Evidence of bioequivalence and positive patient user handling of a tocilizumab autoinjector

Figures & data

Figure 1. Study design. (a) Bioequivalence. (b) Real-life human factors study. AE, adverse event; AI, autoinjector; CG, caregiver; gen, generation; HAQ-DI, Health Assessment Questionnaire–Disability Index; HCP, health care professional; HF, human factors; ISR, injection site reaction; PFS, prefilled syringe; SC, subcutaneous; SJC, swollen joint count; TJC, tender joint count. ^a,bTocilizumab 162 mg/0.9 mL SC using AI or PFS.

Figure 2. Leak back in the real-life human factors study. (a) Assessment.^a (b) Outcomes.^b HCP, health care professional. ^aNot to scale. ^bSelf-injecting patients: visit 1, n = 18; visit 2, n = 17; visit 3, n = 18. Caregiver-injected patients: visit 1, n = 17; visit 2, n = 17; visit 3, n = 16. HCP-injected patients: visit 1, n = 19; visit 2, n = 17; visit 3, n = 18.

Table 1. Baseline demographics of participants enrolled in the bioequivalence and real-life human factors studies.

Baseline demographics	Bioequivalence safety population N = 188 Healthy subjects	Real-life human factors safety population N = 54 RA patients
Age, years, mean (SD)	37.6 (12.5)	52.1 (13.6)
Female, n (%)	33 (17.6)	39 (72.2)
Race, n (%) White Black or African American	134 (71.3) 46 (24.5)	50 (92.6) 2 (3.7)
Asian Other	4 (2.1) 4 (2.1)	1 (1.9) 1 (1.9)
Height, cm, mean (SD)	174.9 (8.7)	166.3 (9.3)
Weight, kg, mean (SD)	83.5 (17.3)	83.4 (20.4)
Left-handedness, n (%)	–	4 (7.4)

RA, rheumatoid arthritis; SD, standard deviation.

Table 2. Summary statistics of tocilizumab serum PK parameters by administration device.

	Tocilizumab by AI (test)				Tocilizumab by PFS (reference)
Descriptive statistic	Cmax (µg/mL)	AUClast (day/µg·mL)	AUCinf (day/µg·mL)	Tmax (days)	Cmax (µg/mL)	AUClast (day/µg·mL)	AUCinf (day/µg·mL)	Tmax (day)
n	161	161	156	161	161	161	155	161
Mean (SD)	10.9 (4.67)	87.5 (42.5)	90.0 (42.1)	3.70 (1.17)	11.6 (5.51)	92.5 (47.9)	96.7 (45.8)	3.56 (1.23)
Median (range)	10.6 (1.86, 25.6)	87.1 (5.50, 213)	91.7 (5.96, 215)	3.22 (1.91, 9.08)	11.9 (0.83, 29.8)	91.3 (3.80, 242)	98.3 (10.0, 244)	3.20 (0.95, 7.17)
CV%	42.7	48.6	46.7	31.5	47.3	51.5	47.5	34.5

AI, autoinjector; C_max, peak concentration; AUC_inf, area under the serum concentration–time curve from time 0 to infinity; AUC_last, area under the serum concentration–time curve from time 0 to the time of the last measurable concentration; CV, coefficient of variation; PFS, prefilled syringe; PK, pharmacokinetic; SD, standard deviation; T, time of occurrence of C_max.

Table 3. Statistical analysis of tocilizumab bioequivalence by administration device.

PK parameters	Device	Geometric LS mean	Geometric LS mean ratio (AI/PFS)	90% CI for geometric mean ratio	Intraindividual CV%
Cmax (µg/mL)	AI	9.86	0.99	0.93, 1.05	35.0
	PFS	10.0
AUClast (day/µg·mL)	AI	76.1	1.00	0.94, 1.07	37.2
	PFS	75.9
AUCinf (day/µg·mL)	AI	78.6	0.97	0.92, 1.03	31.6
	PFS	80.9

AI, autoinjector; AUC_inf, area under the serum concentration–time curve from time 0 to infinity; AUC_last, area under the serum concentration–time curve from time 0 to the time of the last measurable concentration; CI, confidence interval; C_max, peak concentration; CV, coefficient of variation; LS, least squares; PFS, prefilled syringe; PK, pharmacokinetic; SD, standard deviation.

