Phase 1 Completed N=26 Randomized Treatment

To Assess Bioavailability, Food Effect and Pharmacokinetics of Gepotidacin Tablets: A Phase I, Single-Dose, 2 Part Study in Healthy Subjects.

Infections, Bacterial

Source: ClinicalTrials.gov NCT02853435 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Nov 2018

Primary outcomePrimary: Area Under the Concentration-time Curve From Time 0 (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) of Plasma Gepotidacin for Part 1a — 16733; 17495; 18646 hours*nanograms/milliliter

Summary

This study is divided in 2 parts. Part 1a is being conducted to evaluate the safety, tolerability, and relative bioavailability of the 2 free base tablet formulations (roller compacted [RC] and high shear wet granulation [HSWG]) compared to the reference capsule formulation under fasted conditions. This is a 3-period; cross-over study that will guide which gepotidacin formulation will be used for future studies. Following review of pharmacokinetic (PK) and safety data in Part 1a, a decision will be made whether to proceed with Parts 1b and 2. Part 1b is a 2-period, cross-over study and will assess the effect of food on the PK of the selected gepotidacin tablet formulation from Part 1a. In Part 2, the PK of the selected gepotidacin tablet formulation from Part 1a in Japanese (2a) and Chinese (2b) subjects will be evaluated under fasted conditions. The duration of the study (from Screening to the Follow-up visit) will be approximately 44 days (Part 1a), 41 days (Part 1b) and 38 days (Part 2a and 2b each), respectively. The approximate number of subjects enrolled in Part 1a will be 27 (9 subjects in each of the 3 treatment sequences), 16 in Part 1b (8 subjects in each of the 2 treatment sequences) and 12 Japanese and 12 Chinese subjects in Part 2a and 2b, respectively.

