The Paris Cancer Institute CARPEM has developed a pharmaceutics cancer program integrating the 3 hospital pharmacies of Cochin, EGP, Necker which are involved in cancer patient care, preclinical and/or clinical research programs. This pharmaceutical research takes place both in Paris hospitals and Paris Universities (e.g. pharmacokinetic, pharmaco-chemistry, clinical pharmacy). On three sites, there are high medical and pharmacy strengths and numerous clinical trials have been managed (for details see annex 1).

In 2019, the pharmaceutical departments took in charge about 5 608 patients treated for cancer including 3 024 new patients. Three centralized antineoplastic agent preparation units housed in each hospital sites involve pharmacist with both strong clinical oncology expertise and pharmacotechnology skills to:

• Before the prescription: implement drug-related protocols, clinical trials and local formularies,
• During the prescription: monitor, detect and prevent harmful drug interaction, adverse reactions, medication error and guidance to the dosage of drugs,
• After the prescription, handle more than 73 131 personalized preparations with quality insurance (including analytical controls) of the preparations before administration to patient,
• Patient care: pharmaceutical consultations for ~450 cancer patients treated by oral therapies with educational, therapeutically and life advices. Early systematic multidisciplinary risk assessment (323 patients; Cochin) before antitumor treatment initiation is also performed.

The strength of these 3 sites is to synergize the pharmaceutical expertise developed by pharmacists to progress on practices, patient care, to ensure the security of drug management from the prescription to the administration and participate to the development of new therapeutic approaches. The recent quality certification of the EGP unit according to ISO 9001 V 2015 obtained in 2019 is an example of this pharmaceutical dynamic.

Clinical research

Research in the Clinical Pharmacy focuses on the personalized relationship between patients and their medications. The fundamental goal is to ensure the safest and the most effective use of medications for all patients. This goal might be accomplished via a clinical study on the care pathway of a patient group to a drug, or through a practice study that looks at a new way to ensure patients are taking their medications as prescribed and reporting any medical problems or lifestyle challenges with their regimens. More recently, data extraction from massive data banking issued from health institution brings a new and complementary approach for clinical pharmacy research developments. This reinforces therapeutics and comprehensive drug management to patients and providers (includes physicians and nurses). Pharmacist intervention outcomes include management of administration errors, adverse drug events (ADEs), and adverse drug reactions (ADRs) and improve health-related quality of life, patient satisfaction and medication appropriateness. Early and systematic detection of drug-drug interactions and multidisciplinary risk assessment has become a priority in our center and in our shared clinical research project (CHOPIN Project CCH/HEGP). Moreover, we have made many methodological contributions in adaptive designs for early phase or small samples in clinical trials. In the last years several publications have stated that the average for the combined success rate at Phase III and submission has fallen to ~50% in recent years. They have shown that bringing two doses forward into phase III testing increased the probability of success and improved the expected net present value. They have stressed out that if the estimation of dose-response curves were better evaluated, phase III confirmatory trials could fail less. Thus, proposing statistical methods to better estimate the dose recommended to further studies is critical. Our research projects focus on how to better estimate the dose-toxicity and dose-efficacy relationships, this is even more complexes in the setting of small samples as in pediatrics and rare diseases. We develop statistical methods for clinical trials and routine data for better understanding how doses, medical decision and observations are linked and what is the best way to estimate them according to covariables and multiple doses administration over time.

Experimental and translational research

The pharmacists involved in this program belong to and collaborate with research teams with a particular emphasis for drug transporters, body barriers and in particular the blood-brain barrier (BBB), the main interface between the blood and the brain parenchyma. The BBB acts both as a physical and a biochemical hindrance to the brain accessibility of many drugs, including anticancer drugs. Drug transporters strictly regulate the pharmacokinetics of compounds into the body, and at the BBB to the primary or metastasis tumor cells. The BBB is also a key feature of the neuro-glio-vascular unit that can affect the prognosis through processes such as neuroinflammation. This research is organized in two main axes. i) First, basic knowledge of the brain cells and the BBB to determine key parameters responsible for both the variability of response or therapeutic failure. This aspect of research also includes the use of molecular and cellular techniques, as well as preclinical investigations. Non-invasive tools such as the nuclear imaging techniques are also preferred to set this research in a translational approach to be applied in Humans. ii) Second, and in accordance with the clinical needs, original pharmaceutical strategies are developed to modulate brain interfaces and bypass the identified impediments, or to vectorize therapeutics to improve their efficacy. A recent illustration of this research is the identification of the molecular mechanisms responsible for the brain efflux of erlotinib, a tyrosine kinase inhibitor, and the resulting impact in vivo (see references and grants).

