TY - JOUR
T1 - Single dose tocilizumab for COVID-19 associated cytokine storm syndrome
T2 - Less is more
AU - Boone, Niels W.
AU - Moes, Dirk Jan A. R.
AU - Ramiro, Sofia
AU - Mostard, Remy L. M.
AU - Magro-Checa, Cesar
AU - van Dongen, Christel M. P.
AU - Gronenschild, Michiel
AU - van Haren, Eric
AU - Buijs, Jacqueline
AU - de Vries, Annick
AU - Peeters, Ralph
AU - Landewé, Robert B. M.
AU - Wong, Dennis R.
N1 - Publisher Copyright: © 2023 British Pharmacological Society.
PY - 2023
Y1 - 2023
N2 - Aims: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). Methods: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 μg/L or D-dimers >1500 μg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration–time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. Results: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 μg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. Conclusions: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.
AB - Aims: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). Methods: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 μg/L or D-dimers >1500 μg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration–time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. Results: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 μg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. Conclusions: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.
KW - COVID-19
KW - cytokine storm syndrome
KW - dose rationale
KW - pharmacokinetics
KW - tocilizumab
UR - http://www.scopus.com/inward/record.url?scp=85149658440&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/bcp.15690
DO - https://doi.org/10.1111/bcp.15690
M3 - Article
C2 - 36791777
SN - 0306-5251
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
ER -