Outcome Measures

Outcome	Result	p-value
PRIMARY Area Under the Concentration-time Curve From Time 0 (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) of Plasma Gepotidacin for Part 1a	16733; 17495; 18646	—
PRIMARY Area Under the Concentration-time Curve (AUC) From Time 0 (Pre-dose) to Time of the Last Quantifiable Concentration (AUC [0-t]) of Plasma Gepotidacin for Part 1a	16409; 17125; 18317	—
PRIMARY Relative Bioavailability of Drug (Frel) of Plasma Gepotidacin for Part 1a	NA; 1.05; 1.11	—
PRIMARY Maximum Observed Concentration (Cmax) Determined Directly From the Concentration Time Data of Plasma Gepotidacin for Part 1a	4648; 4487; 5349	—
PRIMARY Time to First Occurrence of Cmax (Tmax) of Plasma Gepotidacin for Part 1a	1.50; 1.50; 1.00	0.309
PRIMARY Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Plasma Gepotidacin for Part 1a	0.00; 0.00; 0.00	—
PRIMARY Terminal Phase Half-life (t1/2) of Plasma Gepotidacin for Part 1a	10.29; 10.24; 10.24	—
PRIMARY Total Unchanged Drug (Total Amount of Drug Excreted in Urine [Ae Total]) for Part 1a	274.925; 286.751; 284.510	—
PRIMARY Percentage of the Given Dose of Drug Excreted in Urine (fe%) of Plasma Gepotidacin for Part 1a	18.329; 19.116; 18.968	—
PRIMARY Renal Clearance of Drug in Urine (CLr) for Part 1a	16.761; 16.740; 15.532	—
PRIMARY Amount of Drug Excreted in Urine in a Time Intervals for Pre-dose, 0 to 2 Hours, 2 to 4 Hours, 4 to 6 Hours, 6 to 8 Hours, 8 to 12 Hours, 12 to 24 Hours, 24 to 36 Hours, and 36 to 48 Hours (Ae [t1-t2]) for Part 1a	65.817; 60.915; 85.584; 72.734; 77.650; 67.419	—
PRIMARY Area Under the Urine Concentration-time Curve Over Time 0 (Pre-dose) to 12 Hours (AUC [0-12]) for Part 1a	1904; 1948; 2156	—
PRIMARY Area Under the Urine Concentration-time Curve Over Time 0 (Pre-dose) to 24 Hours (AUC [0-24]) After Dosing for Part 1a	2373; 2464; 2599	—
PRIMARY Area Under the Urine Concentration-time Curve Over Time 0 (Pre-dose) to 48 Hours (AUC [0-48]) After Dosing for Part 1a	2597; 2725; 2768	—
PRIMARY AUC (0-infinity) of Plasma Gepotidacin for Part 1b	—	—
PRIMARY AUC (0-t) of Plasma Gepotidacin for Part 1b	—	—
PRIMARY Cmax of Plasma Gepotidacin for Part 1b	—	—
PRIMARY Tmax of Plasma Gepotidacin for Part 1b	—	—
PRIMARY Tlag of Plasma Gepotidacin for Part 1b	—	—
PRIMARY t1/2 of Plasma Gepotidacin for Part 1b	—	—
PRIMARY AUC (0-infinity) of Plasma Gepotidacin for Part 2	23137; 46537	—
PRIMARY AUC (0-t) of Plasma Gepotidacin for Part 2	22777; 46120	—
PRIMARY Cmax of Plasma Gepotidacin for Part 2	9177; 15335	—
PRIMARY Tlag of Plasma Gepotidacin for Part 2	0.00; 0.00	—
PRIMARY Tmax of Plasma Gepotidacin for Part 2	1.00; 0.56	—
PRIMARY t1/2 of Plasma Gepotidacin for Part 2	10.73; 8.81	—
PRIMARY Total Unchanged Drug (Ae Total) for Part 2	203.853; 546.263	—
PRIMARY Ae (t1-t2) for Part 2	50.893; 115.793; 47.995; 131.013; 21.381; 97.651	—
PRIMARY AUC (0-12) for Part 2	1298; 4758	—
PRIMARY AUC (0-24) for Part 2	1714; 5594	—
PRIMARY AUC (0-48) for Part 2	1875; 5845	—
PRIMARY fe% for Part 2	13.591; 18.207	—
PRIMARY CLr for Part 2	8.950; 11.834	—
PRIMARY AUC (0-infinity) of Plasma Gepotidacin for Part 3	22921; 37235; 50178	—
PRIMARY AUC (0-t) of Plasma Gepotidacin for Part 3	22709; 36938; 49789	—
PRIMARY Cmax of Plasma Gepotidacin for Part 3	6502; 9812; 12889	—
PRIMARY Tmax of Plasma Gepotidacin for Part 3	2.25; 2.05; 2.00	—
PRIMARY Tlag of Plasma Gepotidacin for Part 3	0.50; 0.00; 0.00	—
PRIMARY t1/2 of Plasma Gepotidacin for Part 3	9.23; 8.19; 7.93	—
PRIMARY Total Unchanged Drug (Ae Total) for Part 3	390.099; 613.635; 895.556	—
PRIMARY Urine Ae (t1-t2) for Part 3	27.763; 54.827; 142.546; 132.423; 247.448; 333.805	—
PRIMARY Urine AUC (0-12) for Part 3	1573; 2812; 3517	—
PRIMARY Urine AUC (0-24) for Part 3	1879; 3301; 4197	—
PRIMARY Urine AUC (0-48) for Part 3	2024; 3455; 4390	—
PRIMARY fe% for Part 3	26.008; 27.273; 29.858	—
PRIMARY CLr for Part 3	17.196; 16.598; 17.969	—
SECONDARY Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) for Part 1a	8; 5; 9; 0; 0; 0	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Carbon Dioxide, Serum Chloride, Serum Potassium, Serum Sodium and Serum Urea Nitrogen for Part 1a	0.010; 0.049; 0.094; 0.099; 0.304; 0.381	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Alanine Aminotransferase (ALT), Serum Alkaline Phosphatase (AP), Serum Aspartate Aminotransferase (AST) and Serum Creatinine Kinase (CK) for Part 1a	-1.1; -0.1; -0.3; -3.0; 0.1; 5.4	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 1a	1.5; 1.8; 1.8; -0.3; -0.7; -0.6	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatinine and Serum Direct Bilirubin for Part 1a	2.08; 1.59; 1.98; 2.34; -1.08; -1.19	—
SECONDARY Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils and Blood Platelets for Part 1a	0.004; 0.004; -0.004; 0.000; 0.000; 0.000	—
SECONDARY Change From Baseline in Hematology Parameters Blood Erythrocyte (Ery.) Mean Corpuscular Hemoglobin Concentration (MCHC) and Blood Hemoglobin for Part 1a	0.4; 0.9; 0.4; 2.5; 4.1; 3.0	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. Mean Corpuscular Hemoglobin (MCH) for Part 1a	-0.03; 0.00; -0.02; -0.03; 0.14; 0.04	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. Mean Corpuscular Volume (MCV) for Part 1a	-0.21; -0.26; -0.23; -0.73; -0.58; -0.72	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. for Part 1a	0.279; 0.293; 0.296; -0.130; -0.190; -0.101	—
SECONDARY Change From Baseline in Hematology Parameter Blood Hematocrit for Part 1a	2.32; 2.43; 2.48; -1.50; -1.87; -1.20	—
SECONDARY Change From Baseline in Vital Sign Parameters Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) for Part 1a	1.8; -1.3; 1.1; 0.1; -2.8; -1.8	—
SECONDARY Change From Baseline in Vital Sign Parameter Heart Rate for Part 1a	-0.7; 0.0; 1.7; -0.7; 0.6; 1.7	—
SECONDARY Change From Baseline in Electrocardiogram (ECG) Parameter Heart Rate for Part 1a	-1.1; -1.0; 0.4; 0.2; -0.4; 0.3	—
