Treatment with liraglutide-a once-daily GLP-1 analog-does not reduce the bioavailability of ethinyl estradiol/levonorgestrel taken as an oral combination contraceptive drug

Design

Single-center, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic study

N= 21

Objective

To investigate the effect of liraglutide on the pharmacokinetics of the components of an oral contraceptive drug containing ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg

Study Groups

Liraglutide + oral contraceptive (n= 21)

Placebo + oral contraceptive (n= 21)

Inclusion Criteria

Postmenopausal women who had undergone oophorectomy or had at least 1 year of amenorrhea; body mass index (BMI) between 18 and 30 kg/m²; subjects in good health based on medical history and physical examination, including 12-lead electrocardiogram, vital signs, and blood and urinary laboratory assessments

Exclusion Criteria

Clinically significant renal, hepatic, cardiovascular, pulmonary, gastrointestinal, metabolic, or neurological diseases or other major disorders

Methods

Patients were randomly assigned to receive liraglutide (0.6 mg for week 1, followed by 1.2 mg for week 2, then liraglutide 1.8 mg during week 3) or a corresponding placebo subcutaneously into the abdomen daily before switching to the alternative therapy after 14 to 24 days. After five days of week three injections, the patient consumed breakfast following their liraglutide/placebo injection and, after 7 hours, received one contraceptive tablet (ethinyl estradiol 0.03 mg/levonorgestrel 0.15 mg) with 100 ml of water. Two hours before and after administration of the oral contraceptive, a small meal was provided (high carbohydrates, low protein, low fat). Patients were given 200 ml of water for the first meal and were allowed water for the last meal. Serum concentrations of ethinyl estradiol/levonorgestrel were followed for 74 hours (15 minutes before dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 17, 24, 48, and 74 hours post-OC dose). Nine blood samples were collected at each visit post administration of liraglutide/placebo. Daily dosing of liraglutide or placebo was continued during the blood sampling period.

Treatment: 3 weeks

Follow-up: 74 hours

Outcome Measures

Primary: Area under the curve (AUC) for ethinyl estradiol and levonorgestrel

Baseline Characteristics

Liraglutide + OC (N= 21)

Age, years

100% 

Weight, kg

BMI, kg/m²

Abbreviations: OC, oral contraceptive; BMI, body mass index

Results

Endpoint

Ethinyl estradiol (n= 21)^a

Levonorgestrel (n= 21)^b

Liraglutide

Placebo

Liraglutide

Placebo

AUC, hr·pg/mL

856 ± 226

776 ± 188

1.06 (0.99 to 1.13)

63,153 ± 25,496

55,231 ± 17,072

1.18 (1.04 to 1.34)

AUC_0-t, hr·pg/mL^c

752 ± 171

707 ± 146

1.06 (1.00 to 1.11)

47,150 ± 24,260

39,528 ± 17,448

1.15 (1.06 to 1.24)

Cmax, pg/mL

0.88 (0.79 to 0.97)

t_max, hour

1.5 (1.0 to 2.5)

t_1/2, hour

0.98 (0.79 to 1.23)

CL/F, L/hr

Vz/F, L

0.96 (0.87 to 1.07)

Abbreviations: CI, confidence interval; AUC, area under the curve; AUC_0-t, AUC from 0 to 74 hours; Cmax, maximum concentration; CL/F, apparent total plasma clearance; t_max, time to maximum concentration; t_1/2, half-life; Vz/F, apparent volume of distribution

^aEthinyl estradiol, n= 20 (liraglutide) and n= 19 (placebo) for AUC, CL/F, Vz/F
^bLevonorgestrel n= 12 (liraglutide and placebo) for AUC, CL/F, Vz/F
^cAUC_0-48h for ethinyl estradiol and AUC_0-t for levonorgestrel

Adverse Events

More adverse effects were reported with liraglutide, predominantly gastrointestinal (nausea, eructation, abdominal pain, constipation, dyspepsia). No patients withdrew from the study. 

