Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume

Figures & data

Table 1. Comparisons between IV and SC formulations.

Outcome	IV	SC
Bioavailability	100% bioavailability^Citation11	Less than 100% bioavailability^Citation11
Efficacy	Preferred for conditions that are acute or require a high Cmax for therapeutic effect^Citation12	Preferred for chronic conditions; suboptimal for conditions that require a high Cmax for therapeutic effect^Citation12
Safety	Cmax-related adverse events are observed^Citation12	SC dosing has demonstrated safety profile improvements with biologics^Citation13,Citation14 and fewer dosing errors due to fixed dosing with SC biologics.^Citation15 Compared with IV dosing, SC administration decreases peak cytokine levels, which suggests a potential safety benefit for patients due to a subtler immune activation.^Citation16
Formulation	Low concentration due to a high dose volume and high-volume capacity in the delivery method^Citation5,Citation7,Citation8	The common practice is to reformulate to a high-concentration formulation since a high dose volume is required and traditional combination products (PFS/autoinjector) have a low volume capacity.^Citation17 This can be circumvented by using alternative SC delivery devices such as OBDS.
Drug container	Vial mixed into a fluid bag	PFS, autoinjector, or OBDS*
Time and motion	Set-up and administration take much longer and require healthcare provider oversight^Citation18–20 Chair time** Daratumumab: 238 minutes (3.97 hours) Rituximab: 180.9 minutes (3.02 hours) Trastuzumab: 75.5 minutes (1.26 hours)	Substantial improvements in time and motion for treatments that have transitioned from IV to SC^Citation19,Citation20 Chair time Daratumumab: 8.1 minutes (0.14 hours) Rituximab: 8.3 minutes (0.14 hours) Trastuzumab: 20.9 minutes (0.35 hours)
Patient preference	Not preferred by patients^Citation21–23	Preferred by patients due to improved quality of life, self-administration, and a wider range of anatomical site options^Citation21–23
Site of care	Administered in a more costly site of care (hospital/infusion center/home infusion)^Citation24,Citation25	Options in the site of care with potential for patient self-administration, which is the site of care with the lowest cost^Citation24,Citation25
Provider preference	Not preferred by providers^Citation26,Citation27	Preferred by providers^Citation26,Citation27 Improved patient adherence, feasible in patients with poor venous access, decreased burden on healthcare providers due to increased clinic throughput, and lower drug delivery-related costs and resource requirements^Citation6,Citation7,Citation12,Citation28,Citation29

*Volume capacity varies with autoinjectors having the lowest and OBDS the greatest capacity. **Lack of infusion chair capacity is a global challenge. Abbreviations: IV, intravenous; OBDS, on-body delivery system; PFS, prefilled syringe; SC, subcutaneous.

Table 2. High-volume mAb formulations for SC delivery.

Company	Brand Name	Drug Name	Approval Year	Delivery Method	Needle Gauge	Volume and Time	Concentration
CSL Behring	HIZENTRA®	Immune globulin infusion 20% (human)	2010	SC syringe pump	24 or lower	Volumes vary by disease and weight and may be up to 100 mL	200 mg/mL
CSL Behring	HYQVIA®	Immune globulin infusion 10% (human) with hyaluronidase	2014	Peristaltic pump or syringe pump	24	1–2 mL per minute for up to 3 hours (median 2 hours)	100 mg/mL
Amgen	Repatha®	Evolocumab	2016	OBDS	29	3.5 mL over 5 mins	120 mg/mL
Genentech	RITUXAN HYCELA®	Rituximab/hyaluronidase	2017	Syringe	25	11.7 mL over ~5 mins; 13.4 mL over ~7 mins	120 mg/mL
Genentech	Herceptin HYLECTA®	Trastuzumab/hyaluronidase	2019	Syringe	25	5 mL over 2–5 mins	120 mg/mL
Genentech	PHESGO®	Pertuzumab/trastuzumab/ hyaluronidase	2020	Syringe	25	10 mL over 5 mins; 15 mL over 8 mins	120 mg/mL
Janssen	DARZALEX FASPRO®	Daratumumab/hyaluronidase	2020	Syringe	23	15 mL over 3–5 mins	120 mg/mL
Apellis	EMPAVELI®	Pegcetacoplan	2021	OBDS or SC syringe pump	29	20 mL over 20 mins	54 mg/mL
Alexion/AstraZeneca	ULTOMIRIS® SC	Ravulizumab	2022	OBDS	29	7 mL over 10 mins	70 mg/mL
UCB	RYSTIGGO®	Rozanolixizumab	2023	SC syringe pump	26	3–6 mL – infusion pump over 9–18 minutes	140 mg/mL
Argenx	VYVGART HYTRULO®	Efgartigimod/hyaluronidase	2023	Syringe	25	5.6 mL over 1.5 minutes	180 mg/mL

