Clinical Pharmacokinetics of Semaglutide: A Systematic Review

Figures & data

Figure 1 PRISMA flow chart diagram.

Table 1 Characteristics of Included Studies

No.	Study	Population (Ethnicity)		No. of Subjects	Age (Years)	Dosage Form	Dose	Frequency
Subcutaneous Injections
1	Jensen et al (2017)^Citation28	Healthy (NA)		7	48–64	Subcutaneous injection	0.5 mg	Once
2	Ikushima et al (2018)^Citation33	Healthy (Japanese)		8	34.1 (23–44)	Subcutaneous injection	0.25 mg (4 weeks) 0.5 mg (9 weeks)	Once-weekly
		Healthy (Japanese)		8	39.1 (29–47)	Subcutaneous injection	0.25 mg (4 weeks) 0.5 mg (4 weeks) 1.0 mg (5 weeks)	Once-weekly
		Healthy (Japanese)		6	41.4 (27–51)	Subcutaneous injection	Placebo (13 weeks)	Once-weekly
		Healthy (Caucasian)		8	33.4 (26–52)	Subcutaneous injection	0.25 mg (4 weeks) 0.5 mg (9 weeks)	Once-weekly
		Healthy (Caucasian)		8	35.0 (25–51)	Subcutaneous injection	0.25 mg (4 weeks) 0.5 mg (4 weeks) 1.0 mg (5 weeks)	Once-weekly
		Healthy (Caucasian)		6	36.5 (26–49)	Subcutaneous injection	Placebo (13 weeks)	Once-weekly
3	Shi et al (2021)^Citation34	Healthy (Chinese)		12	33.6 (23–44)	Subcutaneous injection	0.25 mg (4 weeks)→ 0.5 mg (9 weeks)	Once-weekly
		Healthy (Chinese)		12	33.3 (22–44)	Subcutaneous injection	0.25 mg (4 weeks)→ 0.5 mg (4 weeks)→ 1.0 mg (5 weeks)	Once-weekly
		Healthy (Chinese)		12	33.3 (27–52)	Subcutaneous injection	Placebo (13 weeks)	Once-weekly
4	Kapitza et al (2015)^Citation35	Postmenopausal women with T2D (NA)		43	62.2±6	Subcutaneous injection	0.25 mg (4 weeks)→ 0.5 mg (4 weeks)→ 1.0 mg (5 weeks)	Once-weekly
5	Blundell et al (2017)^Citation36	Subjects with obesity		30	42 (21–70)	Subcutaneous injection	0.25 mg (4 weeks)→ 0.5 mg (4 weeks)→ 1.0 mg (5 weeks)	Once-weekly
6	Marbury et al (2017)^Citation37	Healthy (NA)		14	54.6±9.1	Subcutaneous injection	0.5 mg	Once
		Mild RI (NA)		11	62.9±8.0	Subcutaneous injection	0.5 mg	Once
		Moderate RI (NA)		11	66.5±6.6	Subcutaneous injection	0.5 mg	Once
		Severe RI (NA)		10	62.8±9.1	Subcutaneous injection	0.5 mg	Once
		ESRD (NA)		10	48.2±7.2	Subcutaneous injection	0.5 mg	Once
7	Jensen et al (2018)^Citation29	Normal hepatic function (NA)		19	52 (34–67)	Subcutaneous injection	0.5 mg	Once
		Mild HI (NA)		8	52 (34–64)	Subcutaneous injection	0.5 mg	Once
		Moderate HI (NA)		10	56 (35–67)	Subcutaneous injection	0.5 mg	Once
		Severe HI (NA)		7	55 (45–61)	Subcutaneous injection	0.5 mg	Once
8	Enebo et al (2021)^Citation38	Overweight participants who are otherwise healthy (Hispanic or Latino or other)		96	40.6±9.2	Subcutaneous injection	Cagrilintide (0.16–4.5 mg) + semaglutide 2.4 mg	Once-weekly
Oral administration
9	Granhall et al (2019)^Citation39		Healthy (White/Black or African American/ Asian/Other)	135	30.1±8.0	Tab. (Oral administration)	2–20 mg Placebo	Once
			Healthy (White/Black or African American/ Other)	84	44.7±11.6	Tab. (Oral administration)	20 or 40 mg Placebo (10 weeks)	Once-daily
			Type 2 diabetic (White/Black or African American)	23	54.5±8.3	Tab. (Oral administration)	40 mg Placebo (10 weeks)	Once-daily
10	Bækdal et al (2021a)^Citation40		Healthy (NA)	26	38±11	Tab. (Oral administration)	10 mg with 50 mL water 10 mg with 240 mL water	Twice (2-period crossover trial)
11	Bækdal et al (2021b)^Citation41		Healthy (White/Black or African American/ Other)	78	55.1±13.9	Tab. (Oral administration) Food-effect trial: fasting/fed/reference	Semaglutide 5 mg (5 days) → 10 mg (5 days)	Once-daily
			Healthy (White/Black or African American/ Other)	158	40.5±9.7	Tab. (Oral administration) Dosing conditions trial: with 50 or 120 mL water, and 15–120 min post-dose fast	10 mg (10 days)	Once-daily
12	Hauge et al (2021)^Citation42	Healthy (NA)		45	36±8	Tab. (Oral administration)	Semaglutide 14 mg (5 days); Semaglutide 14 mg + five placebo tablets (5 days)	Once-daily
13	van Hout et al (2023)^Citation43	Healthy (Hispanic or Latino or Other)		156	40±12	Tab. (Oral administration)	3 mg (5 days) → 7 mg (5 days)	Once-daily
14	Bækdal et al (2018a)^Citation44	Normal hepatic function (NA)		24	49±11	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		Mild HI (NA)		12	52±10	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		Moderate HI (NA)		12	54±10	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		Severe HI (NA)		8	52±8	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
15	Granhall et al (2018)^Citation45	Normal renal function (NA)		24	52±8	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		Mild RI (NA)		12	57±13	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		Moderate RI (NA)		12	59±11	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		Severe RI (NA)		12	57±12	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
		ESRD (NA)		11	54±13	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
16	Meier et al (2022)^Citation46	Type 2 diabetic with upper gastrointestinal disease (All White)		36	62±8	Tab. (Oral administration)	3 mg (5 days) → 7 mg (5 days)	Once-daily
		Type 2 diabetic without upper gastrointestinal disease (18 White and 1 Black or African American)		19	58±12	Tab. (Oral administration)	3 mg (5 days) → 7 mg (5 days)	Once-daily
17	Bækdal et al (2018b)^Citation47	Healthy (NA)		28	52±13	Tab. (Oral administration)	5 mg (5 days) → 10 mg (5 days)	Once-daily
				26	59±7	Tab. + gastro-resistant capsules (Oral administration)	semaglutide 5 mg + omeprazole 40 mg (5 days) → semaglutide 10 mg + omeprazole 40 mg (5 days)	Once-daily

