A Phase 1 Study to Demonstrate the Relative Bioavailability of Fixed Dose Combinations of Ambrisentan and Tadalafil in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 112
- 试验地点
- 1
- 主要终点
- AUC From Time of Dose to Last Measurable Concentration (AUC [0-t]), in FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 1
研究概览
简要总结
This study is designed to understand the relative bioavailability (proportion of the administered dose that is absorbed into the bloodstream) of several fixed dose combinations (FDCs) tablets of ambrisentan and tadalafil for further development and to provide pharmacokinetic (PK - what the body does to the drug) data to enable a pivotal bioequivalence (BE - the relationship between two preparations of the same drug in the same dosage form that have a similar bioavailability) study. Depending on formulation work, the study will allow up to 8 new FDCs to be compared with the reference of ambrisentan and tadalafil monotherapies. The study will also evaluate up to 2 of the new formulations, that may be taken in to a BE study, to be tested for any effect on pharmacokinetics of the FDC in both fed and fasted state. This is a single centre, Phase 1, single dose, randomised, open label crossover study with 3 study parts; each study part will have up to a 5 way crossover in healthy subjects. Part 1 of the study will evaluate four formulations of the FDC (ambrisentan 10 milligram [mg] + tadalafil 40 mg) and the reference of the 2 monotherapy components taken concurrently (ambrisentan 10 mg and tadalafil 40 mg) in the fasted stated. If successful formulations are identified in this part of the study, then they will be re-formulated and tested in part 2. If no successful formulations are identified in part 1 of the study, then part 2 will be utilized to look at up to 4 new FDC formulations. However, if only two formulations, or less, are evaluated in part 2 then the FDC formulations may be tested both fed and fasted to assess food effect and part 3 will not be required. If successful formulations are identified in this study part, then up to 2 of these may be tested, for food effect, in Part 3 if not already assessed in this part. Therefore, part 3 is optional and utility is dependent on the results of the previous study parts.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Between 18 and 60 years of age inclusive, at the time of signing the informed consent.
- •Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, vital signs and cardiac monitoring (ECG and 24 hour Holter). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator, in consultation with Medical Monitor if required, judges and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- •Body weight >= 50 Kilogram (kg) (110 pounds [lbs]) for men and >= 45 kg (99lbs) for women and body mass index (BMI) within the range 18 - 30 kg per square metre (m^2) (inclusive)
- •Male or Female. Female with non-reproductive potential defined as, Pre-menopausal females with one of the following: Documented tubal ligation or Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or Hysterectomy or Documented Bilateral Oophorectomy, Documented Postmenopausal defined as 12 months of spontaneous amenorrhea
- •Capable of giving signed informed consent.
排除标准
- •A blood pressure <100/55 millimetre of Mercury (mm Hg).
- •Haemoglobin (Hb) below normal range: Hb <133 (gram per litre) g/L for males and Hb <114 g/L for females
- •Alanine amino transferase (ALT) and bilirubin >1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35 percentage [%]).
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- •Corrected QT (QTc) >450 milliseconds (msec). The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.
- •Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- •History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (~240 millilitre [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
- •Smoking more than 5 cigarettes per week and subjects must be able to abstain from smoking for a 24 hour period prior to dose and any time whilst in the clinical unit.
- •History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
- •Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study treatment.
- •A positive test for human immuno-deficiency virus (HIV) antibody
- •A positive pre-study drug/alcohol screen.
- •Where participation in the study would result in donation of blood or blood products in excess of 500 mL within previous 3 months
- •The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
研究组 & 干预措施
Part 1
Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC1, FDC2, FDC3 and FDC4, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDC and reference formulations contains 10 mg ambrisentan and 40 mg tadalafil. Each dosing period will be separated by 7 days wash out period.
干预措施: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose (Drug)
Part 1
Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC1, FDC2, FDC3 and FDC4, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDC and reference formulations contains 10 mg ambrisentan and 40 mg tadalafil. Each dosing period will be separated by 7 days wash out period.
干预措施: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently) (Drug)
Part 2
Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC5, FDC6, FDC7 and FDC8, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDCs and reference formulations contains 10 mg ambrisentan and 40mg Tadalafil. OR Subjects will receive single dose of two FDCs from Part 1 in fed and fasted state. Each dosing period will be separated by 7 days wash out period.