Abbreviations: OBDS, on-body delivery system; PFS, prefilled syringe; SC, subcutaneous.

Figure 1. Drug volumes administered by SC delivery systems per single device.

Table 3. Dose-volume matrix.

Matrixed dose-volumes are shown in mL of formulation needed and are based on a patient weighing 80 kg and a subcutaneous on-body delivery system that can deliver a volume of 5–25 mL. Green: one device is sufficient for delivery of the dose-volume; yellow: a dilution is required for SC delivery of the dose-volume; orange and red: at least two SC devices are required for delivery of the dose-volume.

Table 4. Bioavailability and other aspects of SC mAb formulations with hyaluronidase compared with IV administration.

SC mAb Formulation	Bioavailability Compared with IV Formulation	SC Bioavailability Improved with Hyaluronidase Co-formulation	Other Comparisons with IV Administration
HYQVIA® (immune globulin infusion 10% [human] with hyaluronidase)	93.3%^Citation94	Yes	Hyaluronidase allows for the full monthly dose of IgG (≤600 mL) to be delivered with a single injection site every 3–4 weeks rather than multiple times weekly^Citation95 with similar bioavailability and a lower peak concentration compared with IV IgG.^Citation94 Co-formulation with hyaluronidase was reported to improve bioavailability by approximately 20% compared to SC IgG without hyaluronidase in 31 patients with PID in a prospective open-label study evaluating co-formulation who had previously participated in a prospective open-label study of 49 patients with PID evaluating SC IgG without co-formulation.^Citation94
Amivantamab with hyaluronidase	Unavailable	Unknown	An ongoing Phase 1b dose-escalation study with 81 patients with various advanced solid tumors found that SC amivantamab 1600 mg (or 2240 mg in patients weighing ≥80 kg) administered every other week had similar exposure to the approved IV dose (1050 mg every other week, or 1400 mg in patients weighing ≥80 kg); resulted in lower Cmax and equal or higher Ctrough and AUC0-336 h; and was associated with a lower incidence of infusion-related reactions and related symptoms.^Citation13
Crenezumab with hyaluronidase	66%^Citation96	No	A Phase 1 study with 72 adult participants receiving SC crenezumab at different combinations of dose (1,700–6,800 mg), flow rate (2–4 mL/minute), and infusion volume (10–40 mL) and with and without co-formulation with hyaluronidase found that hyaluronidase decreased infusion site swelling incidence but was associated with larger areas of infusion site erythema, and co-formulation with hyaluronidase did not significantly affect patient pain, dose proportionality, bioavailability, drug half-life, or systemic exposure.^Citation96
VYVGART HYTRULO® (efgartigimod with hyaluronidase)	~50%^Citation97	Unknown	VYVGART HYTRULO® has comparable half-life to that of IV administration but is associated with more injection site reactions (reported in 21 of 55 patients, or 38%), including rash, skin redness, itching, bruising, pain, and hives.^Citation97
Herceptin HYLECTA® (trastuzumab/hyaluronidase)	77%^Citation98	Unknown	Ctrough and AUC0–21 are slightly higher in patients receiving SC trastuzumab and differences were larger at the extremes of body weight.^Citation99 Bioavailability of the SC regimen is estimated to be 77%.^Citation100 Within-patient pharmacokinetic comparison of SC and IV data were not obtained, but estimated bioavailability was comparable to that seen a Phase I study with four patients receiving both SC and IV trastuzumab.^Citation100 When administered SC, trastuzumab has an absorption half-life of 2.5 days.^Citation101
RITUXAN HYCELA® (rituximab/hyaluronidase)	64.6% for follicular lymphoma, 63.4% for chronic lymphocytic leukemia^Citation102	Unknown	Ctrough and AUC for rituximab SC are non-inferior to rituximab IV.^Citation95
PHESGO® (trastuzumab/pertuzumab/hyaluronidase)	70% for pertuzumab, 80% for trastuzumab^Citation103	Unknown	In a randomized, open-label, Phase 3 study, PHESGO® produced similar serum Ctrough, safety, and efficacy compared with IV administration.^Citation104
DARZALEX FASPRO® (daratumumab/hyaluronidase)	70%^Citation105	Unknown	Efficacy and pharmacokinetics with DARZALEX FASPRO® SC are non-inferior to IV.^Citation74
Tocilizumab/hyaluronidase	79.5%^Citation106	Yes	In a study in healthy volunteers, tocilizumab in combination with hyaluronidase slightly improved tocilizumab exposure compared with tocilizumab alone; PD markers were similar.^Citation107

