Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial

Figures & data

Figure 1 Study design diagram.

Figure 2 Flow chart of participant distribution.

Abbreviations: FAS, full analysis set; SS, safety set; PKCS, pharmacokinetics concentration set; PKPS, pharmacokinetics parameter set.

Table 1 Demographic Data and Baseline Characteristics of the Study Participants (mean±SD)

Parameter	0.75mg (N=12)	1.5mg (N=11)	3.0mg (N=10)	Total (N=33)
Age (years)
Mean±SD	36.3±12.25	28.3±8.47	28.9±6.42	31.4±10
Min~Max	19~56	19~43	19~36	19~56
Sex
Male, n (%)	5(41.7%)	8(72.7%)	4(40.0%)	17(51.5%)
Female, n (%)	7(58.3%)	3(27.3%)	6(60.0%)	16(48.5%)
Ethnicity
Han Chinese n(%)	10(83.3%)	9(81.8%)	10(100.0%)	29(87.9%)
Other n(%)	2(16.7%)	2(18.2%)	0(0%)	4(12.1%)
Height(cm)
Mean±SD	163.79±9.245	166.23±6.802	165.35±9.713	165.08±8.454
Min~Max	152.5~179.5	156.5~178.0	153.0~181.5	152.5~181.5
Weight(kg)
Mean±SD	64.53±10.445	67.65±11.282	62.04±14.699	64.82±11.968
Min~Max	46.4~84.2	51.6~85.9	49.8~90.0	46.4~90.0
BMI(kg/m^2)
Mean±SD	23.98±2.652	24.43±3.512	22.40±2.993	23.65±3.086
Min~Max	19.6~29.3	20.2~29.5	19.7~28.2	19.6~29.5

Abbreviation: BMI, body mass index.

Figure 3 Mean plasma concentration–time curves. (a) Mean plasma concentration-time plot (Mean+SD) (b) Semilogarithmic scale diagram (Mean+SD) (c) Mean plasma concentration-time plot (0–1h) (Mean+SD) (d) semilog scale diagram (0–1h) (Mean+SD) (e) Mean plasma concentration-time plot (0–4h) (Mean+SD) (f) semilog scale diagram(0–4h) (Mean+SD).

Table 2 Oliceridine Pharmacokinetic Parameters (GeoMean (CV%) or Median (Min, Max))

Parameter	0.75 mg (GeoMean(CV%))	1.5 mg (GeoMean(CV%))	3.0 mg (GeoMean(CV%))
N	12	10*	10
Cmax	51.293 (58.47)	65.969 (71.03)	81.914 (69.84)
AUC0-t	19.199 (22.13)	34.249 (11.22)	69.096 (26.39)
AUC0-∞	19.528 (22.24)	34.668 (11.38)	69.783 (25.85)
AUC−%Extrap	1.620 (30.33)	1.064 (57.55)	0.748 (105.00)
Tmax	0.034 (0.034, 0.087)	0.034 (0.033, 0.035)	0.083 (0.034, 0.168)
t1/2	1.850 (28.01)	1.874 (14.85)	2.084 (28.80)
λz	0.375 (28.01)	0.370 (14.85)	0.333 (28.80)
CL	38.406 (22.24)	43.267 (11.38)	42.991 (25.85)
Vz	102.522 (23.63)	116.961 (11.85)	129.273 (40.11)
MRT	1.992 (22.60)	2.147 (19.53)	2.272 (28.07)

Notes: T_max(day): median (min, max); CV: coefficient of variation; *C_max and T_max values of subject TRV-B102 assigned to the 1.5 mg group were not included in the primary analysis of PKPS due to (1) blockage of the intravenous line during drug administration and (2) the resultant increased administration time required which exceeded protocol requirements. However, this subject’s data were included in the sensitivity analysis for the robustness of the test results. As such, only 9 subjects were pooled for the PKPS analysis.

Abbreviations: C_max, peak serum concentration; AUC_0-t, area under the blood concentration-time curve from 0 to t time; AUC_0-∞, area under the blood concentration curve from 0 to infinity time; AUC_−%Extrap, percentage of residual area; T_max, time of occurrence of C_max; t_1/2, terminal phase half-life; λ_z, terminal rate constant in noncompartmental mental analysis; CL, clearance; V_z, volume of distribution during terminal phase after intravenous administration; MRT, mean dissolution time.

