Phase 1
Completed N=98
Evaluation of Safety, Tolerability, Pharmacokinetics, Drug-Drug and Food Interactions of Single and Multiple Doses of S-648414 in Healthy Adults
Healthy Volunteer
Source: ClinicalTrials.gov NCT04147715 ↗
Enrolled (actual)
98
Serious AEs
0.0%
Results posted
Oct 2021
Primary outcomePrimary: Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) — 2; 0; 0; 1 Participants
Summary
The primary objective of Part 1 of the study is to evaluate the safety and tolerability of S-648414 after administration of a single oral dose of S-648414 in healthy adult study participants.
The primary objective of Part 2 is to evaluate the safety and tolerability of S-648414 after administration of multiple oral doses of S-648414 in healthy adult study participants.
The primary objectives of Part 3 are evaluate the safety and tolerability of S-648414 after administration of multiple oral doses of S-648414 in healthy adult study participants, and to evaluate the effect of S-648414 on the pharmacokinetics (PK) of dolutegravir and the effect of dolutegravir on the PK of S-648414 in healthy adult study participants.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs) |
2; 0; 0; 1; 2; 2 | — |
| PRIMARY Part 2: Number of Participants With Treatment-emergent Adverse Events |
0; 2; 2; 3; 0; 1 | — |
| PRIMARY Part 3: Number of Participants With Treatment-emergent Adverse Events |
3; 3; 4; 2; 5; 2 | — |
| PRIMARY Part 3: Maximum Plasma Concentration (Cmax) of S-648414 |
2740; 2720; 5150; 5020 | — |
| PRIMARY Part 3: Time to Maximum Plasma Concentration (Tmax) of S-648414 |
2.00; 2.25; 2.50; 2.25 | — |
| PRIMARY Part 3: Plasma Concentration of S-648414 at the End of the Dosing Interval τ (Cτ) |
1210; 1250; 2590; 2360 | — |
| PRIMARY Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for S-648414 |
40800; 41080; 81010; 79820 | — |
| PRIMARY Part 3: Apparent Total Clearance (CL/F) of S-648414 |
2.45; 2.43; 2.47; 2.51 | — |
| PRIMARY Part 3: Maximum Plasma Concentration (Cmax) of Dolutegravir |
4910; 5800; 4720; 4950 | — |
| PRIMARY Part 3: Time to Maximum Plasma Concentration (Tmax) of Dolutegravir |
3.50; 2.75; 3.50; 4.00 | — |
| PRIMARY Part 3: Plasma Concentration of Dolutegravir at the End of the Dosing Interval τ (Cτ) |
1980; 2660; 1850; 2000 | — |
| PRIMARY Part 3: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) for Dolutegravir |
74790; 89290; 69850; 73210 | — |
| PRIMARY Part 3: Apparent Total Clearance (CL/F) of Dolutegravir |
0.669; 0.560; 0.716; 0.683 | — |
| SECONDARY Part 1: Maximum Plasma Concentration (Cmax) of S-648414 |
151; 498; 1620; 1430; 3820; 9260 | — |
| SECONDARY Part 1: Time to Maximum Plasma Concentration (Tmax) of S-648414 |
1.00; 1.00; 1.25; 3.00; 1.50; 1.50 | — |
| SECONDARY Part 1: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) of S-648414 |
3431; 10610; 36370; 34910; 89330; 215300 | — |
| SECONDARY Part 1: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of S-648414 |
3620; 11040; 38300; 36940; 95510; 226600 | — |
| SECONDARY Part 1: Terminal Elimination Half-life (t1/2,z) of S-648414 |
23.0; 20.7; 22.2; 22.8; 24.1; 22.2 | — |
| SECONDARY Part 1: Terminal Elimination Rate Constant (λz) of S-648414 |
0.0301; 0.0336; 0.0313; 0.0305; 0.0288; 0.0312 | — |
| SECONDARY Part 1: Mean Residence Time (MRT) of S-648414 |
32.5; 29.2; 31.5; 33.8; 34.2; 32.6 | — |
| SECONDARY Part 1: Apparent Total Clearance (CL/F) of S-648414 |
2.76; 2.72; 2.61; 2.71; 2.62; 2.21 | — |
| SECONDARY Part 1: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 |
91.7; 81.0; 83.5; 88.9; 91.0; 70.8 | — |
| SECONDARY Part 1: Fraction of S-648414 Dose Excreted in Urine From 0 to 96 Hours Postdose (Feu0-96) |
30.3; 25.5; 25.3; 25.1; 28.7; 31.5 | — |
| SECONDARY Part 1: Renal Clearance (CLR) of S-648414 |
0.884; 0.721; 0.695; 0.720; 0.804; 0.732 | — |
| SECONDARY Part 2: Maximum Plasma Concentration (Cmax) of S-648414 Following Single and Multiple-dose Administration |
411; 623; 719; 1320 | — |
| SECONDARY Part 2: Time to Maximum Plasma Concentration (Tmax) of S-648414 Following Single and Multiple-dose Administration |
3.02; 4.50; 2.03; 1.25 | — |
| SECONDARY Part 2: Area Under the Concentration-time Curve Over the Dosing Interval τ (AUC0-τ) of S-648414 Following Single and Multiple-dose Administration |
5519; 8983; 10540; 18400 | — |
| SECONDARY Part 2: Terminal Elimination Half-life (t1/2,z) of S-648414 Following Multiple-dose Administration |
21.6; 23.7 | — |
| SECONDARY Part 2: Terminal Elimination Rate Constant (λz) of S-648414 Following Multiple-dose Administration |
0.0321; 0.0292 | — |
| SECONDARY Part 2: Apparent Total Clearance (CL/F) of S-648414 Following Multiple-dose Administration |
2.85; 2.72 | — |
| SECONDARY Part 2: Apparent Volume of Distribution in the Terminal Elimination Phase (Vz/F) of S-648414 Following Multiple-dose Administration |
88.7; 93.0 | — |
| SECONDARY Part 2: Fraction of S-648414 Dose Excreted in Urine Over the Dosing Interval (Feu0- τ) Following Multiple-dose Administration |
33.3; 35.0 | — |
