Effects of CYP3A4 Inhibition/Induction and OATP Inhibition on the Pharmacokinetics of Atogepant in Healthy Adults

Figures & data

Figure 1. Study design for study A and B. Black bar indicates confinement days.

*Dosing occurred after 10 h fast.

Table 1. Participant characteristics.

Characteristic	Study A (N = 40)	Study B (N = 32)
Age, mean (range), years	34.8 (19–45)	31.3 (18–45)
Sex
– Female, n (%)	22 (55)	19 (59)
– Male	18 (45)	13 (41)
Race, n (%)
– Black/African–American	7 (17.5)	15 (46.9)
– White	33 (82.5)	16 (50.0)
– Asian	NA	1 (3.1)
Ethnicity (%)
– Hispanic or Latino	37 (92.5)	13 (40.6)
Body mass index, mean (SD), kg/m^2	27.41 (2.47)	25.67 (2.60)

NA: Not applicable; SD: Standard deviation.

Figure 2. Study A: the mean plasma atogepant concentration–time profiles following oral administration of 60 mg atogepant alone or in presence of steady-state itraconazole.

(A) Linear scale, (B) semilogarithmic plot. Error bars represent standard deviation.

Table 2. Pharmacokinetic parameters of atogepant following administration with and without itraconazole in healthy participants; Study A (N = 40).

PK parameter	Atogepant + Itraconazole (test)	Atogepant alone (reference)	GMR (%)	90% CI
Cmax (ng/ml)	1580 (496)	740 (231)	215.11	195.25, 236.99
AUC0-t (ng*h/ml)	18,500 (4860)	3440 (1030)	543.26	501.54, 588.45
AUC0-∞ (ng*h/ml)	18,900 (4990)	3470 (1040)	550.78	508.64, 596.42
Tmax (h)^†	3.0 (1.5–4.0)	2.0 (1.0–3.0)	1.0^‡
t1/2 (h)	14.9 (3.96)	11.2 (7.78)

† Median (minimum–maximum).

‡ Difference of median results.

AUC_0-t: Area under the plasma concentration vs time curve from time 0 to time t; AUC_0-∞: Area under the plasma concentration vs time curve from time 0 to infinity; C_max: Maximum plasma drug concentration; GMR: Geometric mean ratio; ng: Nanogram; t_1/2: Terminal elimination half-life; T_max: Time to reach maximum plasma drug concentration.

Figure 3. Study B: mean plasma atogepant concentration–time profiles following oral administration of 60 mg atogepant alone or in combination with single-dose 600 mg rifampin.

(A) Linear scale, (B) semilogarithmic plot. Error bars represent standard deviation.

Figure 4. Study B: mean plasma atogepant concentration–time profiles following oral administration of atogepant 60 mg alone or in combination with multidose rifampin 600 mg.

(A) Linear scale, (B) semilogarithmic plot. Error bars represent standard deviation.

Table 3. Pharmacokinetic parameters of atogepant following administration with and without rifampin in healthy participants; study B (N = 31).

PK parameter	Atogepant + Rifampin (test)	Atogepant alone (reference)	GMR (%)	90% CI
The effect of single-dose rifampin (OATP inhibition) on atogepant PK
AUC0-24 (ng*h/ml)	7631.86	2679.39	284.84	260.29, 311.69
Cmax (ng/ml)	1444.14	648.61	222.65	198.55, 249.68
Tmax (h)^†	1.50 (0.50–2.00)	2.00 (1.00–4.00)	0.5^‡
The effect of multiple-dose rifampin (CYP3A4 induction) on atogepant PK
AUC0-∞ (ng*h/ml)	1091.54	2809.41	38.85	34.56, 43.68
AUC0-t (ng*h/ml)	1121.66	2772.16	40.46	36.16, 45.28
Cmax (ng/ml)	454.44	648.61	70.06	60.27, 81.44
t1/2 (h)	2.39^§ (1.09)	11.4 (5.55)
Vz/F (L)	197 (105)	390 (271)
CL/F (L/h)	58.3 (21.8)	22.8 (8.44)
λz (1/h)	0.325 (0.0833)	0.0778 (0.0411)

† Median (minimum–maximum).

