Effect of Various Dosing Schedules on the Pharmacokinetics of Oral Semaglutide: A Randomised Trial in Healthy Subjects

2.1 Trial Design

This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects (Fig. 1a). The trial was conducted in the UK between August 2020 and May 2021 and was registered at ClinicalTrials.gov (NCT04513704). All subjects were treated with oral semaglutide co-formulated with SNAC. Four of the treatment arms tested alternative dosing schedules for oral semaglutide with dosing in the evening:

Pre-dose fasting times of 2, 4, or 6 h followed by a 30-min post-dose fast (treatment arms 2 h–30 min, 4 h–30 min, 6 h–30 min).

Pre-dose fasting time of 2 h followed by a post-dose overnight fast (treatment arm 2 h–night).

Fig. 1figure 1

Trial design (a) and overview of fasting and mealtime requirements (b). aOvernight fast of at least 6 h; due to the timing of the evening snack at the clinical site, the average overnight fast for treatment arm night–30 min was approximately 11 h. bOral semaglutide was to be dosed at 8 am (treatment arm night–30 min) or 8 pm (all other treatment arms) ± 2 h. Water intake was allowed in the specified fasting periods except from 2 h prior to dosing (all treatment arms) and until 30 min (treatment arms: 2 h–30 min, 4 h–30 min, 6 h–30 min, and night–30 min) or 2 h (treatment arm: 2 h–night) post-dosing. cSubjects were expected to be asleep during this time period. The post-dose meal was the first meal served for the 2 h–night treatment arm

The fifth treatment arm was included as a reference and followed dosing recommendations in the oral semaglutide prescribing information [1], consisting of an overnight pre-dose fast of at least 6 h, treatment administration in the morning, and then a 30-min post-dose fast (night–30 min treatment arm) followed by a standardised breakfast meal. Due to the timing of the evening snack at the clinical site, the duration of the overnight pre-dose fast for this arm was approximately 11 h.

2.2 Participants

Eligible subjects were men and women aged ≥ 18 to ≤ 64 years with a body mass index of ≥ 20 to ≤ 29.9 kg/m2. Subjects had to be considered generally healthy, as judged by the investigator, based on their medical history, physical examination, vital signs, electrocardiogram, and clinical laboratory tests performed during the screening visit.

Subjects were excluded if they had glycated haemoglobin ≥ 6.5% (48 mmol/mol) at screening; presence or symptoms of clinically significant gastrointestinal disorders; personal or first-degree relative history of multiple endocrine neoplasia type 2 or medullary thyroid cancer, or of major surgical procedures involving the stomach; or presence or history of pancreatitis. Subjects who smoked > 5 cigarettes per day or who were not able or willing to refrain from smoking whilst at the clinical site were excluded. Use of prescription medicinal products or non-prescription drugs or herbal products (including St John’s wort), except for highly effective contraceptive methods, hormone replacement therapy, routine vitamins, topical medication not reaching the systemic circulation, and occasional use of paracetamol, was not permitted from within 14 days prior to the day of screening to 24 h after the last dosing. Subjects avoided any permitted oral medications from 2 h prior to, and until 30 min (treatment arms: 2 h–30 min, 4 h–30 min, 6 h–30 min, and night–30 min) or 2 h (treatment arm: 2 h–night) after each administration of oral semaglutide.

2.3 Procedures

Following an initial screening visit, subjects were randomised to the four alternative dosing schedule arms and the reference arm (1:1:1:1:2, respectively). Subjects were assigned a unique randomisation number in ascending numerical order for males and descending numerical order for females, to ensure that sex was balanced across the treatment arms. The randomisation number encoded the subject’s assignment to one of the treatment arms according to the randomisation list generated before the trial, using block randomisation (randomisation lists were provided by PAREXEL International, Nottingham, UK). The first day of dosing was the day after randomisation. Subjects stayed in-house on the site from randomisation until the end of sampling on Day 11 (24 h after 10th dose) and were dosed at the clinical site once daily for 10 days according to their randomised treatment schedule (Fig. 1a); a 3-mg oral semaglutide tablet was administered for the first 5 days, followed by a 7-mg oral semaglutide tablet on the last 5 days. Each dose was taken with no more than 120 mL/4 oz of water. A follow-up visit was scheduled 5 weeks after last dosing.