SECONDARY Change From Baseline in ECG Parameters PR Interval, QRS Duration, QT Interval, Corrected QT Interval Using Bazett's Formula (QTcB) and Corrected QT Interval Using Fridericia's Formula (QTcF) for Part 1a	-2.5; -3.2; -3.8; 1.7; -0.1; -0.5	—
SECONDARY Number of Participants With Abnormal Values on Urinalysis by Dipstick Analysis Part 1a	1; 0; 0; 4; 4; 4	—
SECONDARY Number of Participants With AEs and SAEs for Part 1b	—	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Carbon Dioxide, Serum Chloride, Serum Potassium, Serum Sodium and Serum Urea Nitrogen for Part 1b	—	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum ALT, Serum AP, Serum AST and Serum CK for Part 1b	—	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 1b	—	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatinine and Serum Direct Bilirubin in Part 1b	—	—
SECONDARY Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils and Blood Platelets for Part 1b	—	—
SECONDARY Change From Baseline in Hematology Parameters Blood Ery. MCHC and Blood Hemoglobin for Part 1b	—	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. MCH for Part 1b	—	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. MCV for Part 1b	—	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. for Part 1b	—	—
SECONDARY Change From Baseline in Hematology Parameter Blood Hematocrit for Part 1b	—	—
SECONDARY Change From Baseline in Vital Sign Parameters SBP and DBP for Part 1b	—	—
SECONDARY Change From Baseline in Vital Sign Parameter Heart Rate for Part 1b	—	—
SECONDARY Change From Baseline in ECG Parameter Heart Rate for Part 1b	—	—
SECONDARY Change From Baseline in ECG Parameters PR Interval, QRS Duration, QT Interval, QTcB and QTcF for Part 1b	—	—
SECONDARY Number of Participants With Abnormal Values on Urinalysis by Dipstick Analysis Part 1b	—	—
SECONDARY Number of Participants With Non-serious AEs and SAEs for Part 2	6; 9; 0; 0	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Carbon Dioxide, Serum Chloride, Serum Potassium, Serum Sodium and Serum Urea Nitrogen in Part 2	-0.146; -0.133; NA; -0.211; -0.027; -0.009	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum ALT, Serum AP, Serum AST and Serum CK in Part 2	-0.2; 1.3; NA; 3.1; -0.3; -0.3	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 2	-0.9; 0.0; NA; -1.5; 0.0; -2.1	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatinine and Serum Direct Bilirubin for Part 2	-1.02; -3.62; NA; -0.68; -1.76; -4.42	—
SECONDARY Change From Baseline in Clinical Chemistry Parameter Serum Estradiol for Part 2	NA; 0.00	—
SECONDARY Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils and Blood Platelets for Part 2	0.002; 0.009; NA; 0.004; 0.036; 0.052	—
SECONDARY Change From Baseline in Hematology Parameters Ery. MCHC and Blood Hemoglobin for Part 2	-6.6; -6.6; NA; -6.2; 2.8; 0.9	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. MCH for Part 2	-0.25; -0.06; NA; -0.15	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. MCV for Part 2	1.17; 1.69; NA; 1.28	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. for Part 2	0.118; 0.033; NA; -0.175	—
SECONDARY Change From Baseline in Hematology Parameter Blood Hematocrit for Part 2	1.6; 1.02; NA; -1.09	—
SECONDARY Change From Baseline in Vital Sign Parameters SBP and DBP for Part 2	-8.4; 6.7; -9.6; -3.1; -4.1; -4.2	—
SECONDARY Change From Baseline in Vital Sign Parameter Heart Rate for Part 2	0.1; 3.2; -3.8; -1.4; -3.0; 3.4	—
SECONDARY Change From Baseline in ECG Parameter Heart Rate for Part 2	5.4; 4.9; -1.2; -1.1; 2.1; 3.4	—
SECONDARY Change From Baseline in ECG Parameters PR Interval, QRS Duration, QT Interval, QTcB and QTcF for Part 2	-1.7; 0.5; 7.2; -2.7; 5.1; 3.0	—
SECONDARY Number of Participants With Abnormal Values on Urinalysis by Dipstick Analysis Part 2	0; 1; 0; 1; 2; 0	—
SECONDARY Number of Participants With Non-serious AEs and SAEs for Part 3	0; 1; 6; 0; 0; 0	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Carbon Dioxide, Serum Chloride, Serum Potassium, Serum Sodium and Serum Urea Nitrogen for Part 3	0.038; -0.305; -0.071; -0.415; -0.197; -0.335	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum ALT, Serum AP, Serum AST and Serum CK for Part 3	0.1; -2.5; 2.2; -4.0; 6.0; -4.5	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 3	-2.0; -2.0; -2.0; -3.0; -0.6; -2.5	—
SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin and Serum Creatinine for Part 3	-2.43; -0.85; -3.11; -1.70; -2.28; 0.85	—
SECONDARY Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils and Blood Platelets for Part 3	0.004; 0.000; 0.009; -0.010; 0.009; 0.005	—
SECONDARY Change From Baseline in Hematology Parameters Blood Ery. MCHC and Blood Hemoglobin for Part 3	-2.9; -2.0; -3.2; -1.5; -5.3; -6.5	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. MCH for Part 3	0.08; 0.25; 0.08; 0.15; -0.12; 0.00	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. Mean Corpuscular Volume (MCV) for Part 3	1.10; 1.30; 1.14; 0.70; 1.16; 1.80	—
SECONDARY Change From Baseline in Hematology Parameter Blood Ery. for Part 3	-0.065; -0.275; -0.138; -0.390; -0.060; -0.340	—
SECONDARY Change From Baseline in Hematology Parameter Blood Hematocrit for Part 3	-0.02; -2; -0.65; -3.3; 0.02; -2.35	—
SECONDARY Change From Baseline in Vital Sign Parameters SBP and DBP for Part 3	4.6; 6.0; -4.3; 0.5; -4.8; -1.5	—
SECONDARY Change From Baseline in Vital Sign Parameter Heart Rate for Part 3	1.6; 1.0; 0.1; -4.5; -3.2; -4.0	—
SECONDARY Change From Baseline in ECG Parameter Heart Rate for Part 3	8.0; 5.0; -0.3; -4.0; 4.8; 0.0	—
SECONDARY Change From Baseline in ECG Parameters PR Interval, QRS Duration, QT Interval, QTcB and QTcF for Part 3	-3.3; -1.0; -1.9; -1.0; -3.7; 0.0	—
SECONDARY Number of Participants With Abnormal Values on Urinalysis by Dipstick Analysis Part 3	0; 0; 1; 0; 2; 0	—

