The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Cabotegravir Study Number: LAI117011 Title: An Open-label Study to Evaluate the Pharmacokinetics of an Oral Contraceptive Containing Levonorgestrel and Ethinyl Estradiol when Co-administered with GSK1265744 in Healthy Adult Female Subjects Rationale: The aim of this study was to confirm that oral Cabotegravir (GSK1265744, CAB) did not impact the pharmacokinetics (PK) of an ethinyl estradiol (EE) and levonorgestrel (LNG) containing oral contraceptive (OC). Phase: Phase 1 Study Period: 14 Aug 2014 01 Dec 2014 Study Design: This study was an open-label, fixed-sequence crossover study in healthy adult female subjects. Subjects who were not already on a stable regimen of Microgynon were switched to Microgynon for a minimum of one cycle of 21 days to evaluate tolerability, followed by a washout period of 7 days when no active treatment was received, before continuing to Treatment Period 1. During Treatment Period 1, subjects received Microgynon once daily (QD) on Days 1-10. On Day 10 subjects were dosed with Microgynon and underwent a 24-hour serial PK blood collection for LNG and EE. During Treatment Period 2, subjects were dosed with Microgynon + CAB for 11 days (Day 11 21). On the morning of Day 21, subjects underwent 24-hour serial PK blood collection for LNG, EE, and CAB. Subjects returned to the study center 7-14 days after their last dose of study drug (Days 28-35) for follow-up evaluations. Centres: The study was conducted at one center at Quintiles Drug Research Unit at Guy s Hospital, 6 Newcomen Street, London, United Kingdom SE1 1YR Indication: Human Immunodeficiency Virus Type 1 Treatment: Run-in Period: for a period of up to 49 days (only for subjects not on a stable regimen of Microgynon) Treatment Period 1: Days 1 10 Treatment Period 2: + CAB 30mg QD Days 11 21 Objectives: To demonstrate the lack of an effect of oral cabotegravir (GSK1265744; CAB) 30mg on the exposure of levonorgestrel (LNG) and ethinyl estradiol (EE) in healthy female subjects. Primary Outcome Variable: Plasma area under the concentration-time curve over the dosing interval (AUC[0-τ]) of LNG and EE following Microgynon with and without CAB. Secondary Outcome Variable(s): Safety and tolerability parameters, including adverse events (AEs), clinical laboratory tests, electrocardiogram (ECG), and vital signs assessments. Maximum observed plasma concentration (), plasma concentration at the end of the dosing interval (Cτ), and time to maximum drug concentration (tmax), of LNG and EE after Microgynon alone and after Microgynon with CAB. Predose serum levels of LH and FSH on Days 1, 10, 11, 21 and 22. Predose serum levels of progesterone on Days 1, 10, 11, 21 and 22. CAB PK parameters: AUC(0-τ),, tmax, and Cτ Statistical Methods: The primary objective of this study was to demonstrate lack of effect of multiple doses of CAB on the PK [AUC(0-τ)] of LNG and EE. To assess this, a bioequivalence (BE) approach was employed using Schuirmann s two one-sided t-test procedure with α=0.05 for each test. Lack of effect was to be demonstrated if the 90% confidence interval (CI)s for both LNG and EE ratios of geometric least-squares means for AUC(0-τ) lie within 0.8 and 1.25. All of the PK parameters were log-transformed, except tmax. Following loge-transformation, AUC(0-τ),, and Cτ of EE and LNG were separately analyzed using a mixed effects model with treatment as fixed effects and subject as a random effect. The ratios of the geometric least square (GLS) means and associated 90% CIs were estimated for the differences between test treatment (Microgynon +CAB) and reference treatment (Microgynon). LH, FSH, and progesterone concentrations from both periods were listed and summarized by treatment. 1
Study Population: + Number of subjects randomized, n (%) 20 20 20 Number of subjects completed, n (%) 20 19 19 Number of subjects withdrawn (any reason), n (%) 0 1 (5) 1 (5) Adverse events 0 1 (5) 1 (5) Demographics Age in Years, Mean (SD) 26.5 (5.64) 26.5 (5.64) 26.5 (5.64) Sex, n (%) Female 20 (100) 20 (100) 20 (100) BMI (kg/m 2 ), Mean (SD) 24.48 (3.196) 24.48 (3.196) 24.48 (3.196) Height (cm), Mean (SD) 163.13 (6.347) 163.13 (6.347) 163.13 (6.347) Weight (kg), Mean (SD) 65.09 (8.992) 65.09 (8.992) 65.09 (8.992) Ethnicity, n (%) Not Hispanic or Latino: 20 (100) 20 (100) 20 (100) Race, n (%) African American/African Heritage 2 (10) 2 (10) 2 (10) White White/Caucasian/European Heritage 18 (90) 18 (90) 18 (90) = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg ; + CAB 30 mg = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg + oral cabotegravir 30 mg co-administered Safety Results: Thirteen subjects reported at least 1 AE and only 1 AE was considered drug-related (Grade 2 migraine). All adverse events were mild to moderate in intensity. The most commonly reported AEs were headache (n=6 [30%]), and nausea (n=5 [25%]) and rates of these AEs were similar between treatment periods. There were no deaths, SAEs, or clinically significant trends in post-dose laboratory abnormalities, vital signs or ECG values observed. There were no Grade 3/4 laboratory abnormalities reported in the study. One subject was withdrawn from the study due to an AE of a urinary tract infection that required treatment but was not considered related to study drug. The UTI was not attributed to study drug. 2
All Adverse Events by Treatment + Any Event, n (%) 8 (40) 9 (45) 13 (65) Headache 3 (15) 4 (20) 6 (30) Dizziness 2 (10) 0 2 (10) Migraine 0 1 (5) 1 (5) Nausea 4 (20) 1 (5) 5 (25) Vomiting 0 1 (5) 1 (5) Nasopharyngitis 1 (5) 1 (5) 2 (10) Upper respiratory tract infection 1 (5) 0 1 (5) Urinary tract infection 0 1 (5) 1 (5) Asthenia 0 1 (5) 1 (5) Influenza like illness 0 1 (5) 1 (5) Eczema 1 (5) 0 1 (5) Rash 0 1 (5) 1 (5) Lymphadenopathy 0 1 (5) 1 (5) Musculoskeletal chest pain 1 (5) 0 1 (5) = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg ; + CAB 30 mg = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg + cabotegravir 30mg coadministered Drug-Related Adverse Events by Treatment + Any Event, n (%) 0 1 (5) 1 (5) Migraine 0 1 (5) 1 (5) = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg ; + CAB 30 mg = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg + cabotegravir 30 mg coadministered Serious Adverse Events - On-Therapy There were no deaths or SAEs during this study. Pharmacokinetics: Summary of Steady-state Plasma Levonorgestrel Pharmacokinetic s and Treatment Comparisons Geometric Mean GLS Mean Ratio [95% CI] (CVb%) (90% CI) + Levonorgestrel Microgynon + CAB 30mg CAB 30mg QD vs. Microgynon AUC(0-τ) (h*ng/ml) (ng/ml) Cτ (ng/ml) 77.4 [64.5, 92.9] (39) 6.86 [5.84, 8.06] (34) 2.41 [1.98, 2.95] (43) 87.0 [72.1, 105] (40) 7.20 [6.28, 8.26] (29) 2.59 [2.09, 3.22] (47) 1.12 (1.07, 1.18) 1.05 (0.959, 1.15) 1.07 (1.01, 1.15) tmax 1 ------ (h) (0.5 2.5) (0.5 3.0) 1. Median (range) = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg ; + CAB 30 mg = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg + cabotegravir 30 mg coadministered 3
Summary of Steady-state Plasma Ethinyl Estradiol Pharmacokinetic s and Treatment Comparisons Geometric Mean GLS Mean Ratio [95% CI] (CVb%) (90% CI) Ethinyl Estradiol + Microgynon + CAB 30mg CAB 30mg QD vs. Microgynon AUC(0-τ) 1 (h*pg/ml) (pg/ml) Cτ 1 (pg/ml) 773 [656, 911] (33) 86.2 [72.4, 103] (38) 16.0 [12.5, 20.4] (51) 800 [698, 916] (28) 79.5 [68.0, 92.8] (33) 15.7 [12.9, 19.0] (40) 1.50 1.02 (0.968, 1.08) 0.922 (0.827, 1.03) (0.919, 1.10) tmax 2 ----- (h) (0.5 2.5) (0.5 2.6) 1. N= 17 for Microgynon and n=18 for Microgynon + CAB (Two subjects [] and 1 subject [Microgynon + CAB] had Cτ below the lower limit of quantification and could not have these parameters estimated) 2. Median (range) = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg ; + CAB 30 mg = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg + cabotegravir 30 mg coadministered Summary of Steady State Plasma CAB Pharmacokinetic s following Coadministration with Microgynon CAB Geometric Mean[95% CI] (CVb%) + CAB 30mg QD AUC(0-τ) (h*µg/ml) (µg/ml) Cτ (µg/ml) 133 [121, 148] (21) 7.81 [7.13, 8.56] (19) 4.33 [3.87, 4.86] (24) tmax 3.00 (h) 1 (1.0 4.2) 1. Median (range) + CAB 30 mg = levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg + oral cabotegravir 30 mg coadministered Pharmacodynamic and Biomarker Results: There was no apparent difference in mean LH, FSH and progesterone concentrations between Microgynon alone and Microgynon co-administered with CAB. 4
Conclusion: Co-administration of repeat dose cabotegravir (CAB) and the oral contraceptive Microgynon had no effect on the pharmacokinetic profile of levonorgestrel (LNG) and ethinyl estradiol (EE). There were no deaths, SAEs, or clinically significant trends in post-dose laboratory abnormalities, vital signs or ECG values observed. All adverse events were mild to moderate in intensity and rates were similar between treatment periods. Steady-state CAB plasma PK parameters in this study were comparable to historical values. Co-administration of CAB with Microgynon had no pharmacodynamic effect on LH, FSH, and progresterone compared to when Microgynon was administered alone. 5