Pharmacokinetics and safety of candidate tocilizumab biosimilar CT-P47 administered by auto-injector or pre-filled syringe: a randomized, open‑label, single-dose phase I study

Figures & data

Figure 1. Participant flow diagram.

AI, auto-injector; PFS, pre-filled syringe.

Table 1. Participant demographics and baseline characteristics (intent-to-treat).

	CT-P47 AI (n = 155)	CT-P47 PFS (n = 159)
Median (range) age, years	28 (19–51)	27 (19–53)
Sex, n (%)^#
Male	106 (68.4)	109 (68.6)
Female	49 (31.6)	50 (31.4)
Ethnicity, n (%)
Not Hispanic or Latino	155 (100.0)	159 (100.0)
Race, n (%)
Asian	155 (100.0)	159 (100.0)
Height at screening (cm), median (range)	171.1 (150.9–187.4)	171.8 (154.5–194.7)
Weight at screening (kg), median (range)	69.3 (50.3–92.5)	69.2 (50.5–100.0)
BMI at screening (kg/m^2), median (range)	23.9 (19.0–28.0)	23.8 (18.9–27.9)
Day −1 body weight, n (%)^#,†
<70 kg	81 (52.3)	82 (51.6)
70 to <90 kg	73 (47.1)	72 (45.3)
≥90 kg	1 (0.6)	5 (3.1)
Site number, n (%)^#
1	31 (20.0)	31 (19.5)
2	39 (25.2)	40 (25.2)
3	42 (27.1)	43 (27.0)
4	43 (27.7)	45 (28.3)
Smoking history, n (%)
Yes	50 (32.3)	49 (30.8)
No	105 (67.7)	110 (69.2)
Average cigarette consumption (cigarettes/day), median (range)	7.0 (1.0–10.0)	6.0 (1.0–10.0)

^#Stratification factor for randomization.

^†For participants whose Day − 1 assessments were omitted, screening body weight is considered.

AI, auto-injector; BMI, body mass index; PFS, pre-filled syringe.

Figure 2. Mean (SD) serum concentrations of CT-P47 for CT-P47 AI and CT-P47 PFS (PK set).

Note: PK concentrations that were below the lower limit of quantification were set to zero. AI, auto-injector; PFS, pre-filled syringe; PK, pharmacokinetic; SD, standard deviation.

Figure 3. Summary and statistical analysis of the primary pharmacokinetic endpoints (PK set).

^#Twelve participants (9 CT-P47 AI; 3 CT-P47 PFS) who had an adjusted coefficient of determination (adjusted R²) of <0.85 were excluded from the AUC_0–inf analysis; in addition, AUC_0–inf analysis was not available for six participants (4 CT-P47 AI; 2 CT-P47 PFS) who did not have at least three time points after C_max.

^†Determined by ANCOVA performed with the natural log-transformed PK parameter as the dependent variable, treatment as a fixed effect and stratification factors Day − 1 body weight, sex [male vs female] and study center as covariates.

^‡Three participants in CT-P47 AI group had their last observed concentration as the highest value; all withdrew early, before Day 4. Since truncated profiles of these participants may not represent real PK profiles, PK results (C_max) derived from these participants were considered unreliable and excluded from the analysis.

AI, auto-injector; ANCOVA, analysis of covariance; AUC_0–inf, area under the concentration – time curve from time zero to infinity; CI, confidence interval; C_max, maximum serum concentration; gLSM, geometric least-squares mean; PFS, pre-filled syringe; PK, pharmacokinetic; SD, standard deviation.

Table 2. Secondary pharmacokinetic results (PK set).

	CT-P47 AI (n = 153)	CT-P47 PFS (n = 157)
AUC0–last (day*μg/mL)^#
n	150	157
Mean (SD)	88.852 (43.5558)	92.129 (42.4655)
Tmax (day)^#
n	150	157
Median (range)	4.000 (1.00–9.00)	3.019 (1.96–7.00)
t½ (day)^†
n	140	152
Mean (SD)	1.581 (0.58258)	1.622 (0.72392)
%AUCext (%)^†
n	140	152
Mean (SD)	1.164 (5.9400)	1.130 (5.0248)
λz (1/day)^†
n	140	152
Mean (SD)	0.4666 (0.092180)	0.4634 (0.097573)
CL/F (L/h)^†
n	140	152
Mean (SD)	0.09742 (0.059952)	0.09440 (0.066234)
Vz/F (L)^†
n	140	152
Mean (SD)	5.447 (4.9262)	5.341 (4.8664)

^#Three participants in CT-P47 AI group had their last observed concentration as the highest value; all withdrew early, before Day 4. Since truncated profiles of these participants may not represent real PK profiles, PK results (AUC_0–last and T_max) derived from these participants were considered unreliable and excluded from the analysis.

^†Twelve participants (9 CT-P47 AI; 3 CT-P47 PFS) who had an adjusted coefficient of determination (adjusted R²) of <0.85 were excluded from the t_½, %AUC_ext, λ_z, CL/F, and V_z/F analyses; in addition, these analyses were not available for six participants (4 CT-P47 AI; 2 CT-P47 PFS) who did not have at least three time points after C_max.

%AUC_ext, percentage of AUC_0–inf obtained by extrapolation; λ_z, terminal elimination rate constant; AI, auto-injector; AUC_0–inf, area under the concentration – time curve from time zero to infinity; AUC_0–last, area under the concentration – time curve from time zero to the last quantifiable concentration; CL/F, apparent total body clearance; C_max, maximum serum concentration; PFS, pre-filled syringe; PK, pharmacokinetic; SD, standard deviation; t_½, terminal elimination half-life; T_max, time to maximum serum concentration; V_z/F, apparent volume of distribution during the terminal phase.

Table 3. Adverse events (safety set).

	CT-P47 AI (n = 153)	CT-P47 PFS (n = 157)
Total number of TEAEs	158	164
Participants with ≥1 TEAE, n (%)	82 (53.6)	77 (49.0)
Study drug-related	64 (41.8)	60 (38.2)
Participants with ≥1 TESAE, n (%)	0	0
Participants with ≥1 TEAE leading to study drug discontinuation, n (%)	0	0
Participants with ≥1 TEAE leading to death, n (%)	0	0
Participants with ≥1 TEAESI, n (%)
Infection^#	18 (11.8)	15 (9.6)
Study drug-related	13 (8.5)	13 (8.3)
ISR^†	14 (9.2)	5 (3.2)
Study drug-related	14 (9.2)	5 (3.2)
Hepatic event^†	4 (2.6)	4 (2.5)
Study drug-related	2 (1.3)	0
Hypersensitivity (including anaphylaxis)^†	4 (2.6)	2 (1.3)
Study drug-related	4 (2.6)	2 (1.3)
Hemorrhage^†	2 (1.3)	3 (1.9)
Study drug-related	0	1 (0.6)
Demyelinating disorder	0	0
Gastrointestinal disorder	0	0
Malignancy	0	0

^#All Grade 1–2 in intensity, other than one Grade 3 study drug-unrelated TEAESI of COVID-19 in two participants in the CT-P47 AI group.

^†All Grade 1–2 in intensity.

AI, auto-injector; ISR, injection site reaction; PFS, pre-filled syringe; TEAE, treatment-emergent adverse event; TEAESI, treatment-emergent adverse event of special interest; TESAE, treatment-emergent serious adverse event.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.