Pharmaceutical technology and analytical research

Securization of antineoplastic circuit involved in complement to the clinical approaches evocated above a special focus onto the compounding units dealing with two aspects:

• the first is related to pharmaceutical technology instrumentation in order to secure the process compounding itself and a second
• the second is to develop the fastest, simplest analytical methodology insuring the characterization of molecules of therapeutic interest.

For this, detection modes as UV-visible, infrared and Raman spectroscopy, including surface-enhanced Raman spectroscopy (SERS) are involved. Also the detection of toxic drug residues in the working environment using atomic absorption spectrometry and mass spectrometry techniques is implementing in order to protect the working staff. The group’s expertise is based both on the practice of existing analytical techniques for the identification and quantification of molecules for therapeutic purposes and on the development of new analytical and chemometric approaches to meet the need for safety in hospitals (drug management and environmental control).

Moreover, another field of research is to investigate the background and knowledge of the pharmacy technicians by replicating the cytotoxic preparation unit with potential errors. In fact, the global professional risk assessment applied to the central unit of antineoplastic agent preparations is part of a mandatory approach required by the European legislation for workers. It is important to identify the hazardous situations related to the staff activity and then enabled the preparation of a formal plan of occupational prevention.

Study of robotic systems for the compounding of injectable drugs is another field of research. At last, recent efforts have been made to transfer the analytical approaches developed in quality control to bioanalysis.

Some of us due to our practionnal expertise and university function are widely involved in teaching of cancer in Paris University and Paris Saclay University and in several national degrees/master degrees in the field of oncology, to cite:

• Teaching unit of DES for resident students: i) Analytical chemistry, quality control and quality assurance for pharmacy students and pharmacy residents, ii) coordinator of the oncology teaching unit
• Bachelor, professional degree “services client en instrumentation et réactif de Laboratoire” and “vente marketing”.
• Pharmacist diploma: Oncology teaching unit (4th and 6th years), in Pharmacy Faculty of Paris
• DU of Oncology (pharmacist continuing education program)
• Master of Biomedical Informatics: Pharmaco-epidemiology and big data in health courses (4^rd semester) initiation to research.
• General pharmacokinetics and masters of Pharmacokinetics
• Biophysic and Radiopharmacy

Based on our skillness we would like to develop different aspects:

Clinical Pharmacy aspects

• To identify common temporal evolution profiles in prescription data and propose a semi-automated method to these patterns in a clinical data warehouse (HEGP CDW;11,4 million drug prescriptions and pharmacist validations) and link with other data warehouse (APHP, SNIIRAM). For example, findings from cohort: i) Oral chemotherapies are associated with what use of care? Ii) Adverse effects of thiazide are associated with risk of skin cancer?
• To explore determinants of the inter individual variability, pharmacokinetic variability and potential drug-drug interactions

Pharmaceutical technology and analytical aspects

• Exploration of surface-enhanced Raman spectroscopy for Therapeutic Purposes: from Analysis of Pharmaceutical Formulations to analysis in biological matrices (TDM: Therapeutic Drug Monitoring).
• Environmental cytotoxic contaminations: an exposure assessment program for hospital staff
• Robotic systems for chemotherapy preparations: qualification and evaluation
• Implementation and evaluation of RFID tag for chemotherapy preparations traceability
• Barcode security of the chemotherapy circuit to reduce administration errors: Oncosafety project

Experimental and translational research

Pharmacological or nutritional strategies, such as the modulation of the activity of drug transporters and specific diets, or physical approaches like BBB disruption using focused ultrasounds, were also investigated to improve the brain delivery/activity of anticancer drugs. Pharmaceutical strategies to better treat diffuse intrinsic pontine glioma, a rare pediatric disease, are under investigation.

The selected following publications highlighted the strength of this research and the strong collaboration between pharmacists, physicians and researchers taking part of pharmaceutics cancer program.