Eligibility Criteria

Inclusion Criteria

Male or female subjects between 18 and 64 years of age inclusive, at the time of signing the informed consent.
Healthy as determined by the investigator based on medical history, clinical laboratory results (serum chemistry, hematology, urinalysis, and serology), vital sign measurements, 12-lead ECG results, and physical examination findings. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the investigator feels and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Additional inclusion criteria for Japanese subjects (Part 2a only): the subject was a non-naturalized Japanese citizen and held a Japanese passport, the subject had 2 Japanese parents and 4 Japanese grandparents who were all non naturalized Japanese citizens, as confirmed by interview and the subject had been living outside of Japan for up to 10 years as confirmed by interview.
Additional inclusion criteria for Chinese subjects (Part 2b only): the subject was a non-naturalized Chinese citizen and held a Chinese passport, the subject had 2 Chinese parents and 4 Chinese grandparents who were all non naturalized Chinese citizens, as confirmed by interview, the subject had been living outside of China for up to 10 years as confirmed by interview.
Body weight for subjects in Part 1a and 1b: more than equal to (>=) 50 kilogram (kg) and body mass index (BMI) within the range 19 and 32 kilogram per meter square (kg/m^2), inclusive and for Japanese and Chinese subjects (Part 2a and 2b): >=50 kg and BMI within the range 18 and 32 kg/m^2, inclusive.
Male or female: a female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin test, not lactating, and at least one of the following conditions applies. Non-reproductive potential defined as: pre-menopausal females with one of the following: documented tubal ligation, documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy, documented bilateral oophorectomy and postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle-stimulating hormone and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose of study medication and until completion of the Follow-up visit.
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria

Subject has a clinically significant abnormality in past medical history or at the Screening physical examination that in the investigator's opinion may place the subject at risk or interfere with outcome variables of the study. This includes, but is not limited to, history or current cardiac, hepatic, renal, neurologic, gastrointestinal, respiratory, hematologic, or immunologic disease.
Subject has any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion of the study drug, or any other condition that may place the subject at risk, in the opinion of the investigator.
QTc more than (>) 450 millisecond (msec).
Use of a systemic antibiotic within 30 days of Screening.
Within 2 months before Scree

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Data sourced from ClinicalTrials.gov (NCT02853435). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.