Study Author Conclusions

Overall, this study indicates no clinically relevant decrease in overall bioavailability, that is, exposure of ethinyl estradiol (0.03 mg) or levonorgestrel (0.15 mg), when this contraceptive drug is coadministered with liraglutide 1.8 mg at steady state in postmenopausal healthy women.

InpharmD Researcher Critique

No Dose Adjustment is Recommended for Digoxin, Warfarin, Atorvastatin or a Combination Oral Contraceptive When Coadministered with Dulaglutide

Design

Observational, pharmacokinetic study

N= 22

Objective

To evaluate the effect of dulaglutide on the pharmacokinetics (PK) of Ortho-Cyclen^®

Study Groups

Norelgestromin (NGMN) + dulaglutide or ethinyl estradiol (EE) + dulaglutide (n= 19)

NGMN or EE alone (n= 14)

Inclusion Criteria

Healthy females aged 18 to 45 years

Exclusion Criteria

Not explicitly stated

Methods

For the purpose of this table, results are only provided for the evaluation of the effect of dulaglutide on the PK of Ortho-Cyclen. Subjects received a full cycle of once-daily oral doses of Ortho-Cyclen treatment during a 28-day lead-in phase and each of the two successive treatment periods. Each treatment period lasted 28 days and was comprised of 21 days of active tablets containing norgestimate 0.25 mg and ethinylestradiol 0.035 mg, as well as 7 days of nonactive tablets. Blood sampling was performed on day 21 at predose and for 24 hours postdose.

Duration

Lead-in phase: 28 days

Treatment periods: 28 days each

Outcome Measures

Area under the concentration-time curve from time zero to infinity (AUC_∞), maximum observed concentration (C_max), apparent half-life (t_1/2), time of maximum observed concentration (t_max)

Baseline Characteristics

Age, years

Female

Body-mass index range, kg/m²

Race

White

Black

68.2%

31.8%

Hispanic or Latino

50%

*Of the 22 participants who entered the study, 15 participants completed the study.

Results

Endpoint

NGMN + dulaglutide (n= 14)

NGMN alone (n= 19)

Ratio of geometric LS means (90% CI)

Geometric LS mean AUC_∞, ng·h/mL

Geometric LS mean C_max, ng/mL

Geometric mean t_1/2, hours (range)

Median t_max, hours (range)

Endpoint

Geometric LS mean AUC_∞, ng·h/mL

Geometric LS mean C_max, ng/mL

Geometric mean t_1/2, hours (range)

Median t_max, hours (range)

Coadministration of dulaglutide had no effect on AUC of norelgestromin and ethinylestradiol, with the 90% CI of the ratios of the geometric LS means falling within 0.80 to 1.25. However, the mean C_max for NGMN and EE were reduced by 26% and 13%, respectively. A delay in t_max by 1 hour was observed for NGMN and EE when coadministered with dulaglutide.

Abbreviations: CI, confidence interval; LS, least squares

Adverse Events

The most frequently observed drug-related adverse events upon dulaglutide coadministration with Ortho-Cyclen were gastrointestinal disorders such as nausea, vomiting, and decreased appetite (incidences not reported).

Study Author Conclusions

Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree in healthy subjects. Based on the PK and PD evaluations, no dose adjustment is recommended for any of the medications evaluated when coadministered with dulaglutide.

InpharmD Researcher Critique

It is unknown if the results of this study can be extrapolated to concomitant administration of other GLP-1 receptor agonists with other hormonal contraceptives.