Clinical Research:

1. Ollier A, Morita S, Ursino M, Zohar S. An adaptive power prior for sequential clinical trials – Application to bridging studies. Stat Methods Med Res. 2019 Nov 15:962280219886609. doi: 10.1177/0962280219886609.
2. Aupiais C, Alberti C, Schmitz T, Baud O, Ursino M, Zohar S. A Bayesian non-inferiority approach using experts’ margin elicitation – application to the monitoring of safety events. BMC Med Res Methodol. 2019 Sep 18;19(1):187. doi: 10.1186/s12874-019-0826-5.
3. Boulet S, Ursino M, Thall P, Landi B, Lepère C, Pernot S, Burgun A, Taieb J, Zaanan A, Zohar S, Jannot AS. Integration of elicited expert information via a power prior in Bayesian variable selection: Application to colon cancer data. Stat Methods Med Res. 2019 Apr 9:962280219841082. doi: 10.1177/0962280219841082.
4. Daupin, G. Perrin, C. Lhermitte-Pastor, MC. Loustalot, S. Pernot, V. Savoldelli, C. Thibault, B. Landi, B Sabatier, E. Caudron. Pharmaceutical interventions to improve safety of chemotherapy-treated cancer patients : A cross-sectional study. J Oncol Pharmacy Practice, 2019; 25-5:1195-203.
5. Berdot, A. Boussadi, A. Vilfaillot, M. Depoisson, C. Guihaire, P. Durieux, L. M Lê, B. Sabatier. Barriers and lessons learned from the integration and the use of a commercial barcode-assisted medication dispensing system in a teaching hospital. Applied Clinical Informatics, 2019 ; 00:1–14.
6. Loustalot MC., Berdot S., Sabatier P., Durieux P., Perrin G., Karras A., and B. Sabatier. Impact of interventions by pharmacists collected in a computerized physician order entry context: a prospective observational study with a 10-year reassessment. Swiss Medical Weekly, 2019;149:w20015
7. Hirsch L, Bellesoeur A, Boudou-Rouquette P, Arrondeau J, Thomas-Schoemann A, Kirchgesner J, Gervais C, Jouinot A, Chapron J, Giraud F, Wislez M, Alexandre J, Blanchet B, Goldwasser F. The impact of body composition parameters on severe toxicity of nivolumab. Eur J Cancer. 2019 Nov 30 ;124 : 170-177
8. Cohen R, Preta LH, Joste V, Curis E, Huillard O, Jouinot A, Narjoz C, Thomas-Schoemann A, Bellesoeur A, Tiako Meyo M, Quilichini J, Desaulle D, Nicolis I, Cessot A, Vidal M, Goldwasser F, Alexandre J, Blanchet B. Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours. Br J Clin Pharmacol. 2019 Jun ;85(6) : 1227-1238
9. Jouinot A, Royer B, Chatelut E, Moeung S, Assié G, Thomas-Schoemann A, Bertherat J, Goldwasser F, Blanchet B. Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study. Endocr Connect 2018 Dec 1;7(12): 1409-1414
10. Bellesoeur A, Thomas-Schoemann A, Allard M, Smadja D, Vidal M, Alexandre J, Goldwasser F, Blanchet B.
11. Pharmacokinetic variability of anticoagulants in patients with cancer-associated thrombosis: Clinical consequences.Crit Rev Oncol Hematol. 2018 Sep;129:102-112.

