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This drug-drug interaction (DDI) study has been designed to investigate the effect of a moderate CYP3A inducer efavirenz on the pharmacokinetics of quizartinib and its major circulating active metabolite AC886.
In vitro, quizartinib is metabolized primarily by CYP3A. Therefore, co-administration of quizartinib with CYP3A inducers may decrease quizartinib exposure. This study will assess the effect of a moderate CYP3A inducer efavirenz on the single dose (60 mg) quizartinib pharmacokinetics in healthy participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Efavirenz 600 mg + Quizartinib 60 mg | Experimental | Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz. |
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| Quizartinib 60 mg | Active Comparator | Participants who received a single, oral dose of quizartinib 60 mg on Day 1. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Efavirenz | Drug | Single oral dose, 600-mg tablet |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Plasma Concentration (Cmax) Following Single Dose of Quizartinib With or Without Efavirenz | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. Cmax was assessed for Quizartinib and active metabolite AC886. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Time to Maximum Plasma Concentration (Tmax) Following Single Dose of Quizartinib With or Without Efavirenz | Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study. Tmax was assessed for Quizartinib and active metabolite AC886. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) Following Single Dose of Quizartinib With or Without Efavirenz | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) Following Single Dose of Quizartinib With or Without Efavirenz | Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and was calculated using non-compartmental analysis. AUCinf was assessed for Quizartinib and active metabolite AC886. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib With or Without Efavirenz | A Treatment-Emergent Adverse Events (TEAE) is defined as any event not present prior to the initiation of the drug treatment of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment. Number of any TEAE that is related and unrelated to study medication is presented. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Global Clinical Leader | Daiichi Sankyo | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Worldwide Clinical Trials | San Antonio | Texas | 78217 | United States |
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This study consisted of two treatment periods. Following a Screening Period of 21 days, eligible participants were randomized in a 1:1 ratio to 1 of 2 treatment groups. Treatment Group A received efavirenz once daily on Day 1 and continued the regimen through Day 35 and a single dose of quizartinib on Day 15. Treatment Group B received a single dose of quizartinib on Day 1.
A total of 32 participants who met all inclusion criteria and no exclusion criteria were enrolled from 19 Aug 2020 to 14 Oct 2020 at 1 clinic in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Efavirenz 600 mg + Quizartinib 60 mg | Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz. |
| FG001 | Quizartinib 60 mg | Participants who received a single, oral dose of quizartinib 60 mg on Day 1. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Efavirenz 600 mg + Quizartinib 60 mg | Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz. |
| BG001 | Quizartinib 60 mg |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Plasma Concentration (Cmax) Following Single Dose of Quizartinib With or Without Efavirenz | Maximum Plasma Concentration (Cmax) is defined as the maximum observed plasma concentration and was an observed value for the study. Cmax was assessed for Quizartinib and active metabolite AC886. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. | Posted | Mean | Standard Deviation | ng/mL | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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Adverse events were collected from the date of signing the informed consent form up to 30 days after last dose, up to 2 months.
Adverse events were defined as any untoward, unfavorable, unintended medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All-cause mortality includes all deaths that occurred during the study and within the 30 days after the last dose of the study drug.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Efavirenz 600 mg + Quizartinib 60 mg | Participants who received efavirenz 600 mg once daily (QD) for 34 days and a single, oral dose of quizartinib 60 mg on Day 15 concurrently with efavirenz. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Contact for Clinical Trial Information | Daiichi Sankyo, Inc. | 908-992-6400 | CTRinfo@dsi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 4, 2020 | Mar 7, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C098320 | efavirenz |
| C544967 | quizartinib |
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| Quizartinib |
| Drug |
Single oral dose, 60 mg (2 x 30 mg) tablets |
|
| Terminal Half-Life (t1/2) Following Single Dose of Quizartinib With or Without Efavirenz | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886. Half-life (t1/2) was assessed for Quizartinib and active metabolite AC886. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib With or Without Efavirenz | AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of AC886 of AUCinf and AUClast are reported and were calculated using non-compartmental analysis. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz | Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz | Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis. | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
| Baseline up to 30 days post last dose, up to approximately 2 months |
Participants who received a single, oral dose of quizartinib 60 mg on Day 1.
