Developing an innovative 3D printing platform for production of personalised medicines in a hospital for the OPERA clinical trial
Abstract
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.
Introduction
Breast cancer is the most frequently diagnosed cancer in women, causing the most deaths globally (Wilkinson and Gathani, 2022). Upon diagnosis, standard breast cancer therapy is based on chemotherapy, surgery, and radiotherapy, followed by a 5-to-10-year hormonotherapy maintenance phase (Trayes and Cokenakes, 2021). Adherence to the hormonotherapy in the maintenance phase is crucial for full recovery and prevention of relapse (Han, Wu et al. 2022).
Tamoxifen is the standard hormonotherapy in the maintenance phase for pre-menopausal women (Osborne, 1998). Tamoxifen is a prodrug mainly hepatically metabolised by the enzyme Cytochrome P450 2D6 (CYP2D6) to generate the active metabolite, endoxifen (Goetz, Kamal et al. 2008). Metabolism of tamoxifen is highly sensitive to CYP2D6 polymorphism, leading to great variation in endoxifen plasma levels and adverse drug reactions (Brooks et al., 2018, Chan et al., 2020). Some of the most frequently experienced adverse effects include severe hot flashes, grade 2–3 musculoskeletal pain, and decreased libido (de Souza and Olopade, 2011). These can be severely disabling and are often a main reason for suboptimal tamoxifen adherence. Additional therapy with antidepressants is recommended to alleviate the side effects, such as venlafaxine for treatment of hot flashes and duloxetine for reduction of musculoskeletal pain (Boekhout et al., 2011, Henry et al., 2018). However, low tamoxifen adherence remains an issue and is a major cause for early relapse and recurrence of breast cancer in recovering women (Mao, Hachem et al. 2020).
A recent clinical study carried out in a large cohort in France concluded that targeted interventions such as reduction of medicines administration to once daily and dose adjustments of tamoxifen and venlafaxine or duloxetine would increase adherence to tamoxifen therapy and thereby reduce breast cancer recurrence rates (Pistilli, Paci et al. 2020). Currently, tamoxifen tablets of 10 or 20 mg are prescribed as immediate release oral dosage forms (Dickschen, Willmann et al. 2012), whereas venlafaxine doses of 37.5 to 75 mg and duloxetine doses of 30 to 60 mg are prescribed as extended release and delayed release oral dosage forms, respectively (Nichols, Focht et al. 2011). Manufacturing combination dosage forms of tamoxifen and either venlafaxine or duloxetine through conventional methods is impractical due to both the release concerns and dose adjustments of each active pharmaceutical ingredient (API).
Three-dimensional (3D) printing is a transformative technology capable of producing bespoke medicines (printlets) with varying drug doses as well as products containing multiple APIs with different release requirements (Khaled et al., 2015, Keikhosravi et al., 2020, Awad et al., 2023, Tracy et al., 2023, Yang et al., 2023, Patel et al., 2024). As such, 3D printing offers a possible solution for targeted tamoxifen interventions such as differentiated doses and combination therapies to increase adherence among recovering breast cancer patients. Moreover, 3D printing offers a rapid method of production for small-batch medicines manufacturing, making it particularly suitable for personalised dosages and an enabler of clinical trials. To date, several 3D printing technologies for pharmaceuticals exist, with the most clinically advanced technologies being fused deposition modelling (FDM), direct powder extrusion (DPE), semisolid extrusion (SSE), binder jetting, and inkjet printing. Whilst implementation of 3D printing in hospital pharmacies is still in its infancy and challenges relating to technical feasibility and printing time are still being addressed (Annereau, Toussaint et al. 2021), a shift in treatment paradigm is anticipated and the first clinical studies assessing bioequivalence, treatment preferences, and printlet disintegration in vivo have already been published (Goyanes et al., 2019, Lyousoufi et al., 2023, Seoane-Viaño, Pérez-Ramos et al. 2023).
The aim of this work was to develop single dosage units comprising tamoxifen in 20 mg combined with either venlafaxine in 37.5 or 75 mg, duloxetine in 30 or 60 mg, or a placebo for usage in the OPERA clinical trial. Requirements for the developed medicines included release behaviour for each API (immediate tamoxifen release according to USP monograph for conventional tablets, and maintained extended venlafaxine and delayed duloxetine release), stability for up to one year of storage, as well as a minimum production rate of 200 dosage units per hour. To accomplish this, the M3DIMAKER 2 3D printer was employed as an innovative and versatile capsule filling platform. Firstly, the tamoxifen pharma-ink (printing feedstock) was deposited via SSE followed by the dispensing of venlafaxine or duloxetine pellets through a novel printhead. The printed medicines were produced in the department of clinical pharmacy in Gustave Roussy according to French compounding regulations and are part of the clinical trial OPERA (Odyssea PERsonalized Approach) which requires the production of more than 40,000 dosage units to investigate targeted tamoxifen interventions on patient adherence among 200 breast cancer patients. This study demonstrates the feasibility of producing multi-active dosage units containing tamoxifen through a pharmaceutical 3D printer in a hospital pharmacy at high production rates enabling a clinical trial to improve tamoxifen adherence in breast cancer patients.
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Materials
Tamoxifen citrate was provided by Hepartex® (Saint-Cloud, France). Duloxetine and venlafaxine were purchased from Lilly (Neuilly-sur-Seine, France) and Zentiva (Paris, France) companies, respectively. White/green size 1 capsules were provided by Cooper® (Melun, France). Polyethylene glycol 4000 (PEG 4000) Emprove® was provided by Merck (Darmstadt, Germany). Commercial dosage forms of tamoxifen, duloxetine, venlafaxine and DBCaps AAA masking were provided by Teva.
Lucas Denis, Anna Kirstine Jørgensen, Thomas Fleury, Emmanuel Daguet, Inès Vaz-Luis, Barbara Pistilli, André Rieutord, Abdul W Basit, Alvaro Goyanes, Maxime Annereau, Developing an innovative 3D printing platform for production of personalised medicines in a hospital for the OPERA clinical trial, International Journal of Pharmaceutics,
2024, 124306, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124306.
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