Table 3 Analysis of Dose-Proportionality

Parameters	N	W-Statistic*	p-value	Correlation Coefficient	Coefficient of determination R^2	Intercept	Slope	95% CI
Cmax(ng/mL)	31	0.964907	0.3718	0.3265	0.1066	4.0396	0.3384	−0.0336, 0.7103
AUC0-t(ng·h/mL)	32	0.964891	0.3715	0.9356	0.8753	3.2023	0.9212	0.7916, 1.0509
AUC0-∞(ng·h/mL)	32	0.97989	0.8096	0.9356	0.8753	3.2175	0.9161	0.7872, 1.0450

Note: *W-Statistic: The test statistic for the Shapiro–Wilk test, which assesses the normality of the data.

Abbreviations: ng, nanogram; mL, milliliter; h, hour; CI, confidence interval.

Figure 4 Main PK parameters versus dose. (a) Dose(mg) versus C_max(ng/mL) (b) Logarithmic plot of dose versus C_max (c) Dose(mg) versus AUC_0-t(ng/mL) (d) Logarithmic plot of dose versus AUC_0-t (e) Dose(mg) versus AUC_0-∞(ng/mL) (f) Logarithmic plot of dose versus AUC_0-∞.

Table 4 Contrast of PK Parameters in the 1.5 Mg Group Between This and Previous Studies (GeoMean)

Parameters	This study(N=10)	CP130-1003(N=29)	CP130-1005A(N=8)
Cmax(ng/mL)	65.969	46.7	46.9
Tmax(h)	0.034	0.167	0.03
AUC0-t (ng·h/mL)	34.249	43.3	28.4
AUC0-∞(ng·h/mL)	34.668	43.8	30.3
Vz(L)	116.961	-*	92.3
CL(L/h)	43.267	34.3	49.5
t1/2(h)	1.874	1.93	1.61

Note: *No relevant data.

Table 5 Contrast of PK Parameters in the 3.0 Mg Group Between This and Previous Studies (GeoMean)

Parameters	This study (N=10)	CP130-1002 (N=6)	CP130-1003 (N=30)	CP130-1005A (N=9)
Cmax(ng/mL)	81.914	55.56	75.9	74.7
Tmax(h)	0.083	0.083	0.167	0.03
AUC0-t (ng·h/mL)	69.096	72.748	81.2	56.5
AUC0-∞(ng·h/mL)	69.783	73.399	81.8	60.5
Vz(L)	129.273	-*	-*	92.1
CL(L/h)	42.991	40.876	36.7	49.6
t1/2(h)	2.084	3.144	1.9	1.55

Note: *No relevant data.

Table 6 Comparison of PK Blood Collection Time Points

	Before Administration	Time 0^c	5 min	10 min	15 min	0.5 h	1 h	2 h	3 h	4 h	6 h	8 h	12 h	24 h	48 h
This study^a	X	X	X	X		X	X	X	X	X	X	X	X	X	X
CP130-1002^a	X	X	X		X	X	X	X		X		X	X	X
CP130-1003^b	X	X		X		X	X	X	X	X		X	X	X
CP130-1005A^b	X	X	X		X	X	X	X	X	X	X

Notes: The CP130-1005A study employed a repeated dosing regimen, administering doses every 6 hours. For the purpose of this comparison, only the blood collection time points within the first 6-hour period post-initial dosing are included. ^aThe post-dose time point is the time after the start of the study drug infusion. ^bThe post-dose time point refers to the time after the end of the study drug infusion. ^c“time 0” is 2 minutes after the start of the study drug infusion or at the end of the study drug infusion.

Table 7 Comparison of “Time 0” PK Blood Collection Time Point Between This and Previous Studies

“time 0”	This study	CP130-1002	CP130-1003	CP130-1005A
Specify the acquisition time point	Immediately after the end of infusion	Immediately before the end of the infusion	Before the end of infusion	Within 30s before the end of infusion
Actual average acquisition time point	2.04 min	1.75 min	1.5 min	-*

Note: *No relevant data.