Abbreviation: NA, not available.

Table 2 Studies of Semaglutide with Subcutaneous Route

No.	Study	Plasma Pharmacokinetic Parameters
		Population	Administered Dose And Dosage Form	AUC (nmol·h /L)	Cmax (nmol/L)	T1/2 (h)	Tmax (h)	CL/F (L/h)
1	Jensen et al (2017)^Citation28	Healthy (NA)	Single dose 0.5 mg	AUC0-inf: 3123.4±12.0	10.9±18.2	168.3±6.3	56	0.039±12.021
2	Ikushima et al (2018)^Citation33	Healthy (Japanese)	Steady-state 0.5 mg	AUC0-168h: 3583±17.8	25.1±17.8	145±8.0	30 (12–72)	0.034±17.8
		Healthy (Japanese)	Steady-state 1.0 mg	AUC0-168h: 7449±12.2	51.6±11.1	163±10.9	36 (18–96)	0.033±12.2
		Healthy (Caucasian)	Steady-state 0.5 mg	AUC0-168h: 3371±2.4	23.7±7.5	159±9.0	36 (24–72)	0.036±2.4
		Healthy (Caucasian)	Steady-state 1.0 mg	AUC0-168h: 7490±17.9	50.6±17.5	167±13.2	30 (24–72)	0.032±17.9
3	Shi et al (2021)^Citation34	Healthy (Chinese)	Single dose 0.25 mg	AUC0-168h: 918	6.9	NA	36 (24–96)	NA
			Steady-state 0.5 mg	AUC0-168h: 4000	28.8	156	36 (30–42)	0.030
		Healthy (Chinese)	Single dose 0.25 mg	AUC0-168h: 937	7.0	NA	42 (24–120)	NA
			Steady-state 1.0 mg	AUC0-168h: 7961	55.9	159	30 (12–96)	0.031
4	Kapitza et al (2015)^Citation35	Postmenopausal women with T2D	Steady-state 1.0 mg	AUC0–168h: 4602	33.8	165	36 (12.0–167.2)	NA
5	Blundell et al (2017)^Citation36	Obese subjects	Steady-state 1.0 mg	AUC0-168h: 4467	32.0	NA	33.2	NA
6	Marbury et al (2017)^Citation37	Normal	Single dose 0.5 mg	AUC0-inf: 2600±27	10.3±35	183±15	24 (8–66)	0.047±27
		Mild RI	Single dose 0.5 mg	AUC0-inf: 2615±19	9.8±22	169±14	35 (14–96)	CL/F:0.046±19 L/h
		Moderate RI	Single dose 0.5 mg	AUC0-inf: 2999±20	9.0±44	201±14	24 (14–96)	CL/F:0.041±20 L/h
		Severe RI	Single dose 0.5 mg	AUC0-inf: 3179±22	9.8±37	221±26	41 (16–96)	CL/F:0.038±22 L/h
		ESRD	Single dose 0.5 mg	AUC0-inf: 2567±18	7.4±22	243±19	51 (28–72)	CL/F:0.047±18 L/h
7	Jensen et al (2018)^Citation29	Normal hepatic function	Single dose 0.5 mg	AUC0-inf: 3026 AUC0-last: 2731	9.5	150	65.8 (30.0–167.5)	NA
		Mild HI	Single dose 0.5 mg	AUC0-inf: 2872 AUC0-last: 2621	9.3	155	65.9 (54.4–119.8)	NA
		Moderate HI	Single dose 0.5 mg	AUC0-inf: 3080 AUC0-last: 2807	9.7	151	77.8 (23.8–144.1)	NA
		Severe HI	Single dose 0.5 mg	AUC0-inf: 2937 AUC0-last: 2539	10.9	163	53.6 (29.9–144.9)	NA
8	Enebo et al (2021)^Citation38	Overweight participants who are otherwise healthy	Steady-state 2.4 mg + cagrilintide (0.16–4.5 mg)	AUC0–168h: 12,757–15,305	96.4–120	145–165	12–24	NA

