Yan Wang1, Laura Bukkems1, Rob Ter Heine3, Coen Van Hasselt2, Egbert Smit4, Henk-Jan Guchelaar1, Dirk Jan Moes1
1Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2Leiden Academy of Drug research, 3Department of Clinical Pharmacy and Toxicology, Radboud UMC , 4Department of Pulmonology, Leiden University Medical Center
Introduction: The increasing use of immune checkpoint inhibitors, such as nivolumab, places a significant financial burden on healthcare systems, contributes to environmental concerns and strains hospital capacities. At first, nivolumab was approved to be administered as an intravenous (IV) dose of 3mg/kg every 2 weeks (Q2W) [1]. In silico modeling and simulation study subsequently allowed the amendment of this initial dosage to either 240 mg Q2W or 480 mg Q4W. However, standard IV administration of nivolumab are associated relatively long administration times and it therefore strains capacity of infusion centers. Recently a subcutaneous formulation has been approved by EMA and FDA with a fixed dose of 1200 mg Q4W for all patients, which provides a more convenient administration method. The nivolumab exposure in subcutaneous (SC) dosing regimen varied in different bodyweight groups and was on average much higher than the exposure reached with 3 mg/kg IV dosing [2], providing possibilities to explore different administration intervals based on the body weight. In addition, it has been suggested that maintaining a nivolumab Cminss at 2.5 mg/L can already achieve maximum therapeutic effect for melanoma [3, 4]. Objective: We proposed two alternative dosing regimens for subcutaneous nivolumab to assess the impact on costs while ensuring effective exposure. The first dosing regimen was based on patients’ bodyweight while maintaining equivalent systemic drug exposure compared to the 3 mg/kg IV Q2W regimen. The second regimen was based on maintaining a minimum Cminss (2.5 mg/L) which was associated with near-complete target saturation in melanoma. Methods: We developed two alternative dose interval extension strategies based on pharmacokinetic modeling and simulation. We applied PopGen population generator for 500 virtual patients with different bodyweights, height and other relevant covariates [5], which is based on International Cancer Research Partnership database for European patients. Using the 2 compartment population pharmacokinetic model developed by the registration holder [2], we designed body weight-adjusted SC nivolumab dosing strategies for different dose intervals with the fixed SC dose of 1200mg. Adjustments were made to the dosing interval while adhering to the FDA criteria [6] for in silico dose adjustments for PD-1 and PDL-1 inhibitors in the comparison with the 3mg/kg Q2W IV regimen. In addition, we explored the maximum alternative intervals using the fixed SC dose of 1200mg with the requirement of 95% the patients Cminss exceeding 2.5 mg/L. Subsequently, potential cost savings were calculated between the alternative regimens and approved SC regimen (1200mg Q4W). Results: We developed an alternative body weight based regimen consisting of 1200 mg SC Q7W (<60kg), 1200 mg Q6W (60-90kg) and 1200 mg Q5W >90kg. The trough concentrations and average concentration complied with the FDA criteria in comparison to the original IV 3mg/kg Q2W regimen. Based on the estimated price of the 1200 mg SC administration dose, this new alternative dosing regimen would save around €24,345 per patient per year and reduce drug expenses of approximately 35% compared with 1200mg Q4W SC. As for the maximum extended intervals, our simulation showed that 95% patients their steady-state trough concentrations just exceed 2.5 mg/L if administrated by 1200 mg SC Q10W. This more progressive extended-interval dosing regimen would decrease the yearly cost by €27,548 (approximately 60%) per patient compared with the approved SC regimen. Conclusion: The developed regimen with bodyweight dependent dose intervals offers a cost-effective way to optimize subcutaneous nivolumab use, reduce healthcare burdens and environmental impact while ensuring adequate drug exposure and could be evaluated in a PK equivalence study. The more progressive proposed study provides a solid basis for a non-inferiority study compared to standard dosing.
[1] Agrawal, S., et al., Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer, 2016. 4: p. 72. [2] Zhao, Y., et al., Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors. Clin Pharmacol Ther, 2024. 115(3): p. 488-497. [3] Ratain, M.J. and D.A. Goldstein, Time Is Money: Optimizing the Scheduling of Nivolumab. J Clin Oncol, 2018: p. Jco1800045. [4] Administration, U.S.F.a.D., Clinical pharmacology and biopharmaceutic review (nivolumab). APPLICATION NUMBER:125554Orig1s000 [5] McNally, K., et al., PopGen: A virtual human population generator. Toxicology, 2014. 315: p. 70-85. [6] Administration, U.S.F.a.D., Pharmacokinetic-Based Criteria for Supporting Alternative Dosing Regimens of Programmed Cell Death Receptor-1 (PD-1) or Programmed Cell Death-Ligand 1 (PD-L1) Blocking Antibodies for Treatment of Patients with Cancer 2022.
Reference: PAGE 33 (2025) Abstr 11743 [www.page-meeting.org/?abstract=11743]
Poster: Drug/Disease Modelling - Oncology