Malaria, Falciparum
Conditions
Keywords
GSK3772701, Pharmacokinetics, Midazolam, CYP3A4, Healthy participants, Open label
Brief summary
This study aims to evaluate whether GSK3772701 alters the pharmacokinetics (PK) of midazolam (MDZ), a standard probe substrate for the CYP3A4 enzyme. The findings are planned to be used to determine whether GSK3772701 acts as an inducer and/or inhibitor of CYP3A4 and will help guide recommendations for safe co-administration with CYP3A4 substrates.
Interventions
DRUGMidazolam (MDZ)
Participants receive MDZ orally.
DRUGGSK3772701
Participants receive GSK3772701 orally.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Aged 18 to 55 years (inclusive), at the time of signing the informed consent form (ICF). 2. Weight of at least 50 kg with a body-mass index \<=18.0 and \<=30.0 kg/m². 3. Written informed consent obtained from the participant prior to performance of any study specific procedure, and which includes agreement to compliance, with the requirements and restrictions listed in the ICF and in this protocol. 4. Participants, who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of study assessments, return for follow-up visits). 5. Participants who are healthy as established by medical evaluation including medical history, physical examination, cardiac monitoring, and clinical laboratory assessment before entering into the study. Contraception: * Male participants are eligible to participate. * A female participant is eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies: 6. Is a participant of non-childbearing potential (PONCBP). OR 7. Is a POCBP and using a contraceptive method that is highly effective, with a failure rate of \<1%, for 30 days prior to and during the study intervention period and for at least 7 days after the last dose of GSK3772701 and at least 2 days after the last dose of MDZ. 8. A POCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) at Screening and within 24 hours before the first dose of study intervention. 9. A blood sample for simultaneous follicle-stimulating hormone (FSH) may be collected, and estradiol levels may be included at investigator's discretion to confirm non-reproductive potential when menopausal status is uncertain according to the local laboratory reference range.
Exclusion criteria
1. History or presence/significant history of or current cardiovascular, respiratory, hepatic, renal, urological, gastrointestinal, immunological, dermatological, endocrine, hematologic, neurological, or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data. 2. Any condition where the administration of MDZ could be contraindicated, including but not limited to, hypersensitivity (MDZ, any of its excipients, or to any benzodiazepines), sleep apnea, glaucoma (narrow-angle glaucoma, acute or open angle glaucoma, untreated), myasthenia gravis, respiratory insufficiency, impaired pulmonary function, or severe hepatic impairment. 3. History of any malignancy within the past 5 years. Exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy which is considered cured with minimal risk of recurrence. Participants under evaluation for possible malignancy are not eligible. 4. History of any reaction or hypersensitivity likely to be exacerbated by any component (formulation, capsule, or excipients) of the study intervention(s) (including hypromellose \[hydroxypropyl methylcellulose\] for GSK3772701) or allergies to cherries (as per MDZ USPI). 5. Acute or chronic clinically significant pulmonary, endocrinological, cardiovascular, muscular, neurological, hepatic, or renal functional abnormality, as determined by physical examination or laboratory screening tests. 6. Participants should have baseline clinical laboratory values (renal, hepatic, and hematological) within normal limits or clinically acceptable to the investigator. A participant with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum observed concentration (Cmax) of MDZ | At 0 hours (h) (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 |
| Area under the concentration-time curve. from time 0 to the last measurable concentration [AUC(0-t)] of MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 |
| Area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC(0-inf)] of MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of 1-hydroxymidazolam (OH-MDZ) | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| AUC(0-t) of 1-OH-MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| AUC(0-inf) of 1-OH-MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Metabolite-to-parent ratios (1-OH-MDZ/MDZ) based on Cmax | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Metabolite-to-parent ratios (1-OH-MDZ/MDZ) based on AUC(0-t) | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Metabolite-to-parent ratios (1-OH-MDZ/MDZ) based on AUC(0-inf) | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Time to maximum observed concentration (Tmax) of MDZ and 1-OH-MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Terminal half-life (t1/2) of MDZ and 1-OH-MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Apparent oral plasma clearance (CL/F) of MDZ | At 0h (pre-dose) and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours post-dose for each MDZ administration on days 1, 3, 6 and 10 | — |
| Cmax of GSK3772701 | At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5 | — |
| AUC(0-t) of GSK3772701 | At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5 | — |
| Area under the plasma concentration-time curve from time zero to 24 hours [AUC(0-24)] of GSK3772701 | At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5 | — |
| Tmax of GSK3772701 | At 0h (pre-dose) and at 0.5, 1, 2, 3, 4, 6, 12, 20 and 24 hours post-dose on days 3 and 5 | — |
| Concentration at 24 hours post dose (C24h) of GSK3772701 | At Day 4 pre-dose (24 hours post Day 3 dose), Day 5 pre-dose (24 hours post Day 4 dose) and Day 6 (24 hours post Day 5 dose) | — |
| Incidence of adverse events (AEs) overall, by severity and relationship to GSK3772701 | From Day 1 to Day 12 | An AE is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. The severity of AEs is determined by the investigator using the Division of Acquired Immunodeficiency Syndrome (DAIDS) Table for Grading of Severity of Adult and Pediatric Adverse Events, corrected version 2.1. Grades are defined based on numeric criteria as follows Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: potentially life-threatening; Grade 5: death. Higher grades indicate greater severity. The incidence rate describes the rate at which an event occurs. |
| Incidence of serious adverse events (SAEs) overall, by severity and relationship to GSK3772701 | From Day -30 to Day 12 | An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or extends existing hospitalization, causes persistent or significant disability/incapacity, involves a congenital anomaly/birth defect in a participants offspring, includes an abnormal pregnancy outcome, or occurs in any other situation per the investigators judgement. The severity of SAEs is determined by the investigator using the DAIDs Table for Grading of Severity of Adult and Pediatric Adverse Events, corrected version 2.1. Grades are defined based on numeric criteria as follows Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: potentially life-threatening; Grade 5: death. Higher grades indicate greater severity. The incidence rate describes the rate at which an event occurs. |
Countries
United States
Contacts
CONTACTUS GSK Clinical Trials Call Center
CONTACTEU GSK Clinical Trials Call Center
Outcome results
None listed