干预措施: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose (Drug)
Part 2
Enrolled subjects will receive single oral dose of 4 FDCs i.e., FDC5, FDC6, FDC7 and FDC8, and reference formulations of the 2 monotherapy components taken concurrently in the fasted state. The FDCs and reference formulations contains 10 mg ambrisentan and 40mg Tadalafil. OR Subjects will receive single dose of two FDCs from Part 1 in fed and fasted state. Each dosing period will be separated by 7 days wash out period.
干预措施: Reference (ambrisentan 10 mg + tadalafil 40 mg given concurrently) (Drug)
Part 3
Enrolled subjects will receive single oral dose of 2 FDCs from Part 2 in fed and fasted state. The FDCs contains 10 mg ambrisentan and 40 mg Tadalafil. Each dosing period will be separated by 7 days wash out period.
干预措施: FDC (ambrisentan 10 mg-tadalafil 40 mg) single dose (Drug)
结局指标
主要结局
AUC From Time of Dose to Last Measurable Concentration (AUC [0-t]), in FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 1
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples at Part 1, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours. The analysis was done under fasting condition post single dose. The PK Parameter Population was used for analysis. There is no formal hypotheses tested for Part 1 of the study.
Maximum Observed Concentration (Cmax) of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 1
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected at the indicated time points for analysis of ambrisentan and tadafil. The analysis was done under fasting condition post single dose. There is no formal hypotheses tested for Part 1 of the study. The analysis was performed on Pharmacokinetic (PK) parameter population, which included all participants who provided PK parameter data.
Area Under the Plasma Concentration Time Curve (AUC) From Time Zero to Infinite (Inf) Time, AUC (0-inf) of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 1
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples were collected at the indicated time-points. The analysis was done under fasting condition post single dose. There is no formal hypothesis tested for Part 1 of the study.
AUC (0-inf) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 20 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 20 mg) Under Fasted Conditions-3B
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis, was done under fasting conditions post single dose. PK parameter population was used for analysis.
Cmax for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-Part 3A
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fed and fasting condition post single dose. PK parameter population was used.
AUC (0-inf) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36,48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK Parameter Population was used for analysis.
AUC (0-t) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used for analysis.
AUC (0-t) for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 20 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 20 mg) Under Fasted Conditions- Part 3B
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used for analysis.
Cmax of Ambrisentan and Tadalafil in FDC (Ambrisentan 10 mg + Tadalafil 40 mg) and Montherapies (Ambrisentan 10 mg & Tadalafil 40 mg) - Part 2
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples were collected at the indicated time-points, of Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
AUC (0-t) for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-Part 3A
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fed and fasting condition post single dose. PK parameter population was used.
Cmax for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 20 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 20 mg) Under Fasted Conditions-3B
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose. PK parameter population was used.
AUC (0 - Inf) for FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 2
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 2, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis, was done under fasting condition post single dose. PK parameter Populatio was used for analysis. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
AUC (0-inf) for Ambrisentan and Tadalafil, Following Candidate FDC (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fed and Fasted Conditions-3A
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0- inf), is defined as area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity for ambrisentan and tadafil. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3A, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 48 and 72 hours post-dose. The analysis, was done under fed and fasting conditions post single dose. PK parameter population was used.
AUC (0-t) for FDC, (Ambrisentan 10 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 10 mg & Tadalafil 40 mg), Under Fasting- Part 2
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
AUC (0-t), was defined as, the AUC measured from the time of dose to the last measurable concentration. Blood samples of 2.7 mL and 2 mL, were collected for ambrisentan and tadafil respectively. The plasma samples for Part 2, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours. The analysis was done under fasting condition post single dose. PK parameter Population was used for analysis. There is no formal hypotheses tested for Part 2 of the study. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
Cmax for Ambrisentan and Tadalafil, FDCs (Ambrisentan 5 mg + Tadalafil 40 mg) Relative to Reference Monotherapies Tested (Ambrisentan 5 mg & Tadalafil 40 mg) Under Fasted Conditions-3B
时间窗: Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose
Cmax is defined as the maximum (or peak) plasma concentration that the drug achieves, after the drug has been administered. Blood samples of 2.7 mL and 2 mL were collected for ambrisentan and tadafil respectively. The plasma samples for Part 3B, were collected at the time-points pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48 and 72 hours post-dose. The analysis was done under fasting condition post single dose.
