A Study to Learn About the Study Medicine Called CTB+AVP in Healthy Adult People.

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: PF-07612577
Drug: Placebo
Drug: PF-06264006

Registration Number: NCT05554237

Lead Sponsor: Pfizer

Brief Summary: The purpose of this clinical trial is to learn about the pharmacokinetics, safety and tolerability of various single- and multiple-doses of CTB+AVP in healthy adult participants. CTB+AVP is a study medicine that is being developed to treat people with complicated urinary tract infections.

This study is seeking healthy adult male and female participants, 18-60 years of age, with a body weight \> 50 kg and a BMI of 17.5 to 30.5 kg/m2.

Participants in Part-1 of the study will receive increasing single doses of CTB and/or AVP. Participants in Part-2 will receive increasing multiple doses of CTB+AVP three times a day for 7 days. The study team will monitor how each participant is doing with the study treatments via close monitoring in an in-patient setting. Experiences of people receiving CTB+AVP will be compared to those of people who do not. This will help determine if CTB+AVP is safe and well-tolerated at each dose of the study medicine.

Participants will take part in this study for a maximum of 12 weeks for Part-1 (up to 4 weeks for screening, up to 3 weeks of taking study medicine and up to 5 weeks for safety follow-up visit) and for a maximum of 10 weeks for Part-2 (up to 4 weeks for screening, up to 1 week of taking study medicine and up to 5 weeks for safety follow-up visit). During the duration of the study, blood samples for study medicine levels, and various measures for monitoring safety such as blood samples for clinical laboratory measurements, electrocardiograms and vital sign measurements will be taken.

Detailed Description: This is a 2-part study in healthy male and female adult participants.

Part-1 is to evaluate safety, tolerability and pharmacokinetics (PK) of 3 planned and 2 optional doses in 8 participants, in a 5-period sequential single dose design.

Part-2 is to evaluate safety, tolerability and PK of 1 planned and 2 optional cohorts in 8 participants each, in a multiple dose sequential design, with 7 days of repeated every 8 hours (q8h) dosing in each cohort. In addition, 2 optional cohorts in 6 participants each of Japanese descent and Chinese descent will also receive multiple doses of CTB+AVP repeated every 8 hours (q8h) for 7 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

Inclusion Criteria

BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb)
For optional Japanese cohort only: Japanese participants who have 4 Japanese biologic grandparents who were born in Japan
For optional Chinese cohort only: Chinese participants who were born in mainland China, and both parents are of Chinese descent.

Exclusion Criteria

Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing)
Known allergy to the cephalosporin group of antibiotics
History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, or HCVAb. Hepatitis B vaccination is allowed
Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality [or other conditions or situations related to COVID-19 pandemic (eg, Contact with positive case, residence, or travel to an area with high incidence)] that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study
A positive urine drug test
Positive test result for SARS-CoV-2 infection at the time of screening or Day -1

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
PF-07612577	PF-07612577	Part-1: Dose 1, Dose 2, Dose 4, Dose 5 Part-2: Cohort 2-5
Placebo	Placebo	Part-1: Dose 1-5 Part-2: Cohort 2-4
PF-06264006	PF-06264006	Part-1: Dose 3, Dose 5

