Abuse Potential and Pharmacodynamic Characteristics of Oral and Intranasal Eluxadoline, a Mixed μ- and κ-Opioid Receptor Agonist and δ-Opioid Receptor Antagonist

N. Levy-Cooperman; G. McIntyre; L. Bonifacio; M. McDonnell; J. M. Davenport; P. S. Covington; L. S. Dove; E. M. Sellers

doi:10.1124/jpet.116.236547

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Fig. 1.
Subjective “at this moment” measures of drug effects following oral or intranasal drug administration. (A) Drug Liking VAS scores over 24 hours after oral dosing (mean ±S.E.). (B) Drug Liking VAS scores over 24 hours after intranasal dosing (mean ±S.E.). (C) Bad Effects VAS scores over 24 hours after oral dosing (mean ±S.E.). (D) Bad Effects VAS scores over 24 hours after intranasal dosing (mean ±S.E.). PD analysis sets. ELX, eluxadoline; IR, immediate release; OXY, oxycodone; PBO, placebo.
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Fig. 2.
Subjective overall measures of drug effects following oral or intranasal drug administration. (A) Overall Drug Liking VAS scores at 12 and 24 hours after oral dosing (mean ± 95% CI). (B) Overall Drug Liking VAS scores at 12 and 24 hours after intranasal dosing (mean ±95% CI). (C) Take Drug Again VAS scores at 12 and 24 hours after oral dosing (mean ± 95% CI). (D) Take Drug Again VAS scores at 12 and 24 hours after intranasal dosing (mean ±95% CI). PD analysis sets. CI, confidence interval; ELX, eluxadoline; IR, immediate release; OXY, oxycodone; PBO, placebo.
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Fig. 3.
Mean pupil diameter over time following (A) oral or (B) intranasal drug administration. PD analysis sets. Data presented as mean ±S.E. ELX, eluxadoline; IR, immediate release; OXY, oxycodone; PBO, placebo.

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TABLE 1

Participant demographics and baseline characteristics: oral and intranasal abuse potential studies (randomized sets)

	Oral Abuse Potential Study (n = 40)	Intranasal Abuse Potential Study (n = 36)
Mean age, years (S.D.)	39.8 (9.2)	35.6 (8.8)
Male, n (%)	32 (80.0)	26 (72.2)
Race, n (%)
White	29 (72.5)	30 (83.3)
Black or African American	7 (17.5)	5 (13.9)
Asian	3 (7.5)	1 (2.8)
American Indian or Alaska Native	1 (2.5)	–
Ethnicity, n (%)
Hispanic or Latino	3 (7.5)	0 (0.0)
Not Hispanic or Latino	37 (92.5)	36 (100.0)
Mean BMI, kg/m² (S.D.)	26.5 (3.2)	25.5 (3.0)
Prior recreational drug usage, n (%)
Opioids and morphine derivatives	40 (100.0)	36 (100.0)
Cannabinoids	29 (72.5)	32 (88.9)
Stimulants	29 (72.5)	29 (77.8)
Depressants	8 (20.0)	16 (44.4)
Hallucinogens	8 (20.0)	15 (41.7)
Dissociative anesthetics	3 (7.5)	9 (25.0)
Number of times opioids used, mean (S.D.)
In past 8 weeks	10.2 (6.1)	13.1 (11.8)
In past 12 months	54.8 (37.7)	67.6 (50.9)
Number of times intranasal opioids used, mean (S.D.)
In past 3 months	—	11.9 (9.8)
In past 12 months	—	57.7 (51.4)

BMI, body mass index; S.D., standard deviation.

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TABLE 2

Drug Liking VAS E_max and E_min following oral or intranasal drug administration (PD analysis sets)

