Clinical pharmacology of caplacizumab for the treatment of patients with acquired thrombotic thrombocytopenic purpura

Figures & data

Figure 1. Schematic structure of caplacizumab. aa: amino acids; Da: Dalton; MW: molecular weight; vWF: von Willebrand factor.

Figure 2. Mechanism of action of caplacizumab in aTTP [28]. Reprinted from transfus apher sci, volume 46, Holz JB, The TITAN trial–assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura, pages 343–346, Copyright (2012), with permission from Elsevier.

Figure 3. Mean vWF:Ag levels vs time profiles during a 7 days repeated subcutaneous 10 mg daily dosing of caplacizumab in healthy volunteers (a) [31], and during repeated subcutaneous daily administration of 10 mg caplacizumab in aTTP patients (b) [33,34]. aTTP: acquired thrombotic thrombocytopenic purpura; PE: plasma exchange; FU: follow-up; vWF: von Willebrand factor.

Figure 4. Mean (± SD) RICO activity in the phase II (left panel) [32] and the phase III (right panel) [33]. RICO values of <20% represent the threshold for pharmacological activity of caplacizumab. Graphs show mean ± standard error of the mean. PE: plasma exchange; FU: follow-up; RICO: ristocetin cofactor; SD: standard deviation; vWF: von Willebrand factor.

Figure 5. Caplacizumab plasma concentration versus time profile after administration of single ascending subcutaneous doses (a), and after single (Day 1 solid line) and repeated (Day 7 dotted line) administration of 10 mg daily subcutaneous doses for seven days (b) in healthy volunteers [31]. sc: subcutaneous.

Table 1. Pharmacokinetic parameters following single 10 mg intravenous or subcutaneous administration of caplacizumab in healthy volunteers.

Parameter	Intravenous dose (n = 8)	Subcutaneous dose (n = 8)
Tmax (h) Median (range)	0.26 (0.25–6)	3.04 (3–9)
Cmax (µg/mL) Mean (±SD)	1.63 (± 0.59)	0.57 (± 0.12)
AUCinf (µg*h/mL) Mean (±SD)	14.5 (± 7.6)	26.7 (± 10.7)

AUC_inf: area under the concentration-time curve extrapolated to infinity; C_max: maximum concentration; SD: standard deviation; T_max; time to C_max.

Table 2. Simulated mean steady-state pharmacokinetic exposure parameters (AUC, C_max, C_min, and C_avg) and corresponding pharmacodynamic effect (vWF:Ag change from baseline) following 40 days of 10 mg subcutaneous daily administration of caplacizumab in aTTP patients.

Parameter	Steady-state
AUCτ (µg*h/mL), median (5–95%)	12.5 (7.03–23.1)
Cmax (µg/mL), median (5–95%)	0.609 (0.355–1.079)
Cmin (µg/mL), median (5–95%)	0.436 (0.230–0.843)
Cavg (µg/mL), median (5–95%)	0.520 (0.293–0.960)
vWF:Ag change from baseline (%), median (5–95%)	−43.8 (−67.7-0.5)

aTTP: acquired thrombotic thrombocytopenic purpura; AUC_τ: area under the concentration–time curve over the dosing interval; C_avg: average concentration; C_max: maximum concentration; C_min: minimum concentration; vWF:Ag: von Willebrand factor antigen.

Table 3. Simulated median steady-state pharmacokinetic exposure parameters (AUC, C_max, C_min) and corresponding pharmacodynamic effect (vWF:Ag change from baseline) following 40 days of 10 mg subcutaneous daily administration of caplacizumab in aTTP patients with low bodyweight, high baseline vWF levels, and low CrCL.

	aTTP patients
Parameter	BW = 50 kg	vWF = 60 nM	CrCL = 15 mL/min
AUCτ (µg*h/mL), median (5–95%)	13.3 (8.3–24.5)	18.6 (11.9–33.4)	13.3 (7.7–26.1)
Cmax (µg/mL), median (5–95%)	0.662 (0.424–1.159)	0.895 (0.579–1.535)	0.643 (0.389–1.193)
Cmin (µg/mL), median (5–95%)	0.452 (0.266–0.884)	0.670 (0.409–1.260)	0.468 (0.257–0.986)
Cavg (µg/mL), median (5–95%)	0.555 (0.345–1.021)	0.775 (0.498–1.391)	0.554 (0.322–1.085)
vWF:Ag change from baseline (%), median (5–95%)	−45.4 (−69.2 to −1.3)	−43.8 (−67.8 to −0.6)	−45.2 (−68.4 to −1.9)

aTTP: acquired thrombotic thrombocytopenic purpura; AUC_τ area under the concentration-time curve over the dosing interval; BW: bodyweight; C_avg: average concentration; C_max: maximum concentration; C_min: minimum concentration; CrCL: creatinine clearance; vWF: von Willebrand factor; vWF:Ag: von Willebrand factor antigen.

Table 4. Efficacy endpoints by pharmacokinetic quartile at the end of Plasma Exchange and end of the study drug (caplacizumab) treatment period in aTTP patients from the phase II and III studies.

