Clinical Pharmacokinetics of Semaglutide: A Systematic Review

Introduction

Type 2 diabetes (T2D) and obesity are major public health burdens with an important economic impact and their incidences have increased in the past decades.^1,2 It is estimated that approximately 537 million adults around the world affected with diabetes in 2021,³ and this number is expected to increase to over 700 million by 2045.⁴ T2D is the most prevalent type of diabetes, accounting for about 90% of the population suffering from diabetes.^5,6 Patients with T2D are at high risk for long-term macrovascular and microvascular complications including cardiovascular diseases.⁷ The treatment of T2D has greatly improved recent years, but it is necessary to explore new therapeutic strategies. Obesity as a major global health problem is an important risk factor for T2D. Obesity is also associated with various other chronic diseases including hypertension and cardiovascular disease.⁸ According to the World Health Organization, more than 1 billion individuals worldwide are overweight, and about 300 million of whom are clinically obese.⁹ Obesity is also associated with many comorbidities, so new efficacy treatment strategies for obesity are urgently needed too.

Since 2005, there have been several glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), including lixisenatide, exenatide, albiglutide, dulaglutide and liraglutide, recommended for the treatment of T2D approved by the US Food and Drug Administration (FDA).^10–15 Liraglutide was also introduced for the treatment of obesity.¹⁶ GLP-1RAs are a class of recognized hypoglycemic agents, which can induce insulin secretion and suppress glucagon secretion via the stimulation of GLP-1 receptors.^17–19 Semaglutide is a human GLP-1 analog, studied for the management of T2D and obesity. To improve glycemic control, semaglutide induces glucose-mediated insulin secretion stimulation, decreases glucagon secretion, and decreases hepatic glucose output. To promote weight loss, semaglutide delays gastric emptying, increases satiety, decreases appetite and energy intake.²⁰ Semaglutide demonstrated promising efficacy in glycemic control and weight loss compared with placebo and active comparators such as insulin glargine, sitagliptin, dulaglutide and exenatide sustained-release.^21–26 In addition, semaglutide significantly improved cardiovascular outcomes.²⁷ It was approved for the treatment of T2D by FDA in 2017 (Ozempic) and 2019 (Oral semaglutide, Rybelsus), and for obesity management by FDA in 2021 (Wegovy).

Semaglutide is currently the only GLP-1RA that is available in both a subcutaneously injectable and oral formulation. Semaglutide is structurally 94% homologous to native human GLP-1, with specific modifications at positions 8, 26, and 34 to prolong its half-life (t_1/2). It is allowed for once-weekly subcutaneously administration due to the long t_1/2.²⁰ The prolonged exposure of semaglutide is primarily due to slow elimination and, to a lesser extent, delayed absorption,²⁸ which is consistent with the observation that the large majority of semaglutide molecules are bound to albumin.²⁹ The metabolism of semaglutide is not confined to specific organs. It is metabolised across tissues through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty di-acid side chain, and that degradation metabolites are excreted via urine and faeces.²⁸ Semaglutide is administered subcutaneously once-weekly at doses of 0.5 and 1.0 mg, with an initial dose of 0.25 mg/week for the first 4 weeks. Oral semaglutide tablets (Rybelsus) is a modified form of semaglutide with the addition of a carrier sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC).^30,31 Due to the degradation of peptide-based drugs by proteolytic enzymes, the low permeability of intestinal epithelium, and the low pH of the gastrointestinal tract, oral administration of semaglutide is challenging. The absorption enhancer SNAC can temporarily open the tight junctions between the epithelium, promoting the transport and entry of semaglutide into the systemic circulation. Oral semaglutide is administered once-daily at doses of 7 and 14 mg, with an initial dose of 3 mg once-daily for the first 30 days.

In recent years, a variety of studies have been conducted on the pharmacokinetics of semaglutide, including pharmacokinetics in healthy, pharmacokinetics in diseased, and the effects of drug–drug interactions and drug–food interactions on the pharmacokinetics of semaglutide in humans. To date, there is no systematic review that encompasses all the clinical pharmacokinetic parameters of both subcutaneous and oral semaglutide. In this review, we summarized and presented all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide evidence-based recommendations for clinical use.