Oral Administration
Parameter	Statistic	PBO  (n = 37)	OXY IR 30 mg  (n = 37)	OXY IR 60 mg  (n = 37)	ELX 100 mg  (n = 35)	ELX 300 mg  (n = 36)	ELX 1000 mg  (n = 35)
Drug Liking VAS E_max	Mean (S.D.)	54.3 (9.5)	85.8 (14.3)	90.9 (11.5)	56.8 (13.7)	58.7 (13.4)	60.0 (14.8)
	Median	51.0	88.0	100.0	51.0	51.5	51.0
	Median difference (IQR)
	versus PBO	—	34.5 (23.5, 45.5) ***	41.0 (25.0, 49.0) ***	0.0 (–1.0, 1.0)	0.0 (0.0, 9.0) ^*	0.0 (0.0, 12.0) ^*
	versus OXY IR 30 mg	—	—	—	−35.0 (–45.0, –24.0) ***	−31.0 (–43.0, –17.0) **	−33.0 (–45.0, –16.0) **
	versus OXY IR 60 mg	—	—	—	−37.0 (–49.0, –26.0) ***	−33.0 (–49.0, –20.0) ***	−35.0 (–49.0, –21.0) ***
Drug Liking VAS E_min	Mean (S.D.)	46.5 (11.8)	48.6 (5.8)	42.5 (15.0)	45.0 (14.2)	44.9 (11.1)	38.3 (19.6)
	Median	50.0	50.0	50.0	50.0	50.0	50.0
	Median difference (IQR)
	versus PBO	—	0.0 (0.0, 0.0)	0.0 (–1.0, 0.0)	0.0 (–1.0, 0.0)	0.0 (–2.0, 0.0)	0.0 (–14.0, 0.0) **
	versus OXY IR 30 mg	—	—	—	0.0 (–1.0, 0.0) ^*	0.0 (–2.0, 0.0) ^*	0.0 (–16.0, 0.0) **
	versus OXY IR 60 mg	—	—	—	0.0 (–1.0, 0.0)	0.0 (–1.0, 0.0)	0.0 (–16.0, 0.0)
Intranasal Administration
Parameter	Statistic	PBO lactose  (n = 32)	PBO ELX  (n = 34)	OXY IR 15 mg  (n = 32)	OXY IR 30 mg  (n = 32)	ELX 100 mg  (n = 32)	ELX 200 mg  (n = 32)
Drug Liking VAS E_max	Mean (S.D.)	49.1 (9.0)	52.2 (9.1)	79.5 (22.0)	88.7 (14.6)	53.2 (21.7)	54.9 (21.0)
	Median	51.0	51.0	81.0	95.0	51.0	51.0
	Median difference (IQR)
	versus PBO lactose	—	0.0 (0.0, 0.0)	36.0 (16.5, 49.0) ***	47.0 (28.0, 49.0) ***	0.0 (–1.0, 2.0)	0.0 (–1.0, 20.0)
	versus PBO ELX	—	—	—	—	0.0 (–1.0, 1.0)	0.0 (0.0, 12.0)
	versus OXY IR 15 mg	—	—	—	—	−28.0 (–48.0, -12.0) ***	−26.0 (–48.0, -9.0) ***
	versus OXY IR 30 mg	—	—	—	—	−45.0 (–49.0, -26.0) ***	−42.0 (–49.0, -11.0) ***
Drug Liking VAS E_min	Mean (S.D.)	45.3 (14.3)	38.1 (19.2)	48.1 (16.3)	45.6 (16.9)	16.4 (21.7)	12.4 (20.1)
	Median	50.0	49.0	50.0	50.0	0.0	0.0
	LS mean difference (S.E.)
	versus PBO lactose	—	−6.7 (4.1)	2.7 (4.2)	0.1 (4.2)	−28.4 (4.2) ***	−33.0 (4.20) ***
	versus PBO ELX	—	—	—	—	−21.7 (4.1) ***	−26.3 (4.1) ***
	versus OXY IR 15 mg	—	—	—	—	−31.1 (4.2) ***	−35.7 (4.2) ***
	versus OXY IR 30 mg	—	—	—	—	−28.5 (4.2) ***	−33.1 (4.2) ***

ELX, eluxadoline; IQR, interquartile range; OXY IR, oxycodone immediate release; PBO, placebo.
↵* P < 0.05, **P < 0.01, and ***P < 0.0001.

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TABLE 3

Effects on secondary measures following oral drug administration (PD analysis set)

