Subcutaneous administration of rituximab

Rituximab is a therapeutic monoclonal antibody that targets B lymphocytes after binding to the membrane antigen CD20. It has been marketed since 1997 in the United States and since 1998 in Europe, and was first approved as a single-agent therapy of relapsed follicular B-cell non-Hodgkin lymphoma. Since then, other indications have been obtained with chemotherapy (sometimes referred as chemoimmunotherapy) both in indolent and aggressive forms of B-cell non-Hodgkin lymphomas. Moreover, its use has been extended outside oncology in the treatment of rheumatoid arthritis, granulomatosis with polyangiitidis and microscopic polyangiitidis. It is also prescribed off-label in various steroid-resistant autoimmune diseases.

Rituximab is given intermittently (every 1–12 weeks) by intravenous (IV) infusion over 2h–4.5h in the hospital setting, at a dose based on body size (375mg/m² in lymphomas, granulomatosis, microscopic polyangiitidis and up to 500mg/m² in chronic lymphocytic leukaemia) and at a fixed dose (1g) in rheumatoid arthritis. To avoid fatal infusion reactions, rituximab must be delivered at a progressive rate with increments every 30 minutes. Thus, to facilitate the administration, a subcutaneous (SC) formulation has been developed by the manufacturer. SC rituximab was approved in Europe in March 2014 with a narrower labelling compared with the intravenous form (only patients with B-cell non-Hodgkin lymphoma except those with relapsed or refractory follicular lymphoma) and a fixed-dose regimen (1400mg). Consequently, this formulation will not entirely replace the IV form, meaning that both forms will have to coexist in hospital pharmacies.

SC delivery is performed in the hypodermis (generally abdomen, upper arm, thigh) as a short injection (few seconds or minutes). When compared with the IV route, the benefits are the limitation of infectious problems and the possibility of ambulatory treatment and self-administration in educated patients. It brings convenience for patients and the medical staff and requires less pharmaceutical preparation. However, for pain reasons, the volume of injection has to be limited (1–5ml), necessitating the use of concentrated formulations and excipients that facilitate administration. Furthermore, the absolute bioavailability may be less than 100% because a part of the drug is degraded or lost in the subcutaneous tissue during the absorption phase meaning that a higher dosage may be needed when compared to the intravenous route. Among monoclonal antibodies, some are already administered by the subcutaneous route in various therapeutic areas such as autoimmune diseases, asthma, bone diseases and cancer (trastuzumab and rituximab).¹

The SC formulation of rituximab is 12-fold more concentrated than the intravenous formulation and contains 1400mg in 11.7ml integrating recombinant human hyaluronidase (10,000 IU) an enzyme that temporarily degrades the extracellular matrix and facilitates absorption of large volumes. SC rituximab must be injected in the abdomen. With regards to the potential advantages of subcutaneous injection, this formulation remains administered by a healthcare professional in the hospital setting (currently, no ambulatory treatment and no self–administration). In addition, the treatment must be initiated by the IV route to enable the interruption of the perfusion in case of severe reaction. However, the SC injection duration is much more rapid: five minutes instead of 2h–4.5h for the IV perfusion. Furthermore, the preparation is more convenient since it is ready to use (no dilution) and all the vial has to be administered (fixed dose of 1400mg whatever the size of the patient).

To obtain comparable clinical activity to IV rituximab, the development of the SC formulation had to determine the bioavailability (to set the dosage) and to examine the possibility of a fixed dose (more convenient for SC delivery and more practical because the body surface area-based dosing strategy has not been proved to be better clinically than fixed dosing in adult patients).