Methods

The current systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.³² A systematic literature search was performed for screening the articles related to the pharmacokinetics of semaglutide in PubMed and Embase databases in August 2023. The adopted strategy included following search algorithm: semaglutide AND (pharmacokinetic OR pharmacokinetics OR bioavailability). In addition, a manual snowball search was conducted in the reference lists of all the included studies.

The review included studies written in English investigating pharmacokinetic profiles after subcutaneously and oral applications of semaglutide in healthy or patients had T2D, obesity, hepatic impairment, renal impairment, or upper gastrointestinal disease. Moreover, all the articles containing food interactions, dosing condition interactions and drug interactions with semaglutide were also included to observe the change of semaglutide pharmacokinetics. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (C_max), time to C_max (T_max), t_1/2, and clearance (CL). Only those studies in which at least one of the above pharmacokinetic parameter was reported were included. Studies which did not fulfill these criteria were excluded from this review. Letters to the editor, commentaries and conference abstracts were also excluded. The relevant data were then extracted from the selected studies including the author’s name, year, study population, number of subjects, age of participants, administration route, dose, frequency, and available pharmacokinetic parameters of semaglutide.

Results

Literature Search Results

The complete literature search and detail on the inclusion and exclusion criteria are described in Figure 1. The database searches yielded a total of 547 articles, 61 of which were duplicates. The remaining 486 articles were further screened according to the inclusion and exclusion criteria (Figure 1). A total of 17 articles fulfilled the eligibility criteria were finally included and 469 were excluded on the basis of animal, title, abstract, full-text access, and full-text reading.

Figure 1 PRISMA flow chart diagram.

Characteristics of Included Studies

The characteristics of the included studies are mentioned in Table 1, including the author’s name, year, study population, number of subjects, age of participants, administration route, dose, and frequency. The review included eight studies administered semaglutide by subcutaneous injection in doses ranging from 0.5 to 2.4 mg, nine studies administered semaglutide by oral route in doses ranging from 2 to 40 mg. Eight studies included healthy volunteers. Eight studies included diseased participants with T2D, obesity, hepatic impairment, renal impairment, or upper gastrointestinal disease. One study included both healthy volunteers and diseased participants with T2D. Two studies were related to drug–drug interactions, 2 were related to drug–food interactions, and 3 were relevant to drug-dosing condition interactions of semaglutide.

Table 1 Characteristics of Included Studies

Quality of Included Studies

Critical Appraisal Skills Programme (CASP) scoring system was employed for quality assessment of the 17 included articles.^48,49 CASP scoring consists of 11 redesigned questions that evaluate the validity of the article, where a score of >6 indicates high quality, 4–6 moderate, and <4 means low quality. A total of 15 articles were of high quality, and 2 articles were of moderate quality. The summary of quality assessment is presented in Supplementary Table S1.

Subcutaneous Route of Semaglutide

Eight pharmacokinetic studies of semaglutide administered subcutaneously including single dose pharmacokinetic study and steady-state pharmacokinetic study after multiple administrations. We summarized the above pharmacokinetic studies of semaglutide in healthy and diseased participants. Among all the included studies, eight subcutaneous studies were conducted in different populations, of which three studies were conducted in healthy participants, five in diseased participants. Four studied the single-dose pharmacokinetics and five studied the steady-state pharmacokinetics of semaglutide (One studied both single-dose and steady-state pharmacokinetics). In addition, one of these studies evaluated the effect of drug–drug interactions on the pharmacokinetics of subcutaneous semaglutide. AUC, C_max, and T_max were the main pharmacokinetic parameters mentioned in all studies whereas parameters like t_1/2 and CL/F were present in some studies, as mentioned in Table 2.

