. CONCLUSIONS: This work highlights how a collaborative quality-improvement approach based on PDSA cycles can meet the challenge of implementing MR to improve medication management at admission.

[The medication history: a tool to optimize the preoperative anesthesia consultation?]. / L'historique médicamenteux: un outil pour optimizer la consultation d'anesthésie du patient de chirurgie programmée?

Since 2011, medication histories (MH) are performed at patient's admission in orthopaedic and visceral surgery wards, 40% patients have their surgery planned. During the anaesthesia's consultation, the anaesthetist reported usual treatments on a consultation report (CRI) which is also the preoperative prescription. The objective of this study was to evaluate if MH done prior to anaesthesia's consultation improve treatments report on the CR. A comparative prospective study was conducted over 3 months, including all patients for planned surgery. In the intervention group (I/G), a first MH was performed before the anaesthesia's consultation. When MH was not completed before the anaesthesia's consultation, patients were included in the control group (CG). For every patient, a MH was carried out at admission. Discrepancies between MH at patient's admission and CR, the clinical impact of these discrepancies and the sources used to write the MH were evaluated. 91 patients were included. Discrepancies were found in 56% of the JG and 42% in the CG (p=0.56). Main discrepancies were: missing drug on CR (25% vs. 22%; p=0.71). missing dose (21% vs. 25%; p=0.13) and missing dosage (8% vs. 18%; p=0.06). In the JG, discrepancies with potential significant severity were reduced by half (7% vs. 15%; p=0.26). 2±0.9 sources (average) were consulted to write the MH in the IG and 2.8±0.9 in the CG [p<0.05l. The MH availability before the anaesthesia's consultation does not seem to reduce discrepancies in the CR. This may be explained by the way the MH was elaborated in the CG, using the CR used as source in 75%. However, MH provides more reliable inforrr:tation on treatments for the anaesthetist than previously with a reduction of discrepancies with potential significant severity. However, the medication conciliation at admission process should be re-engineered and CR not considered anymore as a relevant source. In any case, MH has to be updated at patient's admission in order to take account of any undercurrent treatment's modification.

Effectiveness of cleaning of workplace cytotoxic surface.

PURPOSE: To minimize the risk of chronic occupational exposure of antineoplastic drugs, cleaning procedures must be evaluated. This study was conducted to compare the detergent efficiency of cleaning solutions (two hydro-alcoholic solutions, three disinfectants and two detergents) used in different cleaning protocols. METHODS: The central surface of a stainless steel plate (30 × 50 cm) was exposed to a carboplatin solution equivalent to 105,100 ng of platinum. After cleaning according to a standardized protocol, residual platinum contaminations were assayed on 10 × 10 cm sections. RESULTS: After standardized cleaning, the residual quantity of platinum on the surface of the deposit accounted for between 1.0 and >15 % of the initial deposit. Spread of contamination on the plate depended on the cleaning movement and was between 2.1 and 53.9 % of the total quantity on the plate. The two detergents were more efficient (2,793-4,780 ng/plate) than hydro-alcoholic solutions (>20,000 ng/plate). The efficacy of the disinfectant was intermediate (5,891-6,122 ng/plate for solutions and 15,360 ng/plate for pre-soaked gauze). The cleaning protocol was also important with better efficiency of 8 mL of cleaning solution for 1,500 cm(2) (versus 4 mL), sprayed directly on the plate (versus wiping) with no contact time (versus 5 min). CONCLUSION: The efficacy of chemical decontamination of cytotoxic work surfaces depends not only on the cleaning solution used, but also on the cleaning protocol. It is necessary to adapt the protocol to the surface to clean and it must be standardized and validated. This work is an example of an experimental procedure to evaluate the efficacy of cleaning solutions and protocols used at a workstation after exposure to antineoplastic drugs.

Cutaneous side effects associated with sunitinib: an analysis of 8 cases.

OBJECTIVE: Sunitinib is an antineoplastic agent, specifically a tyrosine kinase inhibitor. Thanks to its targeted action, this drug is relatively well tolerated. The main side effects are asthenia, gastrointestinal disturbances, and dermatological effects. The aim of our study was to collect information about dermatological side effects and assess them in patients treated with sunitinib. METHOD: A retrospective study was performed on 8 patients treated with sunitinib between January 2006 and July 2009. RESULTS: Twelve different types of side effects were observed: genital lesion (9), cutaneous eruption (7), hand-foot syndrome (6), yellow discoloration of skin (4), hair depigmentation (4), xerosis (4), pigmented lesion (4), vascular lesion (3), erythema (3), splinter haemorrhage of fingernails (1), facial oedema (1), and pruritus (1). To date vascular and pigmented lesions associated with sunitinib have not been recorded in literature, genital lesions have only been described in the scrotal region. These genital lesions led to discontinuation of treatment by 4 patients in our study. CONCLUSION: Although the risk/benefit ratio is favourable for sunitinib, all health care professionals must be aware of the risk of such adverse events. When genital lesions are observed, dose adjustment is recommended. Thorough clinical examination and patient interviews are necessary to detect these effects.

A limited sampling strategy to estimate individual pharmacokinetic parameters of methotrexate in children with acute lymphoblastic leukemia.

PURPOSE: The objectives of this study were to characterize the population pharmacokinetics of MTX in patients with acute lymphoblastic leukemia (ALL) with ages ranging from 2 to 16 years and to propose a limited sampling strategy to estimate individual pharmacokinetic parameters. METHODS: Seventy-nine children were enrolled in this study; they received 1-4 courses of chemotherapy. MTX was administered at a dose of 5 g/m2. MTX population parameters were estimated from 61 patients (231 courses; age range: 2-16 years). The data were analyzed by nonlinear mixed-effect modeling with use of a two-compartment structural model. The interoccasion variability was taken into account in the model. Eighteen additional patients (70 courses) were used to evaluate the predictive performances of the Bayesian approach and to devise a limited sampling strategy. RESULTS: The following population parameters were obtained: total clearance (CL) = 8.8 l/h (inter-individual variability: 43%), initial volume of distribution (V1) = 17.3 l (48%), k12 = 0.0225 h(-1) (41%), and k21 = 0.0629 h(-1) (24%). The inter-individual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Intercourse variability was limited, with a mean variation of 13.2%. The protocol involving two sampling times, 24 and 48 h after the beginning of infusion, allows precise and accurate determination of individual pharmacokinetic parameters and consequently, it was possible to predict the time at which the MTX concentration reached the predicted threshold (0.2 microM) below which the administration of folinic acid could be stopped. CONCLUSION: The results of this study combine the relationships between the pharmacokinetic parameters of MTX and patient covariates that may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.