Analyses were performed on log-transformed parameters with treatment, period, sequence, and subject nested within sequence as fixed effects.

Table 4. Tocilizumab bioequivalence by administration site.

	LS mean ratio (AI/PFS)
	Abdomen			Thigh			Upper arm
Descriptive statistic	Cmax (µg/mL)	AUClast (day/µg·mL)	AUCinf (day/µg·mL)	Cmax (µg/mL)	AUClast (day/µg·mL)	AUCinf (day/µg·mL)	Cmax (µg/mL)	AUClast (day/µg·mL)	AUCinf (day/µg·mL)
Estimate	1.05	1.07	1.08	1.01	1.02	0.94	0.89	0.91	0.90
90% CI	0.95, 1.17	0.96, 1.20	0.96, 1.20	0.89, 1.14	0.90, 1.16	0.85, 1.04	0.81, 0.98	0.82, 1.00	0.83, 0.98
CV%	32.2	35.1	34.0	41.8	44.1	33.6	28.3	28.4	24.9

AI, autoinjector; AUC_inf, area under the serum concentration–time curve from time 0 to infinity; AUC_last, area under the serum concentration–time curve from time 0 to the time of the last measurable concentration; CI, confidence interval; C_max, peak concentration; CV, coefficient of variation; LS, least squares; PFS, prefilled syringe.

Analyses were performed on log-transformed parameters with treatment, period, sequence, and subject nested within sequence as fixed effects.

Figure 3. Analysis of tocilizumab pharmacokinetic parameters by administration device in the bioequivalence study. (a) Mean serum concentration–time profiles. (b) Bioequivalence. AI, autoinjector; AUC_inf, area under the serum concentration–time curve from time 0 to infinity; AUC_last, area under the serum concentration–time curve from time 0 to the time of the last measurable concentration; CI, confidence interval; C_max, maximum concentration; PFS, prefilled syringe; SD, standard deviation; TCZ, tocilizumab. Analyses were performed on log-transformed parameters with treatment, period, sequence, and subject nested within sequence as fixed effects. Dashed vertical lines represent the predefined bioequivalence range.

Table 5. Safety in the bioequivalence and real-life human factors studies.

	Bioequivalence study		Real-life human factors study
Parameter, n (%)	AI n = 176	PFS n = 177	Self-injecting patients n = 18	Caregiver-injected patients n = 17	HCP-injected patients n = 19
Subjects with ≥1 AE	51 (29.0)	60 (33.9)	4 (22.2)	4 (23.5)	3 (15.8)
Subjects with ≥1 treatment-related AE	33 (18.8)	30 (16.9)	0	0	0
Subjects with ≥1 AE by grade CTCAE grade 1 CTCAE grade 2 CTCAE grade 3	38 (21.6) 7 (4.0) 6 (3.4)	49 (27.7) 7 (4.0) 4 (2.3)	4 (22.2) 0 0	3 (17.6) 1 (5.9) 0	1 (5.3) 2 (10.5) 0
Subjects with ≥1 serious AE	0	0	0	0	0
Subjects discontinued because of AEs	0	1 (0.6)	0	1 (5.9)	0

AE, adverse event; AI, autoinjector; CTCAE, Common Terminology Criteria for Adverse Events; HCP, health care professional; PFS, prefilled syringe.

Figure 4. Summary of patient assessment of injection pain. (a) 100-mm VAS score by injection group and (b) categorical pain scores in all patients at 0 and 15 minutes after injection in the real-life human factors study. HCP, health care professional; SD, standard deviation; VAS, visual analog scale.