Primary Outcome Measures

Name	Time	Method
Apparent Volume of Distribution (Vz/F) of AVP, AVI and HPA : Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Apparent Clearance (CL/F) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	CL/F was calculated as Dose/AUCinf.
Time for Cmax (Tmax) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	The lower limit of quantification for AVP was 1.0 ng/mL.
Dose-Normalized Cmax (Cmax[dn]) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Dose-normalized Cmax was determined as Cmax/Dose. The lower limit of quantification for AVP was 1.0 ng/mL.
Maximum Observed Concentration (Cmax) of Cis-Ceftibuten (CTB): Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose
Time for Cmax (Tmax) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUClast was determined using the linear/log trapezoidal method.
Dose-Normalized Cmax (Cmax[dn]) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	Dose-normalized Cmax was determined as Cmax/Dose.
Dose-Normalized AUClast (AUClast[dn]) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUClast(dn) was determined as AUClast/Dose.
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUCinf was calculated as AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis.
Dose-Normalized AUCinf (AUCinf[dn]) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUCinf(dn) was calculated as AUCinf/Dose.
Terminal Half-Life (t1/2) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Apparent Volume of Distribution (Vz/F) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Apparent Clearance (CL/F) of CTB: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	CL/F was calculated as Dose/AUCinf.
Maximum Observed Concentration (Cmax) of AVP, Avibactam (AVI) and Hydroxy Pivalic Acid (HPA): Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	The lower limit of quantification for AVP was 1.0 ng/mL.
Dose-Normalized AUClast (AUClast[dn]) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUClast(dn) was determined as AUClast/Dose. The lower limit of quantification for AVP was 1.0 ng/mL.
Time for Cmax (Tmax) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	The lower limit of quantification for AVP was 1.0 ng/mL.
Dose-Normalized Cmax (Cmax[dn]) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	Dose-normalized Cmax was determined as Cmax/Dose. The lower limit of quantification for AVP was 1.0 ng/mL.
Area Under the Plasma Concentration Time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUClast was determined using the linear/log trapezoidal method. The lower limit of quantification for AVP was 1.0 ng/mL.
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUCinf was calculated as AUClast + (Clast/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis.
Dose-Normalized AUCinf (AUCinf[dn]) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	AUCinf(dn) was calculated as AUCinf/Dose.
Terminal Half-Life (t1/2) of AVP, AVI and HPA: Part 1	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,14 and 24 hours post dose	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Severe TEAEs and Related TEAEs: Part 1	From start of treatment up to 28 to 35 days post last dose of study intervention (approximately 52 days)	An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were are any untoward medical incidence in a participant during administered study intervention, whether or not these events are related to study intervention. Severe TEAEs were defined as type of AE that interrupted usual activities of daily life (ADL), or significantly affects clinical status, or may require intensive therapeutic intervention. Related TEAEs are defined as all TEAEs considered by the investigator to have at least a 'possible' relationship with the study intervention.
Number of Participants With Withdrawals Due to TEAEs: Part 1	From start of treatment up to 28 to 35 days post last dose of study intervention (approximately 52 days)	An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were are any untoward medical incidence in a participant during administered study intervention, whether or not these events are related to study intervention.
Number of Participants With Laboratory Test Abnormalities: Part 1	Up to 24 hours post-dose	The laboratory abnormalities with non-zero participants were reported and it included: monocytes or leukocytes (greater than \[\>\] 1.2\* upper limit of normal \[ULN\]), urine hemoglobin scalar (greater than or equal to \[\>=1\]) and leukocyte esterase scalar (\>=1).
Number of Participants With Clinically Significant Changes in Vital Signs Abnormalities: Part 1	Up to 24 hours post-dose	Vital signs included blood pressure and pulse rate and were measured in a supine position after approximately 5 minutes of rest for the participant. Clinically significant changes in vital signs were determined by the investigator.
Number of Participants With Electrocardiogram (ECG) Abnormalities: Part 1	Up to 24 hours post-dose	Twelve lead ECGs were collected using an ECG machine that automatically calculated heart rate and measured PR interval, QRS duration, QT interval, QT interval correct by Bazzette's formula (QTcB) and QT interval correct by Frederica formula QTcF. ECG abnormalities included: PR interval aggregate (millisecond \[msec\], maximum \[max.\] \>=300; baseline \> 200 and max. increase \>= 25 percent (%); baseline \> 200 and max. increase \>= 25%), QRS duration aggregate (msec, max \>=140; max. increase \>= 50%), QT interval aggregate (msec, value \> 500), QTCB interval aggregate and QTCF interval aggregate (msec, 450 \< max \<= 480; 480 \< max. \<= 500; max. \> 500; 30 \< max. increase \<= 60; max. increase \> 60).
Maximum Observed Concentration (Cmax) of Cis-CTB and Trans-CTB: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7
Time for Cmax (Tmax) of Cis-CTB and Trans-CTB: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7
Area Under the Plasma Concentration Time Curve From Time Zero to Time Tau, the Dosing Interval (AUCtau) of Cis-CTB and Trans-CTB: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 7	Area under the plasma concentration time profile from time zero to time tau, the dosing interval, where tau is equal to 8 hours for three times daily (TID) dosing.
Dose-Normalized Cmax (Cmax[dn]) of Cis-CTB and Trans-CTB : Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Dose-normalized Cmax was determined as Cmax/Dose.
Dose-Normalized AUCtau (AUCtau[dn]) of Cis-CTB and Trans-CTB: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Area under the plasma concentration time profile from time zero to time tau, the dosing interval, where tau is equal to 8 hours for three times daily (TID) dosing.
Terminal Half-Life (t1/2) of Cis-CTB and Trans-CTB on Day 7: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Apparent Volume of Distribution (Vz/F) of Cis-CTB and Trans-CTB : Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Apparent Clearance (CL/F) of Cis-CTB and Trans-CTB: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	CL/F was calculated as Dose/AUCinf.
Maximum Observed Concentration (Cmax) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	The lower limit of quantification for AVP was 1.0 ng/mL.
Area Under the Plasma Concentration Time Curve From Time Zero to Time Tau, the Dosing Interval (AUCtau) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 7	Area under the plasma concentration time profile from time zero to time tau, the dosing interval, where tau is equal to 8 hours for three times daily (TID) dosing.
Dose-Normalized AUCtau (AUCtau[dn]) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Area under the plasma concentration time profile from time zero to time tau, the dosing interval, where tau is equal to 8 hours for three times daily (TID) dosing.
Terminal Half-Life (t1/2) of AVP, AVI and HPA on Day 7: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on day 7	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. The lower limit of quantification for HPA was 10.0 ng/mL.
Apparent Volume of Distribution (Vz/F) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. The lower limit of quantification for AVI and HPA was 10.0 ng/mL.
Apparent Clearance (CL/F) of AVP, AVI and HPA: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	CL/F was calculated as Dose/AUCinf.
Number of Participants With TEAEs, Severe TEAEs and Related TEAEs: Part 2	From start of treatment up to 28 to 35 days post last dose of study intervention (approximately 42 days)	An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were are any untoward medical incidence in a participant during administered study intervention, whether or not these events are related to study intervention. Severe TEAEs were defined as type of AE that interrupted usual ADL, or significantly affects clinical status, or may require intensive therapeutic intervention. Related TEAEs are defined as all TEAEs considered by the investigator to have at least a 'possible' relationship with the study intervention.
Number of Participants With Withdrawals Due to TEAEs: Part 2	From start of treatment up to 28 to 35 days post last dose of study intervention (approximately 42 days)	An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were any untoward medical incidence in a participant during administered study intervention, whether or not these events are related to study intervention.
Number of Participants With Laboratory Test Abnormalities: Part 2	From start of treatment up to Day 7	The laboratory abnormalities with non-zero participants were reported and it included: neutrophils/ leukocytes (less than \[\<\] 0.8x lower limit of normal \[LLN\]), eosinophils/leukocytes (\>1.2x ULN), monocytes/leukocytes (\>1.2x ULN), bicarbonate (\>1.1x ULN), urine glucose (\>=1), ketones scalar (\>=1), urine hemoglobin scalar (\>=1), leukocyte esterase scalar (\>=1).
Number of Participants With Clinically Significant Changes in Vital Signs Abnormalities: Part 2	From start of treatment up to Day 7	Vital signs included blood pressure and pulse rate and were measured in a supine position after approximately 5 minutes of rest for the participant. Clinically significant changes in vital signs were determined by the investigator.
Number of Participants With Electrocardiogram (ECG) Abnormalities: Part 2	From start of treatment up to Day 7	Twelve lead ECGs were collected using an ECG machine that automatically calculated heart rate and measured PR interval, QRS duration, QT interval, QT interval correct by Bazzette's formula (QTcB) and QT interval correct by Frederica formula QTcF. ECG abnormalities included: PR interval aggregate (millisecond \[msec\], maximum \[max.\] \>=300; baseline \> 200 and max. increase \>= 25 percent (%); baseline \> 200 and max. increase \>= 25%), QRS duration aggregate (msec, max \>=140; max. increase \>= 50%), QT interval aggregate (msec, value \> 500), QTCB interval aggregate and QTCF interval aggregate (msec, 450 \< max \<= 480; 480 \< max. \<= 500; max. \> 500; 30 \< max. increase \<= 60; max. increase \> 60).

