Pharmacokinetic Modeling Proposes Cost-Effective Dosing for Adalimumab, Etanercept Biosimilars

Using drug concentration samples from patients with rheumatoid arthritis (RA) starting the adalimumab biosimilar Amgevita and the etanercept biosimilar Benepali, a UK cohort study simulated drug concentration during standard and alternate dosing schedules. According to the authors, simulating different dosing intervals “could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.”

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The effectiveness of tumor necrosis factor (TNF)-α inhibitors is affected by circulating drug levels, and there is between-subject variability in circulating drug levels, the authors said. The study included 10, real-world patients with RA starting the adalimumab biosimilar Amgevita and 6 starting the etanercept biosimilar Benepali. The authors noted that the number of participants was “below those planned” due to the COVID-19 pandemic. Drug concentration samples were collected over a 12-week period for each patient, a total of 58 samples of patients receiving adalimumab and 40 from patients receiving etanercept. The drug concentration data was used to estimate pharmacokinetic parameters, which in turn were used to model population pharmacokinetics.

The investigators wrote that plots of predicted vs observed measurements confirmed that the estimated parameters “described the data adequately.” The estimated parameters were used to simulate and compare typical and altered dosing intervals of each drug. The authors added that simulated profiles of typical dosing were overlaid with observed plasma concentration data, which demonstrated that the simulated results “agreed well with the data.” The models produced simulated typical individual profiles, plus medians and fifth and 95th percentiles for each drug and dosing interval combination.

Compared to the usual dosing interval of the adalimumab biosimilar, 40 mg every 14 days, 40 mg every 7 days also resulted in steady-state adalimumab concentrations within the therapeutic window, and differences in time to steady-state concentration between these two dosing intervals were “negligible.” However, a reduction to 40 mg every 21 days did not result in steady-state concentrations within the therapeutic window.

Compared to the typical dosing interval of the etanercept biosimilar 50 mg every 7 days, the simulated dosing intervals of 50 mg every 5 days and 50 mg every 10 days “achieved steady-state drug concentrations well above the therapeutic window,” the authors wrote. Differences between dosing intervals in time to steady-state concentration were “negligible,” but “marginally quicker with an interval of every 10 days on visual inspection.”

The authors added that patients on the adalimumab biosimilar had a higher median body weight than those on the etanercept biosimilars, which could have affected the simulation results, as previous studies have suggested the response to anti-TNF treatment is reduced at higher body mass index. They also acknowledged a lack of testing for antidrug antibodies as a limitation of their study, since anti-adalimumab antibodies “are associated with decreased drug concentrations and reduced rates of treatment response.” Despite these limitations and the small sample size, they said their study “adds valuable information and data in a space where both are very limited,” and findings from simulations of altered dosing intervals could lead to personalized dosing for adalimumab and etanercept.

Reference

Ling SF, Ogungbenro K, Darwich AS, et al. Population pharmacokinetic analysis and simulation of alternative dosing regimens for biosimilars to adalimumab and etanercept in patients with rheumatoid arthritis. Pharmaceutics. 2024;16(6):702. doi:10.3390/pharmaceutics16060702.