This was explored based on the non-inferiority of the pharmacokinetic exposure assessed by the trough plasma concentrations (pre-dose concentration).² First, various doses based on body surface area (375, 625 and 800mg/m²) of SC rituximab were tested to achieve comparable trough plasma concentrations as IV injection (375mg/m²) in four groups of patients with follicular lymphoma (in all, 124). A pharmacokinetic model estimated that non-inferior trough concentrations could be obtained after injecting an SC dose between 625 and 800mg/m². In addition, the absolute bioavailability of SC rituximab was 65%, in the range of those of other monoclonal antibodies (50–80%). Second, a mathematical simulation found that a fixed dose of 1400mg was comparable to the body size-based IV dose of 375mg/m² in terms of pharmacokinetic profile. When tested in 154 patients, it was reported that trough plasma concentration of rituximab following SC injection (1400mg) was non-inferior to that obtained after an IV perfusion of 375mg/m².

IV and SC formulations of rituximab have been compared in a non-inferiority, multicentre, randomised trial that included 127 adult patients with untreated follicular lymphoma.³ The treatment plan comprised two phases: one associating rituximab with chemotherapy every three weeks for eight cycles (called induction) and a second one, in case of response, consisting of single-agent rituximab given every eight weeks for two years (called maintenance).  Rituximab (375mg/m²) was first administered IV to all patients and then either IV (375mg/m²) or SC (fixed dose of 1400mg) every three weeks for seven cycles with chemotherapy and then every eight weeks for two years. In the stage 1 of the trial, pharmacokinetics, safety and efficacy (response rate) were assessed.

The SC formulation was judged non-inferior with respect to the geometric mean trough blood concentrations measured after the first seven cycles (IV: 83.13µg/ml; SC: 134.58µg/ml; ratio 1.62, 90% CI 1.36–1.94). Interestingly, both regimens showed similar variability of the trough concentration (around 40%) meaning that body surface area based dosing did not optimise pharmacokinetic exposure (that is, did not decrease interindividual variability). After a median follow-up of 8.7 months, preliminary tolerance data indicated that, overall, neutropenia (imputable to the phase of co-administration of rituximab with chemotherapy) was the most severe side effect (> grade 3), occurring in 22% and  26 % of the IV and SC groups, respectively. More side effects (mostly grade 1–2) relative to the administration were found in the SC group (50%) than in the intravenous group (32%). Indeed, in what regards local tolerance, 10% of the patients had injection site erythema following SC administration versus none in patients in the IV group. Objective responses (including complete and partial) after independent review were similar in both groups (88% in the IV group and 86% in the SC group). Additional data regarding safety and efficacy are awaited (stage 2 of the study) as well as the results of another randomised trial evaluating patient preference for either SC or IV rituximab.

The main benefits of the SC formulation are the convenience of preparation (no dilution and no adjustment to the body size of the patient) and the very short duration of administration in the abdomen (five minutes). SC delivery may also avoid the use of central venous access in case of single-agent therapy (maintenance treatment of follicular lymphoma).

However, this formulation does not replace IV due to the restricted indications and to the fact that all treatments must be initiated by the IV route for safety reasons. The coexistence of the two formulations with different excipients and strengths at the hospital pharmacy complicates the treatment (first administration based on body size and the following at a fixed dose) and may lead to medication errors. In addition, the SC formulation must be administered by a healthcare professional (no self-administration) and still necessitates premedication before administration (as the IV formulation) with acetaminophen, antihistamine and glucocorticoid (if not included in the treatment) to avoid fatal reactions.

From an economic point of view, the SC formulation may reduce healthcare costs in terms of staff time and reduce patient treatment time. A recent study by Rule et al⁴ showed that total active staff time associated with administration of IV rituximab was 223.3 min (95% CI 218.0–228.7) versus 48.5 min (95% CI 45.5–51.6) for SC rituximab, a saving of 174.8 min (95% CI 172.5–177.1) per session. Patient time in the treatment room was 263.8 min (95% CI 236.6–294.3) for IV rituximab and 70.0 min

(95% CI 57.1–87.2) for SC rituximab, per session. The SC formulation reduced total mean staff costs by £115.17 (95% CI 98.95–136.93) per session. Differing monitoring scenarios during infusion consistently showed time and cost savings for SC rituximab.

Switching from IV to SC rituximab could increase treatment room capacity and patient throughput, as well as improving the patient experience.