Jean-Baptiste Rey

Prevention of cisplatin nephrotoxicity : state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care

Antineoplastic drugs used in the treatment of cancers present with variable renal tolerance profiles. Among drugs with a potential for renal toxicity, platinum salts, and especially cisplatin is a well-known agent that may induce acute and chronic renal failure. The mechanisms of its renal toxicity and the means of its prevention are presented in this article which represent the Clinical Recommendation from the Special Interest Group on Cancer Care of the European Society of Clinical Pharmacy (ESCP).

Contribution of high-performance thin-layer chromatography to a pharmaceutical quality assurance programme in a hospital chemotherapy manufacturing unit

The Department of Clinical Pharmacy (DCP) in the Institut Gustave-Roussy (IGR) is equipped with a high-performance thin-layer chromatography (HPTLC) analytical platform. One of the numerous possible uses of HPTLC is post-production quality control of chemotherapy manufacturing. After 3 years of existence, routine validation of manufactured batches has attained considerable maturity: 24 cytotoxic agents can be controlled in terms of identity, purity and concentration. Approximately 50% of the sampled preparations are assessed. More than 97% were within specifications, 1.6% were not, probably due to incorrect homogenization before sampling; and 1% were not evaluable. Using HPTLC in a hospital manufacturing unit contributes to quality assurance programmes such as accreditation to which the IGR DCP is now committed but also ISO 9001:2000 certification concerning the chemotherapy manufacturing unit.

Microbial growth tests in anti-neoplastic injectable solutions.

The Institut Gustave-Roussy (IGR) Department of Clinical Pharmacy (DCP) ensures the annual preparation of about 30 000 therapeutic batches of anti-neoplastic agents.High performance thin-layer chromatography (HPTLC) allows postproduction quality control of these batches.Although the centralized chemotherapy manufacturing unit has been recently ISO 9001:2000 certified, it was considered to improve the quality level of manufactured batches even further.The viability of micro-organisms (bacteria and fungi) in appropriate sterile media containing various anti-neoplastic agents at therapeutic concentration was assessed to demonstrate the lack of contamination during our manufacturing process in the isolator.After 14 days of incubation in these media, the results show the absence of contamination of the manufactured batches.This leads us to conclude that using sterile drugs and sterile medical devices in a sterile isolator allows the manufacture of sterile therapeutic batches with excellent confidence.

Colony stimulating factors (CSF) biosimilars. Progress

Biosimilars are equivalent drugs for other biotechnological drugs for which patent has expired. These biopharmaceuticals are often looked upon as simple copies of parent drugs whose goal is solely to potentially generate costs savings. The expansion of available drugs is a subject of attention, criticism and quarrels, often related to a lack of product knowledge. These drugs are copies but need scientific development that must meet many strict rules. Many questions arise in connection with the marketing of several biosimilar drugs in the field of hematopoietic growth factors of white and red cells. Many of them should be discussed.

Nouvelle perspective de traitement dans le cancer bronchique non à petites cellules (CBNPC). Place de l’afatinib : un inhibiteur oral et irréversible de la famille ErbB

Tyrosine kinase inhibitors (TKI) that block epidermal growth factor receptor (EGFR) pathway have demonstrated a clinical benefit for patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. The currently available TKI (gefitinib and erlotinib) are EGFR reversible inhibitors. Afatinib is an oral, irreversible ErbB family blocker that covalently binds and blocks signaling from EGFR (ErbB1), HER2 (ErbB2) and ErbB4. The compound inhibits also the transphosphorylation of ErbB3. With this mode of action, afatinib is thought to have a mechanistic advantage over EGFR blockade alone, in that it provides a sustained, covalent inhibition of ErbB homo- and hetero-dimers. In the pivotal LUX-Lung 3 study, afatinib demonstrated a prolonged progression free survival over standard pemetrexed plus cisplatin chemotherapy (11.1 versus 6.9 months; HR = 0.58, 95% CI: 0.43-0.78; P = 0.001) in EGFR mutation positive NSCLC patients. The compound has recently been granted a marketing authorization (MA) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutation(s) and EGFR TKI-naive. In this paper are summarized the efficacy and safety data in this indication.

Gestion des antalgiques chez les patients insuffisants rénaux en cancérologie

Pain is frequent in cancer patients. To date, there is a consequent therapeutic arsenal so to manage pain; the different treatment strategies are the subject of various recommendations. Patients with cancer also frequently suffer from renal insufficiency, and this comorbidity may disrupt or jeopardize the analgesic strategy by changing the risk-benefit ratio of treatment options. This article provides recommendations for the use of drugs used for pain treatment after pointing out: 1) etiological and pathophysiological elements of pain; 2) therapeutic strategies for pain management; 3) data regarding renal failure in cancer and; 4) a point on drugs pharmacokinetics.