Secondary Outcome Measures

Name	Time	Method
Amount Excreted in Urine as Unchanged Drug Over the Dosing Interval Tau (Aetau) of Cis-CTB, Trans-CTB, AVP, AVI and HPA: Part 2	anytime between 0 to 8 hours post dose on Day 6
Percent of Dose Excreted in Urine as Unchanged Drug Over the Dosing Interval Tau (Aetau%) of Cis-CTB, Trans-CTB, AVP, AVI and HPA: Part 2	anytime between 0 to 8 hours post dose on Day 6	Aetau% was calculated as 100\*Aetau/Dose.
Renal Clearance (CLr) of Cis-CTB, Trans-CTBa, AVP, AVI and HPA: Part 2	anytime between 0 to 8 hours post dose on Day 6	Aetau% was calculated as 100\*Aetau/Dose.
Maximum Observed Concentration (Cmax) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 7	The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Time for Cmax (Tmax) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Area Under the Plasma Concentration Time Curve From Time Zero to Time Tau, the Dosing Interval (AUCtau) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 7	Area under the plasma concentration time profile from time zero to time tau, the dosing interval, where tau is equal to 8 hours for TID dosing. The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Dose-Normalized Cmax (Cmax[dn]) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Dose-normalized Cmax was determined as Cmax/Dose. The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Dose-Normalized AUCtau (AUCtau[dn]) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 7	Area under the plasma concentration time profile from time zero to time tau, the dosing interval, where tau is equal to 8 hours for TID dosing. The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Terminal Half-Life (t1/2) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	T1/2 was calculated as loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Apparent Volume of Distribution (Vz/F) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	Vz/F was calculated as Dose/(AUCinf \* kel) where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.
Apparent Clearance (CL/F) of Cis-CTB, AVP, AVI and HPA in Japanese and Chinese Cohorts: Part 2	pre-dose,0.5,1,1.5,2,2.5,3,4,6 and 8 hours post dose on Day 1 and 6; pre-dose,0.5,1,1.5,2,2.5,3,4,6,8,12,16 and 24 hours post dose on Day 7	CL/F was calculated as Dose/AUCinf. The lower limit of quantification for cis-CTB was 100.0 ng/mL, and for AVI and HPA was 10.0 ng/mL.