Table 2 Studies of Semaglutide with Subcutaneous Route

Studies in Healthy Participants

Out of a total of 17 studies, three subcutaneous studies were conducted in healthy individuals. Subcutaneous administration of one-time semaglutide 0.25 mg or 0.5 mg reached C_max in 42 h and 56 h, respectively.^28,34 A dose-dependent increase in AUC, and C_max was found in included single-dose studies. Steady-state pharmacokinetics of semaglutide was investigated in different healthy population including Caucasian, Japanese, and Chinese. The AUC_{0–168, SS} and C_max,SS of semaglutide were similar between Caucasian and Japanese.³³ Exposure in Chinese subjects was slightly higher than that observed in Caucasian and Japanese, however, after adjusting for differences in body weight, exposure in Chinese was similar to exposure seen in Caucasian and Japanese.³⁴ The exposure of semaglutide 1.0 mg appeared to be approximately double that of semaglutide 0.5 mg, while clearance and distribution appeared similar for both doses in all included steady-state pharmacokinetic studies. T_max in steady-state pharmacokinetic studies was similar among the groups (range 30–36 h). T_1/2 value of semaglutide in all three subcutaneous studies was in the range of 145–168 h (approximately 1 week). The other parameters are shown in Table 2.

Studies in Diseased Participants

Among eight included subcutaneous studies, two steady-state pharmacokinetics of semaglutide 1.0 mg was respectively studied in postmenopausal women with T2D³⁵ and obese subjects.³⁶ Exposure of semaglutide in both postmenopausal women with T2D and obese subjects was obviously lower than that in healthy subjects.^35,36 The mean AUC_{0–168h, ss} and C_{max, ss} were respectively 4602 nmol·h /L and 33.8 nmol/L in postmenopausal women with T2D, 4467 nmol·h /L and 32.0 nmol/L in obese subjects, while mean AUC_{0–168h, ss} and C_{max, ss} value in healthy subjects were in the range of 7449–7961 nmol·h /L and 50.6–55.9 nmol/L, respectively. This is most likely due to differences in body weight of the subjects. The average body weight of the included postmenopausal women with T2D was 101.3 kg,³⁵ while the weight of the healthy subjects was within the normal range. Pharmacokinetics in people with hepatic impairment²⁹ and renal impairment³⁷ after a single, subcutaneous dose of 0.5 mg semaglutide were also conducted. Semaglutide exposure did not appear to be affected by hepatic and renal impairment, suggesting that dose adjustment may not be warranted for patients with hepatic or renal impairment. The t_max varied across the hepatic impairment (range 53.6–77.8 h) and renal impairment groups (range 24–51 h); mean t_1/2 in all hepatic impairment groups was comparable; mean t_1/2 was longer in subjects with severe renal impairment (221 h) and those with end-stage renal disease (ESRD) (243 h) than in subjects with mild and moderate renal impairment or normal renal function.

Drug–Drug Interactions

Only one study reported the effect of other drug on pharmacokinetic parameters of subcutaneous semaglutide.³⁸ Ninety-six overweight participants who were otherwise healthy were randomly assigned to cagrilintide (0.16–4.5 mg) or placebo, in combination with subcutaneous semaglutide 2.4 mg. Semaglutide exposure and elimination were similar across treatment groups. AUC_{0–168 h} ranged from 12,757 to 15305 nmol·h /L, and C_max ranged from 96.4 to 120 nmol/L. Semaglutide 2.4 mg had a t_1/2 of 145–165 h, with a median t_max of 12–24 h. Cagrilintide dose did not affect semaglutide exposure and elimination.³⁸

Oral Route of Semaglutide

The degradation of peptide-based drugs by proteolytic enzymes, the low permeability of intestinal epithelium and its mucus layer and the low pH of the gastrointestinal tract, are the major barriers preventing the oral administration of GLP-1RAs. An oral option would overcome the potential fear of injection among patients. These challenges cannot be addressed by increasing the administered dose, as this could lead to a parallel increase in the incidence of adverse reactions. Semaglutide is the first developed oral GLP-1RA by combining it with the absorption enhancer SNAC, which is a small-chain fatty acid that facilitates the absorption of semaglutide by acting transcellularly on the gastric mucosa through local pH elevation.^30,31 Among all the included studies, nine oral studies were conducted in different populations, of which six studies were conducted in healthy participants, four in diseased participants (one in both healthy and diseased participants). Two studied the single-dose pharmacokinetics and eight studied the steady-state pharmacokinetics of semaglutide (One studied both single-dose and steady-state pharmacokinetics). In addition, four of these studies evaluated the effect of food and various dosing conditions and one evaluated drug–drug interactions on the pharmacokinetics of oral semaglutide. Table 3 provides pharmacokinetic Results from oral studies.