‡ Difference of median results.

§ N = 28.

AUC_0-24: Area under the plasma concentration vs time curve from time 0 to 24 h; AUC_0-t: Area under the plasma concentration vs time curve from time 0 to time t; AUC_0-∞: Area under the plasma concentration vs time curve from time 0 to infinity; CL_/F: Apparent total body clearance of drug from plasma after extravascular administration; C_max: Maximum plasma drug concentration; GMR: Geometric mean ratio; ng: Nanograms; t_1/2: Terminal elimination half-life; T_max: Time to reach maximum plasma drug concentration; V_z/F: Apparent volume of distribution during the terminal phase after extravascular administration; λ_z: Terminal elimination rate constant.

Table 4. Number (%) of participants with treatment-emergent adverse events (TEAE) by study treatment, system organ class and preferred term (safety population).

System organ class preferred term (MedDRA Version 22.1)	Study A 60 mg atogepant^† N = 40 n (%)	Study A 200 mg itraconazole^‡ N = 40 n (%)	Study A 60 mg Atogepant + 200 mg itraconazole^§ N = 40 n (%)	Study A all participants N = 40 n (%)	Study B 60 mg atogepant^† N = 32 n (%)	Study B 60 mg atogepant + 600 mg rifampin^¶ N = 31 n (%)	Study B 60 mg atogepant + 600 mg rifampin^# N = 31 n (%)	Study B all participants N = 32 n (%)
Participants with at least one TEAE	2 (5.0)	3 (7.5)	0 (0)	5 (12.6)	0 (0)	8 (25.8)	5 (16.1)	11 (34.4)
Ear and labyrinth disorders	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Ear congestion	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
Gastrointestinal disorders	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	2 (6.5)	2 (6.5)	3 (9.4)
– Nausea	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.2)	2 (6.3)
– Abdominal discomfort	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Diarrhea	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Vomiting	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Abdominal pain	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.1)
– Constipation	0 (0)	1 (2.5)	0 (0)	1 (2.5)	0	0	0	0
Injury, poisoning and procedural complications	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Thermal burn	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
Investigations	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.1)
– Aspartate aminotransferase increased	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.1)
Musculoskeletal and connective tissue disorders	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.2)	2 (6.3)
– Arthralgia	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Joint stiffness	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.1)
Nervous system disorders	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	2 (6.5)	1 (3.2)	3 (9.4)
– Headache	0 (0)	2 (5.0)	0 (0)	2 (5.0)	0 (0)	2 (6.5)	0 (0)	2 (6.3)
– Dizziness	2 (5.0)	0 (0)	0 (0)	2 (5.0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Sedation	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	1 (3.1)
Renal and urinary disorders	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Chromaturia	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
Skin and subcutaneous tissue disorders	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	3 (9.7)	0 (0)	3 (9.4)
– Dermatitis	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Hyperkeratosis	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)
– Pruritus	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	1 (3.2)	0 (0)	1 (3.1)

† Single dose 60 mg atogepant alone on day 1 under fasting conditions.

‡ Once daily 200 mg itraconazole on days 8 through 14 under fed conditions.

§ Co-administration of 60 mg atogepant and 200 mg itraconazole on day 15 under fasting conditions, 200 mg itraconazole once daily on days 16 to 17.

¶ Co-administration of 60 mg atogepant and 600 mg rifampin on day 7 followed by 600 mg rifampin alone, once daily, on days 8, 9, 10 and 11.

# Co-administration of 60 mg atogepant and 600 mg rifampin on day 12 followed by 600 mg rifampin alone on day 13.

MedDRA: Medical Dictionary for Regulatory Activities; N: Number of participants; n: Number of events.

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