Abbreviation: NA, not available.

Table 3 Studies of Semaglutide with Oral Route

No.	Study	Plasma Pharmacokinetic Parameters
		Population	Administered Dose	AUC (nmol·h /L)	Cmax (nmol/L)	T1/2 (h)	Tmax (h)
1	Granhall et al (2019)^Citation39	Healthy	Single dose 2–20 mg	NA	NA	NA	NA
		Healthy	Steady-state 20 mg	NA	NA	153	NA
		Healthy	Steady-state 40 mg	NA	NA	161	NA
		Type 2 diabetic	Steady-state 40 mg	NA	NA	158	NA
2	Bækdal et al (2021a)^Citation40	Healthy	Single dose 10 mg	NA	NA	NA	1.5
3	Bækdal et al (2021b)^Citation41 Food-effect trial:	Fasting: healthy	Steady-state 10 mg	~40% greater for the fasting VS reference	~40% greater for the fasting VS reference	160	1.75 (0.50–6.02)
		Reference: healthy	Steady-state 10 mg			152	1.00 (0.50–4.00)
	Dosing conditions trial: Water volume	Healthy	Steady-state 10 mg	Comparable with 50 or 120 mL water	Comparable with 50 or 120 mL water	Comparable with 50 or 120 mL	Comparable with 50 or 120 mL
	Dosing conditions trial: post-dose fasting period	Healthy	Steady-state 10 mg	increased significantly with longer post-dose fasting	increased significantly with longer post-dose fasting	Comparable	tmax increased with longer post-dose fasting (median range 0.5–2.3 h).
4	Hauge et al (2021)^Citation42	Healthy	Steady-state 14 mg	AUC0–24 h: 544	27.7	NA	1.0 (0.0–11.9)
			Steady-state 14 mg + five placebo tablets	AUC0–24 h: 360	18.8	NA	1.0 (0.0–3.0)
5	van Hout et al (2023)^Citation43	Healthy	Steady-state 7 mg	NA	NA	NA	0.8–1.0
6	Bækdal (2018a)^Citation44	Normal	Steady-state 10 mg	AUC0-24h: 250.3±64	13.3±62.3	156.4 ±12.1	1.0 (0.5–4.0)
		Mild HI	Steady-state 10 mg	AUC0-24h: 221.9±78.3	11.8±82.4	142.1 ±7.6	1.0 (0.5–3.0)
		Moderate HI	Steady-state 10 mg	AUC0-24h: 204.2±71.4	10.5±73.5	146.7 ±13.9	1.0 (1.0–3.0)
		Severe HI	Steady-state 10 mg	AUC0-24h: 227.8±41.6	12.0±41.4	153.7 ±12.5	1.5 (1.0–3.0)
7	Granhall et al (2018)^Citation45	Normal renal function	Steady-state 10 mg	AUC0-24h: 283.7±53.3	14.9±53.2	151.7 ±9.1	1.0 (0.5–4.0)
		Mild RI	Steady-state 10 mg	AUC0-24h: 378.2±78.9	20.2±75.9	159.3 ±12.0	1.0 (0.5–2.5)
		Moderate RI	Steady-state 10 mg	AUC0-24h: 298.5±107.3	16.6±102.0	162.8 ±11.2	1.0 (0.5–4.0)
		Severe RI	Steady-state 10 mg	AUC0-24h: 163.5±65.6	8.6±62.9	164.9 ±8.9	1.5 (0.5–4.0)
		ESRD	Steady-state 10 mg	AUC0-24h: 287.7±128.7	15.7±128.3	152.8 ±49.0	1.0 (0.5–2.0)
8	Meier et al (2022)^Citation46	Type 2 diabetic with upper gastrointestinal disease	Steady-state 7 mg	143.95	7.72	141	1.0 (0.0–6.0)
		Type 2 diabetic without upper gastrointestinal disease	Steady-state 7 mg	122.05	6.63	142	1.0 (0.5–6.0)
9	Bækdal et al (2018b)^Citation47	Healthy	Steady-state 10 mg	AUC0–24 h: 290	15.2	150	1.0 (0.2–4.0)
			Steady-state 10 mg + omeprazole 40 mg	AUC0–24 h: 328	17.6	156	1.0 (1.0–6.0)

Abbreviation: NA, not available.

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Data Sharing Statement

All the data used for this publication are presented in the main article.