次要结局
- Change From Baseline in Vital- SBP and DBP, Part 3B(Baseline and Up to Day 3)
- Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 1(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 3B(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Plasma t1/2 for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part 2(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Plasma t1/2 for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part 3A(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Change From Baseline in Vital- Temperature, Part 2(Baseline and Up to Day 3)
- Change From Baseline in Vital- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP), Part 1(Baseline and Up to Day 3)
- Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 2(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Time Taken to Reach Maximum Concentration (Tmax) for Ambrisentan and Tadalafil in FDC and Reference Treatment - Part 3A(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Plasma t1/2 for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part 3B(Pre-dose, 0.5 hours, 1, 1.5, 2, 2.5, 4, 8, 12, 24, 36, 48, and 72 hours postdose)
- Change From Baseline in Vital Signs-Heart Rate, Part 2(Baseline and Up to Day 3)
- Change From Baseline in Vital- Temperature, Part 3A(Baseline and Up to Day 3)
- Change From Baseline in Vital Signs-Respiratory Rate, Part 3A(Baseline and Up to Day 3)
- Plasma Half Life (t1/2) for Ambrisentan and Tadalafil in FDC and Reference Treatment Under Fed and Fasted Condition- Part1(Pre-dose, 0.5, 1, 1.5, 2, 2.5, 4, 8, 12, 18, 24, 36, 48 and 72 hours post-dose)
- Change From Baseline in Vital Signs-Heart Rate, Part 1(Baseline and Up to Day 3)
- Change From Baseline in Vital Signs-Respiratory Rate, Part 2(Baseline and Up to Day 3)
- Change From Baseline in Vital Signs-Heart Rate, Part 3B(Baseline and Up to Day 3)
- Change From Baseline in Vital- Temperature, Part 1(Baseline and Up to Day 3)
- Change From Baseline in Vital- SBP and DBP, Part 2(Baseline and Up to Day 3)
- Change From Baseline in Vital- SBP and DBP, Part 3A(Baseline and Up to Day 3)
- Change From Baseline in Vital Signs-Heart Rate, Part 3A(Baseline and Up to Day 3)
- Number of Participants With Abnormal ECG Findings, -Part 3A(Up to Day 3)
- Number of Participants With Abnormal ECG Findings, -Part 3B(Up to Day 3)
- Number of Participants With Clinical Chemistry Values of PCI- Part1(Day 2)
- Change From Baseline in Vital Signs-Respiratory Rate, Part 1(Baseline and Up to Day 3)
- Change From Baseline in Vital- Temperature, Part 3B(Baseline and Up to Day 3)
- Change From Baseline in Vital Signs-Respiratory Rate, Part 3-B(Baseline and Up to Day 3)
- Number of Participants With SAEs and AEs-Part 3A(Up to 44 days)
- Number of Participants With Abnormal ECG Findings, -Part 2(Up to Day 3)
- Number of Participants With Hematology Values of PCI - Part 3A(Day 2)
- Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)-Part 1(Up to 42 days)
- Number of Participants With Abnormal Electrocardiogram (ECG) Findings, -Part 1(Up to Day 3)
- Number of Participants With Hematology Values of Potential Clinical Importance (PCI)- Part1(Up to Day 3)
- Number of Participants With Hematology Values of PCI - Part 2(Day 2)
- Number of Participants With Hematology Values of PCI - Part 3B(Day 2)
- Number of Participants With Clinical Chemistry Values of PCI- Part 2(Day 2)
- Number of Participants With Clinical Chemistry Values of PCI- Part 3A(Day 2)
- Number of Participants With Clinical Chemistry Values of PCI- Part 3B(Day 2)
- Number of Participants With Abnormal Urinalysis Results by Dipstick Method-Part 1(Up to Day 2)
- Number of Participants With Urinalysis Results by Dipstick Analysis-Part 2(Up to Day 2)
- Number of Participants With Urinalysis Results by Dipstick Analysis-Part 3A(Up to Day 2)
- Number of Participants With Urinalysis Results by Dipstick Analysis-Part 3B(Up to Day 2)
- Number of Participants With SAEs and AEs-Part 2(Up to 35 days)
- Number of Participants With SAEs and AEs-Part 3B(Up to 44 days)