Semaglutide, A Once-Weekly Human GLP-1 Analog, Does Not Reduce the Bioavailability of the Combined Oral Contraceptive, Ethinylestradiol/Levonorgestrel

Design

Single-center, open-label, one-sequence crossover study

N= 43

Objective

To investigate if semaglutide altered the pharmacokinetics (PK) of components of a commonly used combined oral contraceptive, ethinylestradiol/levonorgestrel, in postmenopausal women with type 2 diabetes (T2D)

Study Groups

All patients (N= 43)

Inclusion Criteria

Age ≥ 18 y/o; bilateral oophorectomy or had ≤ 1 year of spontaneous amenorrhea; serum follicle stimulating hormone > 40 mIU/mL; estrogen deficiency (estradiol levels < 30 pg/mL or a negative gestagen test), documented T2D treated with diet and exercise ± metformin; body mass index (BMI) of 18.5 to 35.0 kg/m²; glycosylated hemoglobin A_1c (HbA_1c) of 6.5% to 10%

Exclusion Criteria

Treatment with antidiabetic drugs other than metformin ≤ 3 months before start of trial; use of hormone replacement therapy in the 4 weeks before start of trial product

Methods

Semaglutide was administered once weekly via subcutaneous injection using a dose-escalation regimen starting at 0.25 mg for 4 weeks, followed by 0.5 mg for 4 weeks, and 1 mg for 5 weeks. Concurrently, an oral contraceptive containing ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg) was administered as one tablet daily for 8 days before and during the last week of semaglutide 1 mg dosing.

Blood samples were collected for PK analysis of the oral contraceptive components and semaglutide at specified intervals. Ethinylestradiol and levonorgestrel levels were determined using gas chromatography-mass spectrometry, while semaglutide concentrations were measured via liquid chromatography-tandem mass spectrometry. Pharmacodynamic (PD) endpoints, including HbA1c, fasting plasma glucose, and body weight were assessed at baseline, as well as during and post-treatment.

Duration

Intervention: 8-day oral contraceptive administration period with blood sampling for PK occurring over 10 days

Follow-up: Semaglutide PK monitored for 5 weeks post-treatment

Outcome Measures

Primary: Area under the curve (AUC_0-24h) for ethinylestradiol and levonorgestrel at steady-state

Secondary: PK during dose escalation (C_trough [1 week after the fourth dose at each dose level]) and at steady state (1 mg) AUC; apparent total plasma clearance (CL/F); maximum concentration (C_max); trough concentration (C_trough); half-life (t_1/2); time to reach C_max (t_max); apparent volume of distribution (VZ/F), safety, tolerability, and pharmacodynamics

Baseline Characteristics

All patients (N= 43)

Age, years

Diet and exercise only/metformin

Weight, kg

BMI, kg/m²

Diabetes duration, years

HbA_1c

Results

Endpoint

Ethinylestradiol (n= 37)

Levonorgestrel (n= 40)

Geometric mean AUC, pg·h/mL (coefficient of variation)

Semaglutide-Free

Semaglutide Steady-State

748.7 (28.2%)

828.9 (30.2%)

52,780 (29.3%)

63,516 (32.2%)

Geometric mean C_max, pg/mL (coefficient of variation)

Semaglutide-Free

Semaglutide Steady-State

93.8 (26.9%)

97.6 (30.6%)

5374 (23.9%)

5642 (31.8%)

Median t_max, hours (range)

Semaglutide-Free

Semaglutide Steady-State

1 (0.5 to 2)

2 (0.5 to 8)

1 (0.5 to 6)

1 (1 to 8)

Geometric mean C_trough, pg/mL (coefficient of variation)

Semaglutide-Free

Semaglutide Steady-State

16.0 (37.7%)

16.6 (41.6%)

1524 (33.9%)

1745 (37.0%)

Geometric mean t_1/2, hours (coefficient of variation)

Semaglutide-Free

Semaglutide Steady-State

23.8 (41.8%)

27.4 (83.9%)

35.1 (20.1%)

33.5 (35.7%)

Geometric mean CL/F, L/h (coefficient of variation)

Semaglutide-Free

Semaglutide Steady-State

40.1 (36.6%)

36.2 (37.9%)

2.8 (35.2%)

2.4 (38.9%)

Geometric mean VZ/F, L (coefficient of variation)

Semaglutide-Free

Semaglutide Steady-State

1300 (53.7%)

1416 (114.9%)

144.0 (35.1%)

114.0 (58.1%)