Abbreviations: AUC, area under the curve; AUC_0-21, area under the curve for 21 hours of exposure; AUC_0-336 h, area under the curve for 336 hours of exposure; C_max, peak concentration; C_trough, trough concentration; IgG, immunoglobin G; IV, intravenous; mAbs, monoclonal antibodies; OBDS, on-body delivery system; PD, pharmacodynamic; PFS, prefilled syringe; PID, primary immunodeficiency disease; SC, subcutaneous.

Sánchez-Félix M, Burke M, Chen HH, Patterson C, Mittal S. Predicting bioavailability of monoclonal antibodies after subcutaneous administration: open innovation challenge. Adv Drug Deliv Rev. 2020;167:66–77. doi:10.1016/j.addr.2020.05.009.

 PubMed Web of Science ®Google Scholar

Bittner B, Richter W, Schmidt J. Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32(5):425–40. doi:10.1007/s40259-018-0295-0.

 PubMed Web of Science ®Google Scholar

Minchom AR. Subcutaneous amivantamab (ami) in patients (pts) with advanced solid malignancies: the PALOMA study—updated safety and identification of the recommended phase 2 dose. Poster presented at: 2023 ASCO Annual Meeting; 2023; Chicago, IL. Session Lung Cancer–Non-Small Cell Metastatic.

 Google Scholar

Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis N, Flogegard M, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370–e80. doi:10.1016/s2352-3026(20)30070-3.

 PubMed Web of Science ®Google Scholar

Hendrikx JJMA, Haanen JBAG, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH. Fixed dosing of monoclonal antibodies in oncology. Oncologist. 2017;22(10):1212–21. doi:10.1634/theoncologist.2017-0167.

 PubMed Web of Science ®Google Scholar

Dekhtiarenko I, Lelios I, Attig J, Sleiman N, Lazzaro D, Schindler E, Eckmann J, Umana P, Jacob W, Schneider M, et al. Intravenous and subcutaneous administration of RG6234, a novel GPRC5DxCD3 T-cell engaging bispecific antibody, is highly active in patients with relapsed/refractory multiple myeloma (RRMM): biomarker results from a phase I study. Blood. 2022;140(Supplement 1):10137–39. doi:10.1182/blood-2022-158146.

 Google Scholar

Badkar AV, Gandhi RB, Davis SP, Labarre MJ. Subcutaneous delivery of high-dose/volume biologics: current status and prospect for future advancements. Drug Des Devel Ther. 2021;15:159–70. doi:10.2147/dddt.s287323.

 PubMed Web of Science ®Google Scholar

Garidel P, Kuhn AB, Schäfer LV, Karow-Zwick AR, Blech M. High-concentration protein formulations: how high is high? Eur J Pharm Biopharm. 2017;119:353–60. doi:10.1016/j.ejpb.2017.06.029.

