A Study Of Oral Palbociclib (PD-0332991), A CDK4/6 Inhibitor, As Single Agent In Japanese Patients With Advanced Solid Tumors Or In Combination With Letrozole For The First-Line Treatment Of Postmenopausal Japanese Patients With ER (+) HER2 (-) Advanced Breast Cancer

DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 as any of the events occurring during 28 days of Cycle 1,attributed to study drug:grade 4 neutropenia(for a duration of greater than \[\>\]7 days); febrile neutropenia (grade greater than or equal to \[\>=\]3 neutropenia,body temperature \>=38.5 degree Celsius);grade \>=3 thrombocytopenia with bleeding episode;grade 4 thrombocytopenia;grade \>=3 non-hematologic toxicity except grade 3 or more nausea, vomiting,electrolyte abnormality(if controllable by therapy);grade 3 QTc prolongation(\>500 millisecond \[msec\])persist after correction of reversible cause such as electrolyte abnormalities or hypoxia. Lack of hematologic recovery (platelets less than \[\<\]50,000/microliter \[mcL\],absolute neutrophil count \<1,000/mcL,hemoglobin \<8.0 gram/deciliter \[g/dL\]) or prolonged non hematologic toxicities that delays initiation of next dose by \>7 days;receipt of \<75 percent of planned dose in first cycle due to toxicity.

Time frame: Lead-in period (Day -7) up to Day 28 (Cycle 1)

Population: DLT analysis set included all participants whom DLTs were evaluable in Part 1 Phase 1.

AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in National Cancer Institute (NCI) CTCAE grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

Time frame: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.

Time frame: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.1-year PFS was defined as the percentage of participants without PFS events (PD or death due to any cause) at 12 months based on the Kaplan-Meier estimate. Percentage of participants with 1-year PFS with 90% confidence interval (CI) were reported.

Time frame: From initiation of treatment up to 12 months

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Rac is the ratio of AUCtau (after multiple doses) to AUCtau (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCinf. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCtau. AUCtau is the area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUC24 is area under the plasma concentration-time curve from 0 to time 24 hours which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUClast is area under the plasma concentration-time curve from 0 to time of last measurable concentration which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: Pharmacokinetic (PK) parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUC24 Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time 24 hours dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUCinf Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to infinity dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUClast Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time of last measurable concentration dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

AUCtau Dose Normalized to 125 mg is area under the plasma concentration-time curve over dosing interval dose normalized to 125 mg which is calculated by log-linear trapezoidal method.

Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

The functional assessment of cancer therapy (FACT) is a modular approach to assess participant's health-related quality of life. FACT-B total score was derived from the sum of these 5 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life, and a breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-B total score range was of 0 (not at all good) to 144 (very well), where higher scores indicating better quality of life.

Time frame: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)

Population: Patient reported outcome (PRO) analysis set included all enrolled participants who receive at least 1 dose of study drug with both baseline and at least 1 complete post-baseline PRO assessment. Number analyzed signifies number of participants evaluable for specified time points.

FACT is a modular approach to assess participant's health-related quality of life. FACT-G total score was derived from the sum of these 4 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-G total score range was of 0 (not at all good) to 108 (very well), where higher scores indicating better quality of life.

Time frame: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)

Population: Patient reported outcome (PRO) analysis set included all enrolled participants who receive at least 1 dose of study drug with both baseline and at least 1 complete post-baseline PRO assessment. Number analyzed signifies number of participants evaluable for specified time points.

FACT is a modular approach to assess participant's health-related quality of life. TOI total score was derived from the sum of the 3 sub-scale scores: physical well-being, functional well-being (both sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life) and breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. TOI total score range was of 0 (not at all good) to 92 (very well), where higher scores indicating better quality of life.

Time frame: Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)

Population: Patient reported outcome (PRO) analysis set included all enrolled participants who receive at least 1 dose of study drug with both baseline and at least 1 complete post-baseline PRO assessment. Number analyzed signifies number of participants evaluable for specified time points.

Cmax Dose Normalized to 125 mg is maximum plasma concentration dose normalized to 125 mg which is observed directly from the actual time-concentration data.

Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]) or PR (a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first.

Time frame: baseline up to 1673 days

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991). Data for this outcome measure was not summarized and individual participant's data was reported. Here, number of participants analyzed (N) signifies the participants evaluable for this outcome measure.

Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease, all target nodes reduced to normal size (short axis \<10 mm) or PR (a \>=30 % decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame: From initiation of treatment up to disease progression (up to 1526 days)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991). Here, Overall Number of Participants Analyzed (N) signifies the participants evaluable for this outcome measure.

Rss is the ratio of AUCtau (after multiple doses) to AUCinf (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Abnormality criteria: hemoglobin: \<0.8\*lower limit of normal \[LLN\], platelets: \<0.5\*LLN or \>1.75\*upper limit of normal \[ULN\], leukocytes: \<0.6\*LLN or \>1.5\*ULN, lymphocytes, total neutrophils: \<0.8\*LLN or \>1.2\*ULN, basophils, eosinophil,monocytes: \>1.2\*ULN); aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GT): \>0.3\*ULN, total protein, albumin: \<0.8\*LLN or \>1.2\*ULN, total bilirubin, direct bilirubin: \>1.5\*ULN; blood urea nitrogen, creatinine: \>1.3\*ULN, uric acid: \>1.2\*ULN; sodium: \<0.95\*LLN or \>1.05\*ULN, potassium, chloride, calcium, magnesium: \<0.9\*LLN or \>1.1\*ULN, phosphate: \<0.8\*LLN or \>1.2\*ULN; creatine kinase: \>2.0\*ULN, glucose fasting: \<0.6\*LLN or \>1.5\*ULN, glycosylated haemoglobin: \>1.3\*ULN;urinalysis dipstick (urine protein, urine blood \>=1); urine protein 24 hour: \>1.1\*ULN; coagulation Activated partial thromboplastin time \[APTT\], Prothrombin, prothrombin international ratio: \>1.1\*ULN.

Time frame: Part 1 Phase 1: Lead-in period (Day -7) up to 308 days; Part 2 Phase 1: Baseline (Day 1) up to 1673 days; Phase 2: Baseline (Day 1) up to 1526 days

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in NCI CTCAE version 4.0 grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

Time frame: Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.

Time frame: Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)

Population: Safety analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Overall survival was defined as the time from first dose of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. OS was estimated with Kaplan-Meier method.

Time frame: From initiation of treatment up to follow-up period (up to 1526 days)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

DC: CR, PR or stable disease (SD) for \>=24 weeks according to RECIST version (v)1.1 recorded in time period between first dose of study treatment and disease progression or death to any cause. CR: disappearance of all target lesions with exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR: \>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. SD was defined as not achieving an OR with confirmed CR or PR according to RECIST v1.1, as determined by investigators, relative to response evaluable population, but remained stable for at least 24 weeks after first dose, then best overall response for such a participant was considered as stable disease. PD was defined using RECIST v1.1 as a 20% increase in sum of longest diameter of target lesions, or a measurable increase in a non-target lesion, or appearance of new lesions.

Time frame: From initiation of treatment up to disease progression (up to 1526 days)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Objective response (OR) was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]). PR was defined as a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.

Time frame: From initiation of treatment up to disease progression (up to 30 months)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Objective response was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR was defined as a \>=30% decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.

Time frame: From initiation of treatment up to disease progression (up to 1526 days)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Tumor tissue biomarker, Ki67 was analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and was selected based on its known relevance to mechanisms involved in cell cycle regulation. Number of participants with less than or equal to and greater than 20 percent of Ki67 tumor tissue biomarker were reported.

Time frame: Baseline (Day 1)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

Tumor tissue biomarkers ER, Rb, BCL-1 and P16 were analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and were selected based on their known relevance to mechanisms involved in cell cycle regulation. Number of participants with positive ER (H-Score), Rb (H-Score), BCL-1 (H-Score) and P16 (H-Score) tumor tissue biomarkers were reported. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors.

Time frame: Baseline (Day 1)

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991).

PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Time frame: baseline up to 1673 days

Population: Full analysis set included all enrolled participants who received at least 1 dose of study drug (PD-0332991). Data for this outcome measure was not summarized and individual participant's data was reported.

t1/2 is terminal elimination half-life which is calculated by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

Time frame: Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

Time frame: 0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.

Vz/F is apparent volume of distribution estimated from terminal phase, which is calculated as CL/F/kel. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method (AUCinf). kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)

Population: PK parameter analysis set included treated participants who had at least 1 of the PK parameters of primary interest in at least 1 PK sampling period.