Table 3 Studies of Semaglutide with Oral Route

Studies in Healthy Participants

In a single-dose trial, 135 healthy subjects received oral semaglutide (2–20 mg) or placebo with 50 mL water while fasting, a high proportion of subjects with oral semaglutide treatment had no measurable semaglutide concentration in plasma (64 of 112 subjects).³⁹ In another single-dose, 2-period crossover trial, 26 healthy subjects received 10 mg oral semaglutide with 50 or 240 mL water while fasting, semaglutide plasma concentrations were measurable. However, C_max and AUC values were not provided.⁴⁰ These findings may be explained by the low bioavailability of oral semaglutide after a single dose. Nevertheless, therapeutic plasma concentrations of semaglutide are obtained at steady state in subjects treated with once-daily oral semaglutide. In a 10-week, once-daily, multiple-dose trial, semaglutide exposure at steady state was about two fold higher with oral semaglutide 40 mg versus 20 mg in healthy subjects. The t_{1/2, ss} was comparable between two dose groups, with geometric means of 153 and 161 h in healthy subjects receiving 20 and 40 mg respectively, which is similar to semaglutide administered subcutaneously, suggesting that the elimination phase of oral semaglutide is comparable with that observed with subcutaneous administration.³⁹

Drug–Food Interactions

Oral semaglutide is absorbed in the stomach, and its absorption is affected by the presence of food. Effect of food and other substances on the pharmacokinetics of oral semaglutide was conducted in healthy participants. In a food-effect trial, limited or no measurable semaglutide plasma concentration at steady-state was observed in the fed group, while all subjects in the fasting group had measurable semaglutide concentrations. AUC_{0–24 h} and C_max at steady-state for the fasting appeared approximately 40% greater than reference group. Median t_max was longer for the fasting (1.75 h) versus reference groups (1.00 h), while no obvious difference was seen for t_1/2 (160 h and 152 h, respectively) between the fasting and reference groups.⁴¹ Besides the usual food, the consequence of other substances in the stomach on oral semaglutide pharmacokinetics should also be considered. At steady-state, semaglutide AUC_0-24h was decreased by 34% (544 VS 360 nmol·h /L) and C_max was decreased by 32% (27.7 VS 18.8 nmol/L) when oral semaglutide was co-administered with five oral placebo tablets compared to oral semaglutide alone.⁴² These results support dosing of oral semaglutide in the fasting state. Food and other substances in the stomach can reduce the semaglutide exposure.

Drug-Dosing Conditions Interactions

Effect of water volume and dosing schedules on the pharmacokinetics of oral semaglutide were also conducted in healthy participants. Bækdal et al published two studies mentioned effect of water volume on oral semaglutide pharmacokinetics in 2021, one is a single-dose study and another is a multiple-dose study. In the single-dose study, subjects received 10 mg oral semaglutide with 50 or 240 mL water while fasting, AUC_0-24h and C_max were approximately 70% higher when dosed with 50 versus 240 mL water. Median t_max was 1.5 hours for both water volumes with a range of 0.5–3.0 hours for 50 mL and a range of 0.5–4.0 hours for 240 mL.⁴⁰ Their other multiple-dose study with the once-daily oral semaglutide 10 mg for 10 days found that steady-state exposure of semaglutide was comparable when the oral semaglutide tablet was administered with 50 or 120 mL water. Water volume had no apparent effect on t_max and t_1/2.⁴¹ These results support dosing of oral semaglutide with up to 120 mL water.

Two randomised trials in healthy subjects evaluated the effect of various dosing schedules (including different pre-dose and/or post-dose fasting times) on the steady-state pharmacokinetics of oral semaglutide. In different pre-dose fasting times groups (2, 4, 6 h or overnight pre-dose fast followed by a 30 min post-dose fast), shorter pre-dose fasting times in the 2, 4 and 6 h treatment groups resulted in significantly lower semaglutide exposure and C_max compared with an overnight pre-dose fast. The median t_max appeared to be similar across the treatment groups (ranged from 0.8–1.0 h).⁴³ This trial supports dosing of oral semaglutide in the fasting state in accordance with the prescribing information. In different post-dose fasting times groups (15, 30, 60, or 120 min) after overnight pre-dose fasting, semaglutide AUC_0–24h and C_max increased with longer post-dose fasting periods, particularly from 15 to 30 min. The median t_max increased with longer post-dose fasting times. Post-dose fasting time had no apparent effect on t1/2.⁴¹ If the post-dose fasting time continues to extend, will the pharmacokinetics of semaglutide be more affected? An overnight post-dose fasting trial was conducted and found that semaglutide AUC _0–24h and C_max at steady state were similar for the 30 min and overnight post-dose fasting treatment groups.⁴³ Administration of oral semaglutide at least 30 min post-dose fasting results in clinically relevant semaglutide exposure.