Table 8 Treatment-Emergent Adverse Events

SOC/PT	0.75 mg(N=12)		1.5 mg(N=10)		3.0 mg(N=10)		Total(N=32)
	Events	Cases (%)	Events	Cases (%)	Events	Cases (%)	Events	Cases (%)
Total	22	8(66.7%)	34	9(90.0%)	44	10(100.0%)	100	27(84.4%)
Nervous system disorders	4	2(16.7%)	13	7(70.0%)	20	10(100.0%)	37	19(59.4%)
Lethargy	2	2(16.7%)	4	4(40.0%)	6	6(60.0%)	12	12(37.5%)
Dizziness	2	2(16.7%)	7	7(70.0%)	3	3(30.0%)	12	12(37.5%)
Vertigo	0	0(0.0%)	0	0(0.0%)	6	6(60.0%)	6	6(18.8%)
Hypoesthesia	0	0(0.0%)	2	2(20.0%)	3	3(30.0%)	5	5(15.6%)
Sleepy	0	0(0.0%)	0	0(0.0%)	1	1(10.0%)	1	1(3.1%)
Pre-syncope	0	0(0.0%)	0	0(0.0%)	1	1(10.0%)	1	1(3.1%)
Various inspections	6	3(25.0%)	11	7(70.0%)	10	7(70.0%)	27	17(53.1%)
Decreased oxygen saturation	2	2(16.7%)	0	0(0.0%)	5	5(50.0%)	7	7(21.9%)
Decreased systolic blood pressure	0	0(0.0%)	0	0(0.0%)	2	2(20.0%)	2	2(6.3%)
Decreased heart rate	0	0(0.0%)	1	1(10.0%)	0	0(0.0%)	1	1(3.1%)
Elevated heart rate	0	0(0.0%)	0	0(0.0%)	1	1(10.0%)	1	1(3.1%)
Elevated blood pressure	0	0(0.0%)	3	1(10.0%)	0	0(0.0%)	3	1(3.1%)
Systemic reactions and various reactions at the administration site	9	6(50.0%)	5	5(50.0%)	5	5(50.0%)	19	16(50.0%)
Feelings of heat	3	3(25.0%)	4	4(40.0%)	2	2(20.0%)	9	9(28.1%)
Relaxed feeling	6	6(50.0%)	0	0(0.0%)	2	2(20.0%)	8	8(25.0%)
Asthenia	0	0(0.0%)	1	1(10.0%)	1	1(10.0%)	2	2(6.3%)
The skin and subcutaneous tissue disorders	0	0(0.0%)	2	2(20.0%)	6	4(40.0%)	8	6(18.8%)
Pruritus	0	0(0.0%)	0	0(0.0%)	4	4(40.0%)	4	4(12.5%)
Sweaty	0	0(0.0%)	2	2(20.0%)	1	1(10.0%)	3	3(9.4%)
Flush	0	0(0.0%)	0	0(0.0%)	1	1(10.0%)	1	1(3.1%)
Gastrointestinal disorders	3	3(25.0%)	1	1(10.0%)	2	2(20.0%)	6	6(18.8%)
Nausea	1	1(8.3%)	1	1(10.0%)	2	2(20.0%)	4	4(12.5%)
Dry mouth	2	2(16.7%)	0	0(0.0%)	0	0(0.0%)	2	2(6.3%)
Respiratory system, chest, and mediastinum disorders	0	0(0.0%)	1	1(10.0%)	1	1(10.0%)	2	2(6.3%)
Dyspnea	0	0(0.0%)	1	1(10.0%)	1	1(10.0%)	2	2(6.3%)
Cardiovascular system disorders	0	0(0.0%)	1	1(10.0%)	0	0(0.0%)	1	1(3.1%)
Palpitations	0	0(0.0%)	1	1(10.0%)	0	0(0.0%)	1	1(3.1%)

Abbreviation: SOC/PT, systematic organ classification and preferred term.

Data Sharing Statement

The clinical raw data in this paper will be available upon reasonable request through an e-mail to the corresponding author (Guoping Yang).