During the on-site period, subjects were served standardised meals at pre- and post-dosing according to the dosing schedule of their randomised treatment arm and were instructed to consume the complete meal within 30 min of serving. No food intake was allowed for at least 4 h prior to the standardised pre-dose meal (treatment arms: 2 h–30 min, 4 h–30 min, 6 h–30 min, and 2 h–night) (Fig. 1b). Standardised meals consisted of a pre-dose meal of approximately 760 kcal and a post-dose meal of approximately 380 kcal. The macronutrient composition of all meals was approximately 36% of energy from fat, 17% from protein, and 47% from carbohydrates. All standardised meals were weighed before serving. While participants were instructed to consume the whole meal, in cases where it was partially consumed, the weight of the meal remaining was recorded.

Blood samples for measuring semaglutide concentration in plasma were taken pre-dose on Days 1 to 9 (0–30 min prior to dosing) and at predefined time points before and after the 10th dose on Days 10 and 11 (pre-dose: 0–5 min prior to dosing; post-dose: 10, 20, 30, 40, and 50 min and 1, 1.5, 2, 2.5, 3, 4, 6, 12, and 24 h post-dose).

2.4 Assessments

Plasma semaglutide concentration was measured at a specialist laboratory using a validated liquid chromatography with tandem mass spectrometry assay, as described previously [4].

Safety assessments included adverse events, concomitant illness, medical history, clinical laboratory tests, vital signs, physical examinations, and technical complaints relating to medicine defects.

2.5 Objectives and Endpoints

The primary objective was to compare the pharmacokinetic profiles of semaglutide in healthy subjects for four different combinations of pre- and post-dose fasting times with a reference dosing schedule. The secondary objective was to compare the pharmacokinetic profiles of semaglutide in healthy subjects dosed according to the same pre-dose fasting time but two different post-dose fasting times. The primary and secondary objectives had the same primary and supportive secondary endpoints. The primary endpoint was the area under the semaglutide plasma concentration–time curve during a 24-h interval after the 10th dose of oral semaglutide (AUC0–24h,sema,Day10). Supportive secondary endpoints included the maximum observed semaglutide plasma concentration after the 10th dose of oral semaglutide (Cmax,sema,Day10) and the time to Cmax after the 10th dose (tmax,sema,Day10).

2.6 Statistical analysis

Sample size was calculated based on the precision of the ratio of AUC0–24h,sema,Day10 between treatment groups using a two-sided 95% confidence interval (CI). The primary endpoint was assumed to have a log-normal distribution and the standard deviation (SD) of the log-transformed AUC0–24h,sema,Day10 was assumed to be the same for the different dosing schedules tested; no adjustment for multiplicity was made. Based on data from previous pharmacokinetic trials of oral semaglutide using a similar 10-day design and trial population [3,4,5,6], the SD of the log-transformed AUC0–24h,sema,Day10 was estimated to be 0.55. Based on this, it was assumed that 24 evaluable subjects would be required for each of the investigated dosing schedules and 48 evaluable subjects would be required for the reference dosing schedule in order to provide an 80% probability that the 95% CI for the true ratio between groups for AUC0–24h,sema,Day10 would fall between 0.75*\(\widehat\) and 1.34*\(\widehat\), where \(\widehat\) was the unknown estimate of the ratio.

Analyses of pharmacokinetic endpoints were conducted in the full analysis set (FAS; all subjects who were randomised and exposed to at least one dose of trial product), while safety analyses were conducted in the safety analysis set (SAS; all subjects who were exposed to at least one dose of trial product). The AUC0–24h,sema,Day10 (primary endpoint) was calculated using the linear trapezoidal method based on observed semaglutide concentrations and actual measurement times. The Cmax,sema,Day10 was calculated as the maximum of all observed valid semaglutide concentrations from nominal time 0–24 h after the 10th dose, whilst tmax,sema,Day10 was calculated as the actual time after the 10th dose to the Cmax.

Statistical analysis of the primary endpoint was performed using a linear normal model for censored data with log-transformed AUC0–24h,sema,Day10 as a dependent variable, dosing schedule group (five levels) and sex as fixed effects, and a residual variance parameter for each dosing group. All statistical analyses were performed in SAS® software (version 9.4). From this model, the estimated mean difference in log-transformed AUC0–24h,sema,Day10 (described as AUC0–24h Day 10 from here on) between pairs of treatment groups was estimated and back-transformed to the original scale and presented as a ratio of geometric means together with the corresponding two-sided 95% CI and p value. Cmax,sema,Day10 (described as Cmax Day 10 from here on) was analysed as for the primary endpoint except the model only allowed for left-censoring. The tmax,sema,Day10 (described as Tmax Day 10 from here on) was summarised descriptively.

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