Adverse Events

Common Adverse Events: Nausea (dose-dependent [0.25 mg to 1 mg]; 0% to 35%), vomiting (9%), diarrhea (14%)

Serious Adverse Events: None

Percentage that Discontinued due to Adverse Events: 2.3% (intermittent nausea, vomiting, and diarrhea) 

Study Author Conclusions

In conclusion, this study, the first to investigate the intended clinical dose and the anticipated dose-escalation regimen of semaglutide, shows that treatment with semaglutide does not decrease the bioavailability of ethinylestradiol or levonorgestrel in postmenopausal women with T2D. Therefore, the coadministration of semaglutide is not expected to affect the efficacy of oral contraceptive medications. Furthermore, the study confirms the pharmacokinetic compatibility of semaglutide for once-weekly dosing and corroborates recent phase II study results, with regard to improved glycemic control and reduced body weight, in combination with a low risk of hypoglycemia. With dose escalation, the incidence of nausea declined, indicating tolerance development. The elevated liver enzyme results will be further investigated in the ongoing semaglutide phase III clinical program. The semaglutide dose and dose-escalation regimen used in this study have been selected for the further development of semaglutide.

InpharmD Researcher Critique

This study maintained a robust design with a detailed dose-escalation regimen and extensive blood sampling, alongside the use of validated LC-MS/MS assays for accurate drug concentration measurements. However, the study's short duration and small sample size limit its ability to capture long-term effects and generalize findings to a broader population.

Effect of exenatide on the pharmacokinetics of a combination oral contraceptive in healthy women, an open-label, randomised, crossover trial

Design

Open-label, randomized crossover study

N= 32

Objective

Study Groups

All subjects (N= 32)

Inclusion Criteria

Healthy pre-menopausal females, aged 18 to 45 years old, body mass index (BMI) between 19 to 35 kg/m², taking an OC prior to study entry

Exclusion Criteria

Diabetes mellitus, received implanted contraceptives for 6 months or injectable contraceptives for 12 months prior, ingestion of grapefruit within 7 days, use of concomitant drug therapies that could induce or inhibit CYP3A within 14 days before first drug administration

Methods

The OC combination product consisted of ethinyl estradiol (EE) 30 mcg and levonorgestrel (LV) 150 mcg. Subjects were randomly assigned to 1 of 3 treatment periods, each of 28 days duration: OC administered alone, OC administered 1 hour before exenatide, and OC administered 30 minutes after exenatide. Subjects received a single dose of OC on day 8 of each period and once-daily doses on days 10 through 28. In treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and evening meals at a dose of 5 mcg twice daily from days 1 through 4 and at a dose of 10 mcg twice daily from days 5 through 22. Single-dose and multiple-dose pharmacokinetic profiles were assessed for each treatment period at day 8 and day 22, respectively.

Duration

Treatment periods: 28 days

Outcome Measures

Single-dose and multiple-dose area under the curve (AUC), max concentration (C_max), 24-hour concentration, time to max concentration (T_max), half-life (t_1/2)

Baseline Characteristics

Subjects (N= 32)

Age, years

Female

Weight, kg

BMI, kg/m²

White, n

Smokers, n

Of the 38 subjects who entered the study, 20 completed the 3 treatment periods, and 18 subjects were withdrawn from the study.

Results

Endpoint

EE single-dose PK

Ratio (90% CI) vs. OC alone

EE single-dose PK

Ratio (90% CI) vs. OC alone

LS geometric mean AUC, pg·h/mL

OC alone

1 hour before exenatide

0.5 hour after exenatide

718.89

691.69

692.56

Reference

0.96 (0.91 to 1.02)

0.96 (0.91 to 1.02)

761.06

716.70

734.01

Reference

0.94 (0.88 to 1.01)

0.96 (0.90 to 1.04)

LS geometric mean C_max, pg/mL

OC alone

1 hour before exenatide

0.5 hour after exenatide

72.18

65.49

38.64

Reference

0.91 (0.83 to 0.99)