Parameter	Statistic	PBO  (n = 37)	OXY IR 30 mg (n = 37)	OXY IR 60 mg (n = 37)	ELX 100 mg (n = 35)	ELX 300 mg (n = 36)	ELX 1000 mg (n = 35)
Overall Drug Liking VAS
At 12 h	Mean (S.D.)	51.4 (13.6)	77.3 (17.5)	77.9 (19.2)	50.5 (19.7)	47.2 (24.9)	49.8 (24.0)
	Median	50.0	81.0	78.0	50.0	50.0	50.0
	P value^a	—	^***	^***	^{††† ‡‡‡}	^{††† ‡‡‡}	^{††† ‡‡‡}
Take Drug Again VAS
At 12 h	Mean (S.D.)	15.1 (30.9)	79.4 (25.7)	74.3 (30.5)	18.0 (33.6)	22.5 (30.7)	26.7 (34.1)
	Median	0.0	86.0	90.0	0.0	0.5	2.0
	P value^a	—	^***	^***	^{††† ‡‡‡}	^* ^{††† ‡‡‡}	^{††† ‡‡‡}
Bad Effects VAS
E_max	Mean (S.D.)	8.8 (21.3)	23.4 (29.8)	40.5 (37.9)	13.3 (29.3)	26.9 (28.3)	23.1 (30.5)
	Median	0.0	3.0	28.0	0.0	14.5	11.0
	P value^a	—	**	^***	NS	**	^*
Pupil diameter
MPC	Mean (S.D.)	0.8 (0.7)	2.2 (0.7)	2.6 (0.8)	0.7 (0.5)	0.9 (0.5)	0.9 (0.5)
	Median	0.7	2.0	2.5	0.8	0.8	0.9
	P value^a	—	^***	^***	^{††† ‡‡‡}	^{††† ‡‡‡}	^{††† ‡‡‡}

ELX, eluxadoline; MPC, maximum pupil constriction; NS, not significant; OXY IR, oxycodone immediate release; PBO, placebo.
↵^a P values are for pairwise comparisons of median differences between treatments, assessed using the Wilcoxon signed-rank test.
↵* Significant versus PBO (P < 0.05); **significant versus PBO (P < 0.01);
↵*** significant versus PBO (P < 0.0001); ^†††significant versus OXY IR 30 mg (P < 0.0001);
^‡‡ significant versus OXY IR 60 mg (P < 0.01); ^‡‡‡significant versus OXY IR 60 mg (P < 0.0001).

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TABLE 4

Effects on secondary measures following intranasal drug administration (PD analysis set)

Pairwise comparisons were assessed using the Wilcoxon signed-rank test.

Parameter	Statistic	PBO lactose  (n = 32)	PBO ELX  (n = 34)	OXY IR 15 mg (n = 32)	OXY IR 30 mg (n = 32)	ELX 100 mg (n = 32)	ELX 200 mg (n = 32)
Overall Drug Liking VAS
At 12 h	Mean (S.D.)	43.8 (16.8)	37.6 (22.9)	76.4 (25.3)	80.9 (22.8)	20.7 (26.9)	17.0 (26.7)
	Median	50.0	50.0	76.0	88.0	6.5	0.0
	P value^a	—	NS	***	***	*** ^{§§ ††† ‡‡‡}	*** ^{§§§ ††† ‡‡‡}
Take Drug Again VAS
At 12 h	Mean (S.D.)	6.6 (17.7)	7.0 (19.0)	78.4 (30.5)	81.4 (22.5)	15.3 (27.5)	9.4 (22.5)
	Median	0.0	0.0	94.0	94.0	0.0	0.0
	P value^b	—	NS	***	***	^{††† ‡‡‡}	^{††† ‡‡‡}
Bad Effects VAS
E_max	Mean (S.D.)	2.2 (8.8)	17.4 (25.0)	22.6 (28.2)	35.2 (35.0)	62.8 (38.7)	74.2 (32.0)
	Median	0.0	0.0	11.5	26.0	74.5	83.5
	P value^b	—	^*	^*	***	*** ^{§§§ ††† ‡‡}	*** ^{§§§ ††† ‡‡‡}
Pupil diameter
MPC	Mean (S.D.)	0.6 (0.5)	0.5 (0.5)	2.2 (0.8)	2.7 (0.8)	1.1 (0.6)	1.1 (0.6)
	Median	0.6	0.5	2.2	2.7	1.0	1.1
	P value^a	—	—	***	***	*** ^{§§§ ††† ‡‡‡}	*** ^{§§§ ††† ‡‡‡}

ELX, eluxadoline; LS, least squares; MPC, maximum pupil constriction; NS, not significant; OXY IR, oxycodone immediate release; PBO, placebo.
↵^a P values are for pairwise comparisons of LS mean differences between treatments.
↵^b P values are for pairwise comparisons of median differences between treatments. Both assessed using the Wilcoxon signed-rank test.
↵* Significant versus PBO lactose (P < 0.05);***significant versus PBO lactose (P < 0.0001);^§§significant versus PBO ELX (P < 0.01); ^§§§significant versus PBO ELX (P < 0.0001); ^†††significant versus OXY IR 15 mg (P < 0.0001); ^‡‡significant versus OXY IR 30 mg (P < 0.01); ^‡‡‡significant versus OXY IR 30 mg (P < 0.0001).