Bioequivalence of oxymorphone extended release and crush-resistant oxymorphone extended release

Figures & data

Figure 1 Subject disposition.

Abbreviations: AE, adverse event; Oxy-ER, oxymorphone extended release; Oxy-CRF, crush-resistant oxymorphone extended release; PK, pharmacokinetics.

Table 1 Subject demographics (safety population)

Characteristic	Treatment
	5 mg, Fasted (n = 30)	40 mg, Fasted (n = 37)	40 mg, Fed (n = 36)
Age, years
Mean ± SD	35 ± 7	33 ± 8	34 ± 8
Range	20–45	19–44	19–44
Women, n (%)	14 (47)	22 (59)	19 (53)
Race, n (%)
White	26 (87)	29 (78)	30 (83)
Black	4 (13)	8 (22)	6 (17)
Ethnicity, n (%)
Hispanic	30 (100)	32 (86)	36 (100)
Non-hispanic	0	5 (14)	0
Height, cm
Mean ± SD	169 ± 9	166 ± 9	167 ± 9
Range	152–187	141–184	145–185
Weight, kg
Mean ± SD	72 ± 10	72 ± 10	71 ± 12
Range	53–95	51–95	51–96
BMI, kg/m^2
Mean ± SD	25 ± 3	26 ± 2	25 ± 3
Range	21–30	22–30	19–30

Abbreviations: BMI, body mass index; SD, standard deviation.

Figure 2 Mean oxymorphone plasma concentrations 0–48 hours after single oral doses of Oxy-ER and Oxy-CRF (A) 5 mg administered under fasted conditions, (B) 40 mg administered under fasted conditions, and (C) 40 mg administered after a high-fat breakfast.

Abbreviations: Oxy-ER, oxymorphone extended release; Oxy-CRF, crush-resistant oxymorphone extended release; SE, standard error.

Table 2 Plasma oxymorphone pharmacokinetic parameters

Parameter	Treatment
	5 mg, Fasted (n = 28)		40 mg, Fasted (n = 31)		40 mg, Fed (n = 30)
	Oxy-ER	Oxy-CRF	Oxy-ER	Oxy-CRF	Oxy-ER	Oxy-CRF
AUC0–t, ng · h/mL Mean ± SD	5.05 ± 1.55	5.29 ± 1.52	31.51 ± 10.95	31.23 ± 10.33	50.16 ± 14.91	49.01 ± 14.03
%CV	30.7	28.7	34.7	33.1	29.7	28.6
AUC0–inf, ng · h/mL Mean ± SD	ND	ND	32.99 ± 11.58	32.65 ± 10.92	52.29 ± 15.98	50.95 ± 14.63
%CV			35.1	33.4	30.6	28.7
Cmax, ng/mL Mean ± SD	0.38 ± 0.11	0.37 ± 0.12	2.37 ± 1.20	2.41 ± 0.94	5.87 ± 1.99	5.63 ± 2.26
%CV	30.5	31.7	50.6	38.9	33.9	40.1
Median tmax, h	6.0	5.0	3.0	5.0	3.5	5.0
Range	1.0–12.0	1.0–16.0	0.5–12.0	0.5–12.0	1.0–6.0	1.0–10.0
Mean ± SD t1/2, ha	ND	ND	10.0 ± 2.5	9.9 ± 2.7	10.5 ± 4.1	10.3 ± 3.6
%CV			25.5	26.9	39.3	35.2

a Note: Not evaluated because monoexponential elimination was not evident in most cases.

Abbreviations: AUC_0–inf, area under the concentration versus time curve from time 0 to infinity; AUC_0–t, AUC from time 0 to the last measured concentration; C_max, maximum plasma concentration; CV, coefficient of variation; ND, not determined; Oxy-CRF, crush-resistant oxymorphone extended release; Oxy-ER, oxymorphone extended release; t_1/2, terminal half-life; t_max, time to C_max; SD, standard deviation.