Renovascular safety of sunitinib in renal cell carcinoma: The prognostic value of hypertension and proteinuria

Background The potential prognostic value of hypertension and proteinuria of anti- vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in metastatic renal cell carcinoma (mRCC). The objectives were to (i) assess the prevalence of proteinuria and hypertension at baseline; (ii) their incidence under anti-VEGF drug treatment; and (iii) evaluate a possible link with overall survival. Methods Patients from 8 centers were included between 2009 and 2011 with a follow-up of 1 year. They were naïve of any previous anti-VEGF drug treatment and planned to be started on one. The results of the group of patients with mRCC receiving sunitinib are presented. Results A total of 1,124 patients were included, among whom 137 had mRCC and 112 received sunitinib. At inclusion, hypertension prevalence was 44%, proteinuria 16%, hematuria 8%, mean modification of diet in renal disease (MDRD) formula 69 mL/min/1.73m2. The incidence of de novo proteinuria and hypertension during follow-up was 75% and 21%, respectively. Among patients with de novo proteinuria, 76% afterwards improved/normalized. Mean MDRD was 72 at the end of follow-up. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria or hypertension were not associated with OS in mRCC patients treated with sunitinib. Conclusions These results showed that (i) hypertension and proteinuria were frequent at baseline in mRCC patients; (ii) de novo hypertension and proteinuria frequently occur under sunitinib treatment; and (iii) neither hypertension nor proteinuria, either at baseline or de novo, were associated with overall survival in our cohort of “real-life” patients.

Cancer du sein hormonodépendant et administration discontinue des inhibiteurs de l’aromatase chez la femme ménopausée : vers un profil de tolérance amélioréRationnel pharmacologique

Une proportion importante de patientes menopausees traitees par inhibiteurs de l’aromatase pour leur cancer du sein rapporte des effets secondaires, notamment des douleurs osseuses. Chez ces patientes, les difficultes a traiter la douleur et a en identifier clairement les causes peuvent conduire a l’arret du traitement. Le vieillissement est associe a des modifications physiologiques qui peuvent avoir un impact sur la pharmacocinetique des medicaments. L’elimination peut etre modifiee, avec une reduction de la clairance des medicaments, resultant en une augmentation de l’exposition au medicament, traduite par une aire sous la courbe augmentee. L’augmentation rapportee de l’exposition aux inhibiteurs de l’aromatase etant d’environ 50 %, un schema posologique discontinu avec une administration tous les deux jours pourrait entrainer une exposition au medicament similaire au schema quotidien habituel.

Rôle du pharmacien hospitalier en soins oncologiques de support

Les soins de support en cancerologie necessitent la mise en commun de competences variees. Au travers de ses connaissances du medicament, le pharmacien est le « partenaire naturel » des medecins qui prescrivent et des soignants qui administrent les produits pharmaceutiques aux patients. De meme, au travers des interventions aupres des patients dans son domaine d’expertise, le pharmacien participe au bon usage et a l’amelioration de la qualite des soins en cancerologie (en hospitalisation ou a l’interface avec les pharmaciens d’officine).

Abstract P1-12-15: Intermittent dosing of aromatase inhibitors (AI) to improve tolerance in post-menopausal women

Clinical rationale: A significant proportion of post-menopausal, patients treated with AI reports side-effects, especially bone pain. In such patients, the difficulties to treat pain and to clearly identify its causes may lead to treatment discontinuation. Individual cases reported an improvement in AI tolerance when dosage is reduced. The aim of this work was thus to analyse pharmacological data in order to validate this concept ie . ensuring that intermittent dosing would not result in a possibly deleterious under-dosing of AI. Pharmacological rationale: Ageing is associated with physiological modifications that may impair drug pharmacokinetics (PKs). The elimination can be altered, with decreased drug clearance (CL), resulting in an increased exposure to the drug, reflected by increased AUCs. Drugs benefit-risk balance can thus be modified. The major sources of PKs alterations in the elderly are hepatic and/or renal impairments (HI/RI). It has been shown that AI PKs are altered in the elderly and/or in case of HI or RI. Exemestane AUC is increased 3-fold in the elderly and in case of RI [1,2]. Letrozole AUC can double in case of HI [3] and a 42%-increase has been reported in the elderly [4]. The renal CL of anastrozole is reduced by 50% in RI, resulting in a 10% decrease in total body CL. In HI, total body CL is 30% lower as compared to normal [5]. These data demonstrate that elderly patients may be overexposed to AI when treated with the usual dosage, resulting in safety issues occurring in some patients. As a result, a dosage adjustment approach could help prevent over-exposure and reduce side-effects incidence/severity. Proof-of-Concept studies: The reported increases in AI exposure being around 50%, an intermittent dosing schedule of 1 administration every other day could result in a similar drug exposure as compared to the usual daily schedule. AI elimination half-lives in the absence of any alteration also are consistent with this dosing schedule (24, 48, and 50 hours for exemestane, letrozole, and anastrozole, respectively). In order not to impair plasma concentrations, such a schedule is preferably suggested as compared to a half-dose daily schedule. Prospective studies are needed, in which the PKs, efficacy, and safety of this intermittent dosing schedule should be conducted. References: [1] Aromasin® FDA Labeling Information; 2013 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020753s014lbl.pdf; accessed 04/29/2014 [2] Jannuzzo MG, et al. Cancer Chemother Pharmacol. 2004; 53(6): 475-81. [3] Femara® FDA Labeling Information; 2014 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020726s027lbl.pdf; accessed 04/29/2014 [4] Pfister CU, et al. Effect of age and single versus multiple dose pharmacokinetics of letrozole (Femara) in breast cancer patients. Biopharm Drug Dispos. 2001; 22(5): 191-7. [5] Arimidex® FDA Labeling Information; 2013 labeling revision; http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020541s027lbl.pdf; accessed 04/29/2014. Citation Format: Vincent Launay-Vacher, Remy Salmon, Jean-Baptiste Rey. Intermittent dosing of aromatase inhibitors (AI) to improve tolerance in post-menopausal women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-15.