End Plasma Exchange	Quartile 1 (149 to <286) N = 21	Quartile 2 (286 to <404) N = 22	Quartile 3 (404 to <517) N = 21	Quartile 4 (517 to 861) N = 22	Placebo- N = 110
Drug concentration (ng/mL)	220.3 ± 38.8	348.7 ± 39.7	445.7 ± 24.4	625.5 ± 87.3	-
Time to confirmed platelet response (days) (95% CI)
N events	18	22	20	22	92
N censored	3	0	1	0	18
25th percentile	2.27 (0.59–2.92)	1.75 (0.70–2.64)	1.82 (0.69–2.68)	1.72 (0.79–1.86)	2.53 (1.87–2.76)
Median	2.95 (2.27–4.00)	2.68 (1.75–2.86)	2.72 (1.82–2.90)	1.88 (1.71–2.74)	3.48 (2.87–3.84)
75th percentile	4 (2.95–4.92)	2.96 (2.70–3.94)	2.99 (2.72–15.11)	2.83 (1.88–4.54)	5.7 (4.49–9.79)

Quartiles are defined for subjects falling within 0% to ≤25%, >25% to ≤50%, >50% to ≤75%, and >75% to 100% of exposure. Subjects who had missing samples at end of Plasma Exchange or at the last treatment visit were excluded from the summary. Mean ± SD drug plasma levels are presented.

aTTP: acquired thrombotic thrombocytopenic purpura; CI: confidence interval; SD: standard deviation.

Table 5. Percentage of patients reporting adverse events by body system and preferred term at end of Plasma Exchange and end of study drug (caplacizumab) treatment by quartile of exposure from the phase II and III studies in aTTP patients.

End of Plasma Exchange	Quartile 1 (149 to <286) N = 21			Quartile 2 (286 to <404) N = 22			Quartile 3 (404 to <517) N = 21			Quartile 4 (517 to 861) N = 22			Placebo- N = 110
Drug concentration (ng/mL)	220.3 ± 38.8			348.7 ± 39.7			445.7 ± 24.4			625.5 ± 87.3			-
	n*	n	%	n*	n	%	n*	n	%	n*	n	%	n*	N	%
Any bleeding TEAE	7	5	(23.8)	9	6	(27.2)	12	6	(28.5)	13	7	(31.8)	41	23	(20.9)
Eye disorders	0	0	-	0	0	-	1	1	(4.7)	0	0	-	1	1	(0.9)
Gastrointestinal disorders	3	3	(14.2)	3	3	(13.6)	2	2	(9.5)	3	3	(13.6)	3	3	(2.7)
General disorders and administration site conditions	2	2	(9.5)	1	1	(4.5)	1	1	(4.7)	2	2	(9.0)	5	5	(4.5)
Injury, poisoning and procedural complications	1	1	(4.7)	2	2	(9.0)	1	1	(4.7)	2	2	(9.0)	17	8	(7.2)
Investigations	0	0	-	0	0	-	0	0	-	0	0	-	1	1	(0.9)
Nervous system disorders	0	0	-	0	0	-	0	0	-	1	1	(4.5)	3	3	(2.7)
Renal and urinary disorders	0	0	-	0	0	-	2	1	(4.7)	1	1	(4.5)	0	0	-
Reproductive system and breast disorders	0	0	-	0	0	-	0	0	-	2	1	(4.5)	2	2	(1.8)
Respiratory, thoracic and mediastinal disorders	1	1	(4.7)	3	3	(13.6)	4	4	(19.0)	1	1	(4.5)	4	2	(1.8)
Skin and subcutaneous tissue disorders	0	0	-	0	0	-	1	1	(4.7)	1	1	(4.5)	5	5	(4.5)
End of treatment	Quartile 1 (100 to <349) N = 24			Quartile 2 (349 to <453) N = 24			Quartile 3 (453 to <582) N = 24			Quartile 4 (582 to <1380) N = 25			Placebo- N = 97
Drug concentration (ng/mL)	257.4 ± 74.1			402.0 ± 29.0			504.6 ± 40.4			750.4 ± 157.3			-
	n*	n	%	n*	n	%	n*	n	%	n*	n	%	n*	n	%
Any bleeding TEAE	52	18	(75.0)	33	13	(54.1)	29	12	(50.0)	24	12	(48.0)	68	34	(35.0)
Eye disorders	0	0	-	0	0	-	1	1	(4.1)	1	1	(4.0)	1	1	(1.0)
Gastrointestinal disorders	11	9	(37.5)	10	6	(25.0)	4	4	(16.6)	6	5	(20.0)	7	7	(7.2)
General disorders and administration site conditions	6	4	(16.6)	3	3	(12.5)	7	5	(20.8)	3	3	(12.0)	14	12	(12.3)
Injury, poisoning and procedural complications	8	5	(20.8)	3	2	(8.3)	2	2	(8.3)	2	2	(8.0)	17	9	(9.2)
Musculoskeletal and connective tissue disorders	0	0	-	0	0	-	0	0	-	0	0	-	1	1	(1.0)
Nervous system disorders	0	0	-	0	0	-	1	1	(4.1)	0	0	-	1	1	(1.0)
Renal and urinary disorders	0	0	-	0	0	-	2	2	(8.3)	2	1	(4.0)	3	2	(2.0)
Reproductive system and breast disorders	6	4	(16.6)	1	1	(4.1)	1	1	(4.1)	2	2	(8.0)	4	4	(4.1)
Respiratory, thoracic and mediastinal disorders	18	10	(41.6)	17	10	(40.0)	9	8	(33.3)	6	4	(16.0)	9	5	(5.1)
Skin and subcutaneous tissue disorders	1	1	(4.1)	1	1	(4.1)	1	1	(4.1)	1	1	(4.0)	9	8	(8.2)

*Number of events. aTTP: acquired thrombotic thrombocytopenic purpura; TEAE: treatment emergent adverse event.

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