Drug–Drug Interactions

Only one study reported the effect of other drug on pharmacokinetic parameters of oral semaglutide.⁴⁷ A randomized study investigated the effect of omeprazole (40 mg once-daily) on the pharmacokinetics of oral semaglutide in 54 healthy subjects. Exposure of semaglutide appeared to be slightly non-statistically significant increased when oral semaglutide was administered with omeprazole versus oral semaglutide alone. T_1/2 and t_max for semaglutide were similar in subjects treated with oral semaglutide alone or with omeprazole.⁴⁷

Studies in Diseased Participants

The effect of hepatic impairment on oral semaglutide pharmacokinetics was studied in 56 patients with varying degrees of hepatic function categorized as having normal hepatic function, and mild, moderate and severe hepatic impairment received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days).⁴⁴ AUC_0–24h and C_max at steady state appeared similar across the four hepatic function groups, indicating that hepatic impairment does not affect oral semaglutide exposure. The t_1/2 and t_max of semaglutide were also similar across all groups.⁴⁴ The effect of renal impairment on oral semaglutide pharmacokinetics was studied in 71 patients with normal renal function, and mild, moderate, severe renal impairment, and ESRD, received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days).⁴⁵ Semaglutide exposure did not vary in a consistent pattern across the 5 renal function groups. T_1/2 and t_max were similar in subjects with different renal function. Further, haemodialysis did not affect the pharmacokinetics of oral semaglutide.⁴⁵ Based on the two above trials, hepatic impairment and renal impairment should not affect dose recommendations for oral semaglutide, which is similar to semaglutide administered subcutaneously.

Considering that oral semaglutide is primarily absorbed in the stomach, the effect of upper gastrointestinal disease on oral semaglutide pharmacokinetics was studied in 55 type 2 diabetes with or without upper GI disease received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days).⁴⁶ Semaglutide exposure (AUC_0–24h and C_max after the tenth dose) was not significantly different between patients with and without upper gastrointestinal disease, hence no dose adjustment is required. Similarly, there was no apparent effect of upper gastrointestinal disease on t_1/2 and t_max of oral semaglutide.⁴⁶ Upper gastrointestinal disease, renal impairment and hepatic impairment did not affect oral semaglutide pharmacokinetic profile.

Discussion

The studies investigating pharmacokinetics of semaglutide administered subcutaneously demonstrated T_max values ranged from 30 h to 56 h in healthy subjects, and from 24 h to 77.8 h in diseased participants. Studies administering oral semaglutide demonstrated T_max values ranged from 0.8 h to 1.75 h in healthy subjects, and from 1.0 h to 1.75 h in diseased participants. These indicate that oral absorption of semaglutide is significantly faster than subcutaneous administration. A t_1/2 of approximately 1 week was observed following both oral and subcutaneous administrations, demonstrating that the elimination phase was similar, irrespective of the route of administration. AUC and C_max are similar following the same dose of subcutaneous semaglutide in healthy subjects with different races.^28,33,34 Although the absorption enhancer SNAC can promote the transport and entry of oral semaglutide into the systemic circulation, semaglutide exposure remains relatively low compared to subcutaneous injection. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions.⁵⁰ Oral absorption is significantly faster and bioavailability is lower, so the variability is greater.⁵¹ The exposure from consecutive doses was overlapped and day-to-day variability in oral absorption was reduced by the once-daily dosing and long t_1/2, resulting in stable steady-state concentrations of oral semaglutide. Combined with the clinically relevant effects of once-daily oral semaglutide were observed in improving glycemic control and weight loss in multiple-dose trials,^39,52 hence oral semaglutide dosed once-daily with higher dose levels compared to subcutaneous injection.