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| OG001 | Quizartinib 60 mg | Participants who received a single, oral dose of quizartinib 60 mg on Day 1. |
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| Primary | Time to Maximum Plasma Concentration (Tmax) Following Single Dose of Quizartinib With or Without Efavirenz | Time of Maximum Plasma Concentration (Tmax) is defined as time of maximum observed plasma concentration and was an observed value from the study. Tmax was assessed for Quizartinib and active metabolite AC886. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. | Posted | Median | Full Range | hours | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Primary | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) Following Single Dose of Quizartinib With or Without Efavirenz | Area Under the Plasma Concentration-Time Curve up to the Last Quantifiable Concentration Post-Dose (AUClast) is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. | Posted | Mean | Standard Deviation | ng*h/mL | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Primary | Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) Following Single Dose of Quizartinib With or Without Efavirenz | Area Under the Plasma Concentration-Time Curve up to Infinity (AUCinf) is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and was calculated using non-compartmental analysis. AUCinf was assessed for Quizartinib and active metabolite AC886. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. Data from participants where AUCinf based on extrapolation was greater than 20% was also excluded from the Efavirenz 600 mg + Quizartinib 60 mg group and Quizartinib 60 mg group. | Posted | Mean | Standard Deviation | ng*h/mL | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Primary | Terminal Half-Life (t1/2) Following Single Dose of Quizartinib With or Without Efavirenz | Terminal Elimination Half-Life (t1/2) is defined as terminal elimination half-life and was calculated using non-compartmental analysis. AUClast was assessed for Quizartinib and active metabolite AC886. Half-life (t1/2) was assessed for Quizartinib and active metabolite AC886. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. | Posted | Mean | Standard Deviation | hours | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Primary | Metabolite to Parent Ratio (MPR) Based on Area Under the Curve for Active Metabolite AC886 Following Single Dose of Quizartinib With or Without Efavirenz | AUCinf is defined as area under the plasma concentration-time curve from the time of dosing extrapolated to infinity and AUClast is defined as AUC from time 0 to the last measurable concentration, as calculated by the linear up-log down trapezoidal method. MPR is defined as a metabolite to parent ratio with metabolite as the numerator and the parent as the denominator. MPR corrected for molecular weight of AC886 of AUCinf and AUClast are reported and were calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. Data from participants where AUCinf based on extrapolation was greater than 20% was also excluded from MPR AUCinf. | Posted | Mean | Standard Deviation | ratio | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Primary | Total Apparent Clearance (CL/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz | Total Apparent Clearance (CL/F) is defined as total apparent clearance and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. | Posted | Mean | Standard Deviation | L/h | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Primary | Volume of Distribution in the Terminal Phase (Vz/F) for Quizartinib Following Single Dose of Quizartinib With or Without Efavirenz | Volume of Distribution in the Terminal Phase (Vz/F) is defined as volume of distribution in the terminal phase and was calculated using non-compartmental analysis. | Pharmacokinetic parameter was assessed using the Pharmacokinetic Analysis Set except for 1 participant from the Efavirenz 600 mg + Quizartinib 60 mg group due to insufficient data. | Posted | Mean | Standard Deviation | L | Predose, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, 216, 288, 360, 432, and 504 hours post-quizartinib dose |
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| Secondary | Number of Participants With Treatment-emergent Adverse Events Following Single Dose of Quizartinib With or Without Efavirenz | A Treatment-Emergent Adverse Events (TEAE) is defined as any event not present prior to the initiation of the drug treatment of the drug treatment or any event already present that worsens in either intensity or frequency following exposure to the drug treatment. Number of any TEAE that is related and unrelated to study medication is presented. | TEAEs were assessed using the Safety Analysis Set. | Posted | Count of Participants | Participants | Baseline up to 30 days post last dose, up to approximately 2 months |
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| 0 |
| 16 |
| 0 |
| 16 |
| 13 |
| 16 |
| EG001 | Quizartinib 60 mg | Participants who received a single, oral dose of quizartinib 60 mg on Day 1. | 0 | 16 | 0 | 16 | 5 | 16 |
| Dizziness | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
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| Disturbance in attention | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
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| Dizziness postural | Nervous system disorders | MedDRA 23.0 | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Abnormal dreams | Psychiatric disorders | MedDRA 23.0 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 23.0 | Systematic Assessment |
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| Nightmare | Psychiatric disorders | MedDRA 23.0 | Systematic Assessment |
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| Restlessness | Psychiatric disorders | MedDRA 23.0 | Systematic Assessment |
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| Chest discomfort | General disorders | MedDRA 23.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 23.0 | Systematic Assessment |
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| Vessel puncture site pain | General disorders | MedDRA 23.0 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
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| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
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| Rhabdomyolysis | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
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| Skin irritation | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
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| Blepharospasm | Eye disorders | MedDRA 23.0 | Systematic Assessment |
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| Conjunctivitis allergic | Eye disorders | MedDRA 23.0 | Systematic Assessment |
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| Eye pruritus | Eye disorders | MedDRA 23.0 | Systematic Assessment |
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| Eyelid irritation | Eye disorders | MedDRA 23.0 | Systematic Assessment |
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| Cellulitis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
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| Syphilis | Infections and infestations | MedDRA 23.0 | Systematic Assessment |
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| Arthropod bite | Injury, poisoning and procedural complications | MedDRA 23.0 | Systematic Assessment |
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| Neutropenia | Blood and lymphatic system disorders | MedDRA 23.0 | Systematic Assessment |
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| Palpitations | Cardiac disorders | MedDRA 23.0 | Systematic Assessment |
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| Throat tightness | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Statistical comparison was analyzed for AC886. | Ratio (%) of Geometric LS Mean | 3.67 | 2-Sided | 90 | 2.47 | 5.45 | For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator. | Other | Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented. |
| AC886 |
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| Statistical comparison was analyzed for AC886. | Ratio (%) of Geometric LS Mean | 3.88 | 2-Sided | 90 | 2.62 | 5.76 | For the comparison, the Efavirenz + Quizartinib treatment group represents the numerator and Quizartinib only treatment group represents the denominator. | Other | Least squares (LS) means were calculated from an analysis of variance (ANOVA) model on log-transformed scale. The LS means for each treatment were back transformed from the log scale to provide estimates of the geometric means (GMS). The ratio (%) of GMS was calculated and 90% Confidence Intervals (CIs) for the ratio (%) of GMS were presented. |
| MPR AUCinf |
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