 PubMed Web of Science ®Google Scholar

Matucci A, Vultaggio A, Danesi R. The use of intravenous versus subcutaneous monoclonal antibodies in the treatment of severe asthma: a review. Respir Res. 2018;19(1):154. doi:10.1186/s12931-018-0859-z.

 PubMedGoogle Scholar

Jiskoot W, Hawe A, Menzen T, Volkin DB, Crommelin DJA. Ongoing challenges to develop high concentration monoclonal antibody-based formulations for subcutaneous administration: quo vadis? J Pharm Sci. 2022;111(4):861–67. doi:10.1016/j.xphs.2021.11.008.

 PubMed Web of Science ®Google Scholar

De Cock E, Kritikou P, Sandoval M, Tao S, Wiesner C, Carella AM, Ngoh C, Waterboer T. Time savings with rituximab subcutaneous injection versus rituximab intravenous infusion: a time and motion study in eight countries. PLoS ONE. 2016;11(6):e0157957. doi:10.1371/journal.pone.0157957.

 PubMed Web of Science ®Google Scholar

De Cock E, Pivot X, Hauser N, Verma S, Kritikou P, Millar D, Knoop A. A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2-positive early breast cancer. Cancer Med. 2016;5(3):389–97. doi:10.1002/cam4.573.

 PubMed Web of Science ®Google Scholar

Epstein RS. Payer perspectives on intravenous versus subcutaneous administration of drugs. Clin Outcomes Res. 2021;13:801–07. doi:10.2147/ceor.S317687.

 PubMed Web of Science ®Google Scholar

Polinski JM, Kowal MK, Gagnon M, Brennan TA, Shrank WH. Home infusion: safe, clinically effective, patient preferred, and cost saving. Healthcare. 2017;5(1):68–80. doi:10.1016/j.hjdsi.2016.04.004.

 Web of Science ®Google Scholar

Gandhi MD, Shapouri S, Ravelo A, Sudharshan L, Beeks A, Dawson KL. NHL patients and nurses in the US prefer subcutaneous rituximab injection versus intravenous rituximab infusion: a real-world study. Blood. 2020;136(Supplement 1):7–9. doi:10.1182/blood-2020-136543.

 Google Scholar

Tsiantou V, Athanasakis K, Theodoropoulou F, Kyriopoulos J. Patients’ and health professionals’ preferences regarding intravenous vs subcutaneous drug administration: a literature review. Value Health. 2015;(7):A742. doi:10.1016/j.jval.2015.09.2852.

 Web of Science ®Google Scholar

Zharkov A, Barton B, Heinzmann D, Bakalos G, Schreitmüller T. Development pathways for subcutaneous formulations of biologics versus biosimilar development. Expert Rev Precis Med Drug Dev. 2022;7(1):62–69. doi:10.1080/23808993.2019.1585806.

 Web of Science ®Google Scholar

Leveque D. Subcutaneous administration of anticancer agents. Anticancer Res. 2014;34:1579–86.

 PubMed Web of Science ®Google Scholar

Usach I, Martinez R, Festini T, Peris J-E. Subcutaneous injection of drugs: literature review of factors influencing pain sensation at the injection site. Adv Ther. 2019;36(11):2986–96. doi:10.1007/s12325-019-01101-6.

 PubMed Web of Science ®Google Scholar

Wasserman RL, Melamed I, Stein M, Engl, W, Leibl, H, McCoy, B, Gelmont, D, Schiff, RI et al. Pharmacokinetics of recombinant human hyaluronidase (rHUPH20)-facilitated subcutaneous infusion of immune globulin (human), 10% (IGHy) in patients with primary immunodeficiency disease (PI). Annual Scientific Meeting of the American College of Allergy, Asthma, & Immunology; 2011; 3-8 November 2011 Boston, MA, USA.

 Google Scholar

Locke KW, Maneval DC, LaBarre MJ. ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv. 2019;26(1):98–106. doi:10.1080/10717544.2018.1551442.