Renal impairment and hepatic impairment did not affect oral and subcutaneous semaglutide pharmacokinetic profile.^29,37,44,45 Oral semaglutide exposure also did not appear to be affected by upper gastrointestinal disease.⁴⁶ Exposure of semaglutide in both postmenopausal women with T2D and obese subjects was obviously lower than that in healthy subjects.^35,36 This is most likely due to differences in body weight of the subjects, which were consistent with those predicted based on population pharmacokinetic models.^50,53,54 In population pharmacokinetic models using data from trials with oral or subcutaneous administration of semaglutide, body weight had an effect on semaglutide pharmacokinetics, which did not warrant dose adjustment.^50,53,54

Unlike most oral medications that are absorbed in the intestines, oral administration of semaglutide is absorbed by the stomach, which is unique to this drug. The absorption enhancer SNAC can temporarily open the tight junctions between the epithelium, promote the transport and entry of semaglutide into the systemic circulation. Oral semaglutide is absorbed in the stomach and its absorption is affected by the presence of food and water. Drug–food interaction studies found that food and other substances in the stomach can reduce the oral semaglutide exposure.^41,42 Drug-dosing condition interaction studies have shown that fasting for at least 30 minutes after administration of oral semaglutide with up to 120 mL water results in clinically relevant semaglutide exposure.^41,43

Drug–drug interaction studies found that cagrilintide dose did not affect subcutaneous semaglutide exposure and elimination.³⁸ Exposure of semaglutide appeared to be slightly non-statistically significant increased when oral semaglutide was administered with omeprazole versus oral semaglutide alone.⁴⁷ Semaglutide reduces gastric emptying and potentially alters the rate of absorption of orally co-administered drugs. With subcutaneous semaglutide treatment at steady state (1.0 mg), the pharmacokinetics of metformin, warfarin, atorvastatin and digoxin, and the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel, were not affected to a clinically relevant degree with semaglutide co-administration.^35,55 Semaglutide affected population pharmacokinetic model parameters of paracetamol and atorvastatin in healthy subjects. However, these effects were considered not to be clinically relevant.⁵⁶ Oral semaglutide did not affect the pharmacokinetics of lisinopril, warfarin, digoxin and combined oral contraceptive, ethinylestradiol/levonorgestrel,^57–62 suggesting that co-administration with oral semaglutide requires no need for dose adjustment. Differences were observed in exposure of certain drugs when co-administered with oral semaglutide compared to administration alone, AUC of furosemide increased by 28%, and C_max decreased by 34%,⁶³ AUC of rosuvastatin increased by 41%, and C_max increased by 10%,⁶³ AUC of metformin increased by 32%,⁵⁷ a small increase in exposure of furosemide and rosuvastatin⁵⁹ and minor increases in AUC of Levothyroxine.⁴² These observed changes were not considered clinically relevant due to the wide therapeutic index of the drugs. The findings supported that the cause of the increase is due to the delayed gastric emptying effects of semaglutide.

The strength of this study may be that it is a systematic review of all pharmacokinetic studies of both subcutaneous and oral semaglutide published up to August 2023. Several systematic reviews on subcutaneous semaglutide or oral semaglutide have recently been published, but their focus is primarily on efficacy and safety, rather than pharmacokinetics.^64–66 In addition, a few of population pharmacokinetic models were established using data from selected clinical pharmacological trials to identify clinically relevant covariates of exposure, but they included limited trial data.^50,53,54 The limitation of this review is that we only searched two databases, so it is possible that we missed one study, which may reduce the validity and subsequent reliability of the findings.

Conclusion

This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. Semaglutide has a predictable pharmacokinetic profile with a long t_1/2 that allows for once-weekly subcutaneous administration. The AUC and C_max of oral and subcutaneous semaglutide were both increase with dose. Oral absorption of semaglutide is significantly faster than subcutaneous administration. The elimination phase of subcutaneous and oral semaglutide is similar. Bioavailability of oral semaglutide is very low. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug–drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. It is possible that body weight may affect semaglutide exposure, but further studies are needed to confirm this. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.