0.54 (0.49 to 0.58)

102.15

87.09

56.32

Reference

0.85 (0.78 to 0.93)

0.55 (0.50 to 0.60)

LS geometric mean 24-hour concentration, pg/mL

OC alone

1 hour before exenatide

0.5 hour after exenatide

8.27

8.13

10.25

Reference

0.98 (0.92 to 1.05)

1.24 (1.16 to 1.33)

14.64

15.03

17.52

Reference

1.03 (0.95 to 1.11)

1.20 (1.10 to 1.30)

T_max median, hours

OC alone

1 hour before exenatide

0.5 hour after exenatide

-

-

-

1.50 (0.50 to 2.50)

1.50 (0.50 to 2.00)

6.00 (2.00 to 6.13)

-

-

-

-

-

-

t_1/2 geometric mean, hours

OC alone

1 hour before exenatide

0.5 hour after exenatide

-

-

-

19.5 (13.8 to 32.1)

18.9 (14.0 to 30.1)

17.4 (8.78 to 31.9)

-

-

-

-

-

-

Endpoint

LV single-dose PK

Ratio (90%) CI vs. OC alone

LV multiple-dose PK

Ratio (90%) CI vs. OC alone

LS geometric mean AUC, pg·h/mL

OC alone

1 hour before exenatide

0.5 hour after exenatide

55,598.79

53,530.64

60,591.89

Reference

0.96 (0.90 to 1.03)

1.09 (1.01 to 1.17)

72,974.62

72,952.67

76,344.29

Reference

1.00 (0.92 to 1.09)

1.05 (0.96 to 1.14)

LS geometric mean C_max, pg/mL

OC alone

1 hour before exenatide

0.5 hour after exenatide

3,882.56

4,061.86

2,284.25

Reference

1.05 (0.94 to 1.16)

0.59 (0.53 to 0.65)

6,598.95

6,657.22

4,800.68

Reference

1.01 (0.92 to 1.10)

0.73 (0.67 to 0.79)

LS geometric mean 24-hour concentration

OC alone

1 hour before exenatide

0.5 hour after exenatide

600.88

571.47

691.10

Reference

0.95 (0.89 to 1.02)

1.15 (1.07 to 1.23)

2,136.51

2,173.05

2,367.68

Reference

1.02 (0.93 to 1.11)

1.11 (1.01 to 1.21)

T_max median, hours

OC alone

1 hour before exenatide

0.5 hour after exenatide

-

-

-

1.00 (0.50 to 2.07)

0.92 (0.50 to 1.50)

4.75 (3.00 to 6.02)

-

-

-

-

-

-

t_1/2 geometric mean, hours

OC alone

1 hour before exenatide

0.5 after exenatide

-

-

-

33.6 (20.0 to 78.5)

32.1 (19.8 to 55.7)

32.6 (17.9 to 72.4)

-

-

-

-

-

-

Abbreviations: CI, confidence interval; LS, least squares

Adverse Events

The incidence of adverse events considered to be related to OC was reported to be similar across all treatments.

An increase in the incidence of adverse events overall was reported with concomitant administration of exenatide and OC compared to administration of OC alone. The majority of subjects experienced adverse events considered to be related to exenatide. Nausea and vomiting were reported by 91% (all mild or moderate) and 81% (one severe case) of subjects, respectively.

A total of 53% of subjects reported skin-related adverse events, including injection-site rash (11 subjects) and skin rash (8 subjects). The skin-related adverse events were considered by the investigator to be related to exenatide in all but one of the cases. Two subjects were withdrawn from the study due to rash.

Ten subjects withdrew from the study due to adverse events.

Study Author Conclusions

The observed reduction in C_max is likely of limited importance given the unaltered oral contraceptive bioavailability and trough concentrations; however, for oral medications that are dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour before exenatide injection.