Experimental and translational research

12. Chaves C., X. Decleves, M. Taghi, Menet MC., Lacombe J., Varlet P., Olaciregui N, Carcaboso A., Cisternino S. Characterization of the blood-brain barrier integrity and the brain transport of SN-38 in orthotopic xenograft rat model of diffuse intrinsic pontine glioma. (submitted)
13. Matet A., Behar-Cohen F., Cassoux N., Declèves X., Cisternino S. Retinal and choroidal cancers: Blood-retinal barriers considerations in ocular chemotherapy. In “Drug Efflux Pumps in Cancer Resistance Pathways: From Molecular Recognition and Characterization to Possible Inhibition Strategies in Chemotherapy”, Elsevier, Academic Press, Vol 7, 2020, 303-335. doi.org/10.1016/B978-0-12-816434-1.00010-3.
14. Tournier N, Bauer M, Pichler V, Nics L, Klebermass EM, Bamminger K, Matzneller P, Weber M, Karch R, Caillé F, Auvity S, Marie S, Jäger W, Wadsak W, Hacker M, Zeitlinger M, Langer O. Impact of P-Glycoprotein Function on the Brain Kinetics of the Weak Substrate 11C-Metoclopramide Assessed with PET Imaging in Humans. J Nucl Med. 2019 Jul;60(7):985-991. doi: 10.2967/jnumed.118.219972. Epub 2019 Jan 10.
15. Goutal S, Gerstenmayer M, Auvity S, Caillé F, Mériaux S, Buvat I, Larrat B, Tournier N. Physical blood-brain barrier disruption induced by focused ultrasound does not overcome the transporter-mediated efflux of erlotinib. J Control Release. 2018 Dec 28; 292:210-220. doi: 10.1016/j.jconrel.2018.11.009. Epub 2018 Nov 8.
16. Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats. Amor D, Goutal S, Marie S, Caillé F, Bauer M, Langer O, Auvity S, Tournier N. EJNMMI Res. 2018 Aug 16;8(1):81. doi: 10.1186/s13550-018-0434-0.
17. Auvity S, Caillé F, Marie S, Wimberley C, Bauer M, Langer O, Buvat I, Goutal S, Tournier N. P-Glycoprotein (ABCB1) Inhibits the Influx and Increases the Efflux of 11C-Metoclopramide Across the Blood-Brain Barrier: A PET Study on Nonhuman Primates. J Nucl Med. 2018 Oct;59(10):1609-1615. doi: 10.2967/jnumed.118.210104. Epub 2018 May 10.
18. Tournier N, Goutal S, Auvity S, Traxl A, Mairinger S, Wanek T, Helal OB, Buvat I, Soussan M, Caillé F, Langer O. Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood-Brain Barrier: A PET Study on Nonhuman Primates. J Nucl Med. 2017 Jan;58(1):117-122. doi: 10.2967/jnumed.116.178665. Epub 2016 Aug 4.

Pharmaceutical technology and analytical research

19. Jobard, ML. Brandely-Piat, F. Chast, R. Batista. Qualification of a chemotherapy-compounding robot. J Oncol Pharm Practice, 2019; 0(0):1-13
20. Dubray Q, Diallo T, Loeuillet R, Andre E, Fauqueur AS, Poil S, Thromas N, Secretan PH, Cisternino S, Schlatter J. Occupational risks evaluation in a centralized antineoplastic agent preparation unit. SAGE Open Med. 2019 Jul 27;7:2050312119866970. doi: 10.1177/2050312119866970. eCollection 2019.
21. Cotteret C, Marry S, Loeuillet R, Videau M, Cisternino S, Schlatter J. A virtual centralized cytotoxic preparation unit simulation to evaluate the pharmacy staff knowledge.J Oncol Pharm Pract. 2019 Jul;25(5):1187-1194. doi: 10.1177/1078155218821426. Epub 2019 Jan 9.
22. Schlatter J, Nguyen D, Zamy M, Kabiche S, Fontan JE, Cisternino S. Safety of intrathecal route: focus to methylprednisolone acetate (Depo-Medrol) use. Eur Spine J. 2019 Jan;28(1):21-30. doi: 10.1007/s00586-017-5387-x
23. Noé G, Bellesoeur A, Golmard L, Thomas-Schoemann A, Boudou-Rouquette P, Tiako Meyo M, Puszkiel A, Arrondeau J, Alexandre J, Goldwasser F, Blanchet B, Vidal M. Differential Kinase Activation in Peripheral Blood Mononuclear Cells from Non-Small-Cell Lung Cancer Patients Treated with Nivolumab. Cancers (Basel). 2019 May 31;11(6)
24. Jaccoulet, T. Daniel, P. Prognon, E. Caudron. Forced degradation of monoclonal antibodies after compounding: impact on routine hospital quality control. J Pharm Sci 108-10 2019, 3252-61.
25. Lê, M. Berge, A. Tfayli, JY Zhou, P. Prognon, A. Baillet-Guffroy, E. Caudron. Rapid discrimination and quantification analysis of five antineoplastic drugs in aqueous solutions using Raman spectroscopy. Eur J Pharm Sci 111 2018 158-66.
26. Jaccoulet, C. Boughanem, L, Auduteau, P. Prognon, E. Caudron. UV spectroscopy and least square matching for high throughput discrimination of taxanes in commercial formulations and compounded bags. Eur J Pharm Sci 123 2018 143-52.
27. Jaccoulet, A. Schweitzer-Chaput, B. Toussaint, P. Prognon, E. Caudron. Simple and ultra-fast recognition and quantitation of compounded monoclonal antibodies: Application to flow injection analysis combined to UV spectroscopy and matching method.  Talanta 187 2018 279-86.

Annex 1:  Main indicators of clinical activities

If you are interested by this program and want to candidate to a PhD, post doctoral position, contact the leader

Dr Brigitte Sabatier