| SECONDARY Part 2: Renal Clearance (CLR) of S-648414 Following Multiple-dose Administration |
0.948; 0.952 | — |
| SECONDARY Part 2: Maximum Plasma Concentration (Cmax) of Midazolam |
18.0; 16.8; 19.5; 19.3 | — |
| SECONDARY Part 2: Time to Maximum Plasma Concentration of Midazolam |
0.76; 1.00; 0.50; 0.50 | — |
| SECONDARY Part 2: Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Concentration After Dosing (AUC0-last) for Midazolam |
70.17; 59.83; 73.28; 64.53 | — |
| SECONDARY Part 2: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Midazolam |
72.81; 61.68; 76.03; 67.02 | — |
| SECONDARY Part 2: Terminal Elimination Half-life for Midazolam |
5.07; 4.64; 4.41; 4.54 | — |
| SECONDARY Part 2: Terminal Elimination Rate Constant for Midazolam |
0.1366; 0.1494; 0.1570; 0.1528 | — |
| SECONDARY Part 2: Mean Residence Time for Midazolam |
5.30; 4.44; 4.93; 4.40 | — |
| SECONDARY Part 1: Change From Baseline in Fridericia's Corrected QT Interval (QTcF) |
-3.2; -3.2; -5.6; -4.8; -4.1; -5.6 | — |
| SECONDARY Parts 1: Change From Baseline in Heart Rate (HR) |
0.9; -0.2; -1.4; -1.1; -0.1; -0.7 | — |
| SECONDARY Part 1: Change From Baseline in PR Interval |
0.4; 1.0; 2.2; -0.1; 1.3; -3.9 | — |
| SECONDARY Part 1: Change From Baseline in QRS Interval |
-0.3; 0.0; -0.4; 0.2; -0.1; 0.1 | — |
| SECONDARY Part 1: Placebo-corrected Change From Baseline in Fridericia's Corrected QT Interval |
0.0; -2.4; -1.6; -0.9; -2.4; 5.2 | — |
| SECONDARY Part 1: Placebo-corrected Change From Baseline in Heart Rate |
-1.1; -2.3; -2.0; -1.0; -1.6; -2.5 | — |
| SECONDARY Part 1: Placebo-corrected Change From Baseline in PR Interval |
0.6; 1.8; -0.5; 0.9; -4.3; -0.4 | — |
| SECONDARY Part 1: Placebo-corrected Change From Baseline in QRS Duration |
0.2; -0.1; 0.5; 0.2; 0.4; 0.2 | — |
| SECONDARY Part 1: Number of Participants With Recorded Outlier Values for QTcF, HR, PR, and QRS |
0; 0; 0; 0; 0; 0 | — |
| SECONDARY Part 1: Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence |
0; 1; 0; 0; 0; 0 | — |
Eligibility Criteria
Inclusion Criteria
- Male or female adults ≥ 18 years in USA or ≥ 20 years in Japan to ≤ 55 years of age, at the time of signing the informed consent form (ICF).
a) Specific to Japan sites: enrollment in Part 3 (Group I and J) will consist of only White or Black or African American race.
- Capable of giving signed informed consent
- Body mass index (BMI) ≥ 18.5 to 3 glasses of alcoholic beverages per day (1 glass is approximately equivalent to: beer [284 mL/10 ounces (oz.)], wine [125 mL/4 oz.] or distilled spirits [25 mL/1 oz.]).
- A positive drug or alcohol screen at the Screening visit or upon admission to the CRU.
- Used tobacco- or nicotine-containing products (including cigarette, pipe, cigar, chewing, nicotine patch, nicotine gum, or Vaping product) within 6 months prior to admission to the CRU or refuses to refrain from using tobacco- or nicotine-containing products throughout the study (including Follow-up period).
- Consumed grapefruit, grapefruit juice, Seville orange juice, orange juice, apple juice, vegetables from the mustard green family (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard greens), or charbroiled meats within 7 days prior to admission to the CRU or refuses to refrain from consuming such products throughout the study (including Follow-up period).
- A corrected QT (QTc) interval of > 450 msec for males and > 470 msec for females (Fridericia's method) at the Screening visit or upon admission to the CRU.
- Systolic blood pressure is outside the range of 90 to 140 mm Hg, diastolic blood pressure is outside the range of 50 to 90 mm Hg, or pulse rate is outside the range of 40 to 100 beats per minute (bpm) or considered ineligible by the investigator or subinvestigator at the Screening visit or upon admission to the CRU.
- Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) values are greater than the upper limit of normal (ULN), or estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m² at Screening or upon admission to the CRU.
- A positive serological test for untreated syphilis, positive hepatitis B surface antigen, positive hepatitis C virus antibody, or positive human immunodeficiency virus (HIV) antigen/antibody result at the Screening visit.
- Participated in any other investigational trials or has been exposed to other investigational drugs within 28 days or 5 half-lives of the previously administered investigational drug (date derived from last study procedure [blood collection or dosing] of previous trial), whichever is longer, prior to admission to the CRU.
- Previously received S-648414.
- Poor venous access.
- Donated blood or had significant blood loss within 56 days of study admission to the CRU or donated plasma within 7 days prior to until admission to the CRU.
- Considered inappropriate for participation in the study for any reason by the investigator or subinvestigator.
Data sourced from ClinicalTrials.gov (NCT04147715). 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.