Evaluation of the Pharmacokinetics of Trazpiroben (TAK-906), a Peripherally Selective D₂/D₃ Dopamine Receptor Antagonist, in the Presence and Absence of Itraconazole, a Potent CYP 3A4 Inhibitor

Figures & data

Figure 1 Study design.

Abbreviation: PK, pharmacokinetics.

Figure 2 Mean plasma concentration–time curves of trazpiroben after administration of a single oral dose of trazpiroben 25 mg in the presence and absence of itraconazole on (A) a linear scale and (B) a semi-log scale.

Figure 3 (A) C_max and (B) AUC_0–∞ of trazpiroben after administration of a single oral dose of trazpiroben 25 mg in the presence and absence of itraconazole.

Abbreviations: AUC_0–∞, area under the concentration–time curve from time 0 to infinity; C_max, maximum plasma concentration.

Table 1 Summary of the Plasma Pharmacokinetic Parameters of Trazpiroben 25 mg in the Presence and Absence of Itraconazole

Plasma Pharmacokinetic Parameters	Trazpiroben 25 mg Alone	Trazpiroben 25 mg with Itraconazole
AUC0–∞ (h*ng/mL) Geometric mean (%CV)	24.41 (31.60)	31.45 (27.50)
AUC0–last (h*ng/mL) Geometric mean (%CV)	24.10 (32.10)	30.73 (26.80)
Cmax (ng/mL) Geometric mean (%CV)	9.53 (43.10)	18.00 (26.20)
CL/F (L/h) Mean (%CV)	886.30 (38.20)	678.40 (34.60)
Vz/F (L) Mean (%CV)	3049.70 (60.10)	4563.90 (53.30)
tmax (h) Median Range (min, max)	1.00 0.50–2.00	1.00 0.50–2.00
t1/2z (h) Mean (%CV)	2.32 (36.40)	5.00 (56.60)

Abbreviations: AUC_0–∞, area under the concentration–time curve from time 0 to infinity; AUC_0–last, area under the concentration–time curve from time 0 to the last quantifiable concentration; C_max, maximum plasma concentration; CL/F, apparent clearance after extravascular administration; t_max, time to maximum plasma concentration; t_1/2z, terminal disposition phase half-life; V_z/F, apparent volume of distribution during the terminal disposition phase after extravascular administration; %CV, percentage coefficient of variation.

Table 2 Summary of the Plasma Pharmacokinetic Parameters of Trazpiroben and M23 After Administration of a Single Oral Dose of Trazpiroben 25 mg in the Presence and Absence of Itraconazole

Analyte	Pharmacokinetic Parameter	Geometric Mean Ratio^a	90% CI of Geometric Mean Ratio^a
Trazpiroben 25 mg	AUC0–∞ (h*ng/mL)	1.28	1.10, 1.49
	AUC0–last (h*ng/mL)	1.29	1.12, 1.49
	Cmax (ng/mL)	1.98	1.64, 2.39
M23	AUC0–∞ (h*ng/mL)	1.47	1.06, 2.04
	AUC0–last (h*ng/mL)	2.13	1.57, 2.90
	Cmax (ng/mL)	2.89	2.26, 3.69

Notes: ^aRatio of test:reference (test, trazpiroben 25 mg with itraconazole 200 mg; reference, trazpiroben 25 mg alone).

Abbreviations: AUC_0–∞, area under the concentration–time curve from time 0 to infinity; AUC_0–last, area under the concentration–time curve from time 0 to the last quantifiable concentration; CI, confidence interval; C_max, maximum plasma concentration.

Figure 4 Mean plasma concentration–time curves of M23 (a pharmacologically inactive metabolite of trazpiroben) after administration of a single oral dose of trazpiroben 25 mg in the presence and absence of itraconazole on (A) a linear scale and (B) a semi-log scale.

Figure 5 Linear mixed-effects model of the predicted ΔΔQTcF at different trazpiroben plasma concentrations after administration of a single oral dose of trazpiroben 25 mg in the presence and absence of itraconazole.

Notes: The solid black line with grey shading denotes the model-predicted mean ∆∆QTcF with 90% CI. ^a300 mg was the maximum oral dose in the single ascending dose study.

Abbreviations: ΔΔQTcF, placebo-corrected change from baseline in QTcF; CI, confidence interval; C_max, maximum plasma concentration; QTcF, QT interval corrected for heart rate by the Fridericia method.

Table 3 Summary of Mean 12-Lead Triplicate ECG QT Intervals Corrected Using Fridericia’s Formula²²

Time Relative to Trazpiroben 25 mg Dosing	Statistic	Trazpiroben 25 mg Alone (n = 12)		Trazpiroben 25 mg and Itraconazole (n = 11)
		Observed Value, ms	Change from Pre-Dose, ms	Observed Value, ms	Change from Pre-Dose, ms
Pre-dose	Mean (SD)	391.0 (12.89)	–	390.5 (15.90)	–
	Median (min, max)	390.3 (368, 412)	–	394.3 (365, 412)	–
1 hour post dose	Mean (SD)	389.8 (13.56)	−1.1 (4.05)	390.2 (13.46)	−0.2 (6.31)
	Median (min, max)	390.0 (365, 408)	−2.0 (−6, 8)	397.0 (366, 402)	1.7 (−14, 7)
2 hours post dose	Mean (SD)	390.7 (14.15)	−0.3 (5.31)	391.8 (13.15)	1.4 (6.35)
	Median (min, max)	392.8 (360, 409)	0.3 (−9, 8)	393.7 (365, 407)	1.3 (−10, 12)
4 hours post dose	Mean (SD)	390.0 (12.02)	−1.0 (2.86)	392.3 (15.53)	1.9 (3.22)
	Median (min, max)	391.8 (368, 408)	−1.2 (−6, 3)	399.0 (367, 409)	3.0 (−3, 6)
8 hours post dose	Mean (SD)	387.3 (13.71)	−3.7 (4.74)	391.3 (14.20)	0.8 (6.68)
	Median (min, max)	385.0 (366, 404)	−3.7 (−12, 5)	393.7 (371, 410)	0.0 (−8, 11)
48 hours post dose	Mean (SD)	389.3 (11.45)	−1.7 (4.71)	391.6 (14.30)	1.2 (6.76)
	Median (min, max)	388.3 (374, 409)	−0.7 (−11, 6)	395.7 (368, 407)	1.3 (−10, 13)

Notes: The mean of each participant’s triplicate ECG reading at each time point was used. Baseline for trazpiroben 25 mg alone and trazpiroben 25 mg with itraconazole was defined as the observation at the pre-dose timepoint relative to trazpiroben 25 mg dosing in the corresponding period.

Abbreviations: ECG, electrocardiogram; SD, standard deviation.

Vandenberk B, Vandael E, Robyns T, et al. Which QT correction formulae to use for QT monitoring? J Am Heart Assoc. 2016;5(6):e003264. doi:10.1161/JAHA.116.00326427317349

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