InpharmD Researcher Critique

Effects of multiple doses of albiglutide on the pharmacokinetics, pharmacodynamics, and safety of digoxin, warfarin, or a low-dose oral contraceptive

Design

Three open-label, sequential, single-center, phase 1 studies

N= 23 (oral contraceptive [OC] study)

Objective

To assess the effect of albiglutide on the pharmacokinetic (PK) of digoxin in healthy adult volunteers

Study Groups

Study cohort (N= 23)

Inclusion Criteria

Women, aged 18-40 years, body mass index (BMI) 19-30 kg/m², body weight 50-114 kg

Exclusion Criteria

Positive test results for hepatitis B antigen, hepatitis C virus, or human immunodeficiency virus; corrected QT interval >450 ms; any identified clinically relevant abnormality; blood pressure ≥140/90 mmHg or heart rate >100 beats per minute at screening; previous receipt of a GLP-1 mimetic compound

Methods

The subcutaneous albiglutide dose utilized in all three studies was 50 mg weekly, with five weekly doses administered in the digoxin and warfarin studies and four weekly doses for the OC study. In the OC study, the standard, low-dose OC utilized contained norethindrone 0.5 mg and ethinyl estradiol 0.035 mg. Treatment was divided into three periods (run-in, period 1, period 2); patients who were not taking a stable dose of OC received an active dose for 21 days, followed by a 7-day washout. Patients who were already receiving OCs may skip the run-in period. During periods 1-2, patients received an OC tablet for 21 days, then an inactive tablet on days 22-28. Subcutaneous albiglutide injections were administered on day 26 of period 1 and days 5, 12, and 19 of period 2. Trough PK was sampled prior to OC doses on days 19-21, with additional PK samples taken temporally up to 24 hours after dosing on day 21. Pharmacodynamic (PD) data for progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were also collected.

Duration

23 weeks

Outcome Measures

PK and PD data

Baseline Characteristics

Age, years

Female

White

BMI, kg/m²

Weight, kg

Results

Endpoint

90% CI

AUC_0-24, pg*h/mL

Norethindrone

Ethinyl estradiol

1.09

1.00

1.06-1.14

0.96-1.04

Cmax, pg/mL

Norethindrone

Ethinyl estradiol

1.20

1.04

1.11-1.29

0.98-1.10

Cmin, pg/mL

Norethindrone

Ethinyl estradiol

1.15

1.03

1.09-1.22

0.94-1.12

t1/2, h

Norethindrone

Ethinyl estradiol

1.02

0.92

0.97-1.07

0.83-1.02

Abbreviations: AUC= area under the curve; CI= confidence interval

*Ratio of OC + albiglutide/OC alone

Data has been only provided for the OC study in this table. Datapoints retrieved were compiled of 21 norethindrone, 18 norethindrone + albiglutide, 21 ethinyl estradiol, and 18 ethinyl estradiol + albiglutide points (the only exception being t1/2, which had only 17 datapoints).

No clinically meaningful differences were observed following albiglutide co-administration in mean maximum concentrations of LH and FSH, nor in mean concentration of progesterone.

Adverse Events

Common Adverse Events: nausea (23.8%), vomiting (19%)

Serious Adverse Events: N/A; all resolved by end of study

Percentage that Discontinued due to Adverse Events: vomiting (1 patient), depressed mood (1 patient; pretreatment adverse event)

Study Author Conclusions

Albiglutide is currently under investigation in phase 3 trials for the treatment of T2DM. Albiglutide has the potential to treat a broad population of patients with T2DM, including those receiving treatment for cardiovascular conditions and women of childbearing age. If approved for clinical use, these data suggest that albiglutide (≤50 mg weekly) can be used safely in combination with digoxin, warfarin, NE, and EE at doses up to 0.5 mg, 25 mg, 0.5 mg, and 0.035 mg, respectively. No dose adjustments should be necessary if these treatments are co-administered with albiglutide.

InpharmD Researcher Critique

Due to the small sample size, clinically relevant effects of albiglutide may have been unable to be captured. Additionally, the use of healthy subjects precludes applicability in other patient populations with comorbidities, concomitant medications, or more critical conditions.