Table 3 Plasma 6-OH-oxymorphone pharmacokinetic parameters

Parameter	Treatment
	5 mg, Fasted (n = 28)		40 mg, Fasted (n = 31)		40 mg, Fed (n = 30)
	Oxy-ER	Oxy-CRF	Oxy-ER	Oxy-CRF	Oxy-ER	Oxy-CRF
AUC0–t, ng · h/mL Mean ± SD	4.15 ± 1.82	4.24 ± 1.95	26.08 ± 9.39	26.10 ± 10.18	33.40 ± 11.94	33.39 ± 11.48
%CV	43.9	46.0	36.0	39.0	35.7	34.4
AUC0–inf, ng · h/mL Mean ± SD	ND	ND	32.96 ± 13.86	33.61 ± 15.57	40.99 ± 16.47	42.05 ± 16.88
%CV			42.1	46.3	40.2	40.1
Cmax, ng/mL Mean ± SD	0.24 ± 0.07	0.20 ± 0.12	1.61 ± 0.59	1.45 ± 0.55	2.24 ± 0.89	2.23 ± 0.87
%CV	28.2	56.9	36.3	37.6	39.7	38.8
Median tmax, h	1.5	3.0	1.5	3.0	4.0	5.0
Range	0.5–6.0	0.5–24.0	0.5–5.0	0.5–24.0	1.0–10.0	1.0–12.0
Mean ± SD t1/2, ha	ND	ND	19.3 ± 9.8	21.5 ± 15.9	17.8 ± 7.3	19.5 ± 8.8
%CV			50.8	73.7	41.1	45.0

a Note: Not evaluated because monoexponential elimination was not evident in most cases.

Abbreviations: 6-OH-oxymorphone, 6-hydroxy-oxymorphone; AUC_0–inf, area under the concentration versus time curve from time 0 to infinity; AUC_0–t, AUC from time 0 to the last measured concentration; C_max, maximum plasma concentration; CV, coefficient of variation; ND, not determined; Oxy-CRF, crush-resistant oxymorphone extended release; Oxy-ER, oxymorphone extended release; t_1/2, terminal half-life; t_max, time to C_max.

Figure 3 Mean 6-OH-oxymorphone plasma concentrations 0–48 hours after single oral doses of Oxy-ER and Oxy-CRF (A) 5 mg administered under fasted conditions, (B) 40 mg administered under fasted conditions, and (C) 40 mg administered after a high-fat breakfast.

Abbreviations: 6-OH-oxymorphone, 6-hydroxy-oxymorphone; Oxy-ER, oxymorphone extended release; Oxy-CRF, crush-resistant oxymorphone extended release.

Table 4 Bioequivalence data: systemic plasma oxymorphone exposure

Parameter	Ratio of least squares geometric means (Oxy-CRF/Oxy-ER)	90% CI
5 mg, fasted
AUC0–t, ng · h/mL	1.05	1.01–1.09
Cmax, ng/mL	0.98	0.93–1.03
40 mg, fasted
AUC0–t, ng · h/mL	0.99	0.95–1.04
AUC0–inf, ng · h/mL	0.99	0.95–1.04
Cmax, ng/mL	1.05	0.98–1.12
40 mg, fed
AUC0–t, ng · h/mL	0.97	0.93–1.02
AUC0–inf, ng · h/mL	0.97	0.93–1.02
Cmax, ng/mL	0.94	0.88–1.02

Abbreviations: AUC_0–inf, area under the concentration versus time curve from time 0 to infinity; AUC_0–t, AUC from time 0 to the last measured concentration; C_max, maximum plasma concentration; Oxy-CR F, crush-resistant oxymorphone extended release; Oxy-ER, oxymorphone extended release; CI, confidence interval.

Table 5 Bioequivalence data: systemic plasma 6-OH-oxymorphone exposure

Parameter	Ratio of least squares mean, Oxy-CRF/Oxy-ER	90% CI
5 mg, fasted
AUC0–t, ng · h/mL	1.01	0.95–1.07
Cmax, ng/mL	0.80	0.75–0.86
40 mg, fasted
AUC0–t, ng · h/mL	0.99	0.94–1.04
AUC0–inf, ng · h/mL	1.01	0.95–1.08
Cmax, ng/mL	0.91	0.86–0.95
40 mg, fed
AUC0–t, ng · h/mL	1.00	0.96–1.05
AUC0–inf, ng · h/mL	1.02	0.97–1.08
Cmax, ng/mL	1.01	0.94–1.07

Abbreviations: 6-OH-oxymorphone, 6-hydroxy-oxymorphone; AUC_0–inf, area under the concentration versus time curve from time 0 to infinity; AUC_0–t, AUC from time 0 to the last measured concentration; C_max, maximum plasma concentration; Oxy-CRF, crush-resistant oxymorphone extended release; Oxy-ER, oxymorphone extended release; CI, confidence interval.