 PubMed Web of Science ®Google Scholar

Dolton MJ, Chesterman A, Moein A, Sink KM, Waitz A, Blondeau K, Kerchner GA, Hu N, Brooks L, Wetzel‐Smith MK, et al. Safety, tolerability, and pharmacokinetics of high-volume subcutaneous crenezumab, with and without recombinant human hyaluronidase in healthy volunteers. Clin Pharmacol Ther. 2021;110(5):1337–48. doi:10.1002/cpt.2385.

 PubMed Web of Science ®Google Scholar

Argenx announces data from phase 1 study of efgartigimod (ARGX-113) subcutaneous formulation demonstrating comparable characteristics to intravenous formulation. 14 June, 2018. http://www.argenx.com.

 Google Scholar

U.S. Food and Drug Administration. Herceptin HYLECTA Package Insert 2019. Accessed 10 August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761106s000lbl.pdf.

 Google Scholar

Duco MR, Murdock JL, Reeves DJ. Trastuzumab/hyaluronidase-oysk: a new option for patients with HER2-positive breast cancer. Ann Pharmacother. 2020;54(3):254–61. doi:10.1177/1060028019877936.

 PubMed Web of Science ®Google Scholar

Quartino AL, Hillenbach C, Li J, Li H, Wada RD, Visich J, Li C, Heinzmann D, Jin JY, Lum BL, et al. Population pharmacokinetic and exposure–response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer. Cancer Chemother Pharmacol. 2016;77(1):77–88. doi:10.1007/s00280-015-2922-5.

 PubMed Web of Science ®Google Scholar

Hourcade-Potelleret F, Lemenuel-Diot A, McIntyre C, Brewster M, Lum B, Bittner B. Use of a population pharmacokinetic approach for the clinical development of a fixed-dose subcutaneous formulation of trastuzumab. CPT Pharmacometrics Syst Pharma. 2014;3(1):1–9. doi:10.1038/psp.2013.63.

 Google Scholar

U.S. Food and Drug Administration. RITUXAN HYCELA Package Insert 2017. Accessed 10 August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf.

 Google Scholar

U.S. Food and Drug Administration. PHESGO Package Insert 2020. Accessed 10 August 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761170s000lbl.pdf.

 Google Scholar

Tan AR, Im SA, Mattar A, Colomer R, Stroyakovskii D, Nowecki Z, De Laurentiis M, Pierga J-Y, Jung KH, Schem C, et al. Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDerica): a randomised, open-label, multicentre, non-inferiority, phase 3 study. Lancet Oncol. 2021;22(1):85–97. doi:10.1016/s1470-2045(20)30536-2.

 PubMed Web of Science ®Google Scholar

Luo MM, Usmani SZ, Mateos MV, Nahi H, Chari A, San‐Miguel J, Touzeau C, Suzuki K, Kaiser M, Carson R, et al. Exposure-response and population pharmacokinetic analyses of a novel subcutaneous formulation of daratumumab administered to multiple myeloma patients. J Clin Pharmacol. 2021;61(5):614–27. doi:10.1002/jcph.1771.

 PubMed Web of Science ®Google Scholar

Usmani SZ, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis NJ, Flogegard M, et al. Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022;107(10):2408–17. doi:10.3324/haematol.2021.279459.

 PubMed Web of Science ®Google Scholar

Abdallah H, Hsu JC, Lu P, Fettner S, Zhang X, Douglass W, Bao M, Rowell L, Burmester GR, Kivitz A, et al. Pharmacokinetic and pharmacodynamic analysis of subcutaneous tocilizumab in patients with rheumatoid arthritis from 2 randomized, controlled trials: SUMMACTA and BREVACTA. J Clin Pharmacol. 2017;57(4):459–68. doi:10.1002/jcph.826.

 PubMed Web of Science ®Google Scholar

Morcos PN, Zhang X, McIntyre C, Bittner B, Rowell L, Hussain Z. Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuph20. Int J Clin Pharmacol Ther. 2013;51(7):537–48. doi:10.5414/cp201847.

 PubMed Web of Science ®Google Scholar