Pharmacokinetics (PK) and Safety of a Single Intravenous (IV) Dose of MK-3866 in Participants With Impaired Renal Function and in Healthy Controls (MK-3866-005)

Renal Impairment Clinical Trial

Official title:

A 2-Part, Open-Label Trial to Evaluate the Pharmacokinetics of MK-3866 Following the Administration of a Single IV Dose to Subjects With Mild, Moderate, and Severe Renal Impairment and End Stage Renal Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03259087
• Other study ID #: 3866-005
• Secondary ID: CA22640MK-3866-0
• Status: Completed
• Phase: Phase 1
• Start date: September 1, 2017
• Est. completion date: February 9, 2018

Study information

• Verified date: January 2019
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare plasma and urine PK parameters of MK-3866 between participants with impaired renal function and healthy control participants, to investigate the extent to which MK-3866 is removed from the plasma by hemodialysis (HD), and evaluate the safety and tolerability of MK-3866 in participants with impaired renal function.

Description:

This is an open-label, 2-part single dose study: Part 1 will include participants with mild, moderate, and severe renal impairment (as well as healthy control participants), and Part 2 will include participants with end stage renal disease (ESRD) undergoing HD. Participants in Part 1 will receive a single IV dose of MK-3866, and plasma and urine samples will be collected over pre-specified time intervals. Participants in Part 2 will receive a single IV dose of MK-3866 on two separate occasions: in Period 1 immediately following their normally-scheduled HD, and in Period 2 approximately 30 minutes prior to their normally-scheduled HD. Plasma, urine, and dialysate samples will be collected over pre-specified time intervals for Part 2.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: February 9, 2018
• Est. primary completion date: January 28, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Females of non-childbearing potential. Male participants with female partner(s) of child-bearing potential agree to use a medically acceptable method of contraception during the study and for 90 days after dosing. If partner is pregnant, males agree to use a condom; if partner is of child-bearing potential, partner must use additional birth control

• Male participants agree not to donate sperm from the first dose until 90 days after dosing

• Adequate venous access

Renal Impaired Participants

• Liver function tests (serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and serum bilirubin (total and direct) within upper limit of normal

• Panels A, B, and C: no clinically significant change in renal status at least 1 month prior to dosing and not currently or previously been on hemodialysis

• Panel E only: ESRD maintained on stable regimen of at least 3 times per week HD for at least 3 months prior to first dosing

Healthy Participants

• Age within ± 15 years of the mean age of participants with impaired renal function to which the healthy participant is matched

• Medically healthy as per medical history, physical examination, vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory safety tests

• Blood urea nitrogen, liver function tests (ALT, AST, alkaline phosphatase [ALP]), and serum bilirubin (total and direct) within upper limit of normal.

Exclusion Criteria:

• Mentally/legally incapacitated, or significant emotional problems or significant psychiatric disorder

• History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, respiratory, genitourinary or major neurological abnormalities or diseases

• History of any illness that might confound the results of the study or poses an additional risk to the participant by their participation in the study

• Clinically significant history of cancer

• Smoker and/or has used nicotine or nicotine-containing products within 3 months prior to screening

• Female participants of childbearing potential, pregnant, or lactating

• Positive results for urine or saliva drug screen and/or urine or breath alcohol screen at screening or check-in

• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)

• Consumes more than 3 glasses of alcoholic beverages within 6 months of screening

• Consumes excessive amounts of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day

• Major surgery, donated or lost 1 unit of blood within 4 weeks prior to screening, or donated plasma within 7 days prior to dosing in Part 1 or first dose in Part 2

Renal Impaired Participants

• Panels A, B, and C: Failed renal transplant or has had nephrectomy

• Panels A, B, and C: Rapidly fluctuating renal function, as determined by historical measurements; or demonstrated/suspected renal artery stenosis

• Panel E only: Has required frequent emergent HD (=3) within a year prior to first dosing

Healthy Participants

• Renal transplant or nephrectomy

Related Conditions & MeSH terms

• Renal Impairment
• Renal Insufficiency

Intervention

Drug:
• MK-3866
Single IV infusion of 200 mg administered over 30 minutes (±5 minutes) on Day 1 of each treatment period.

Locations

Country	Name	City	State
United States	Clinical Pharmacology of Miami ( Site 0001)	Hialeah	Florida
United States	Orlando Clinical Research Center ( Site 0002)	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Area Under the Plasma Concentration-time Curve of MK-3866 From Time Zero to Infinity (AUC0-inf)	Plasma samples were collected at pre-specified time points and AUC0-inf was assessed. Plasma concentrations of MK-3866 were determined using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS).	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 1: Area Under the Plasma Concentration-time Curve of MK-3866 From Time Zero to the Time of the Last Quantifiable Sample (AUC0-last)	Plasma samples were collected at pre-specified time points and AUC0-last was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 1: Area Under the Plasma Concentration-time Curve of MK-3866 From Time Zero to 24 Hours After Dosing (AUC0-24)	Plasma samples were collected at pre-specified time points and AUC0-24 was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, and 24 hours after dosing on Day 1
Primary	Part 1: Plasma Concentration of MK-3866 at the End of the Infusion (Ceoi)	Plasma samples were collected at pre-specified time points and Ceoi was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS.	At the end of the infusion (0.5 hours after infusion start) on Day 1
Primary	Part 1: Maximum Plasma Concentration of MK-3866 (Cmax)	Plasma samples were collected at pre-specified time points and Cmax was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 1: Plasma Clearance of MK-3866 (CL)	Plasma samples were collected at pre-specified time points and CL was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 1: Time to Maximum Plasma Concentration of MK-3866 (Tmax)	Plasma samples were collected at pre-specified time points and Tmax was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 1: Elimination Terminal Half-life of Plasma MK-3866 (t1/2)	Plasma samples were collected at pre-specified time points and t1/2 was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric % coefficient of variation (%CV).	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 1: Volume of Distribution of Plasma MK-3866 (Vz)	Plasma samples were collected at pre-specified time points and Vz was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
Primary	Part 2: AUC0-inf of Plasma MK-3866	Plasma samples were collected at pre-specified time points and AUC0-inf was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: AUC0-last of Plasma MK-3866	Plasma samples were collected at pre-specified time points and AUC0-last was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: AUC0-24 of Plasma MK-3866	Plasma samples were collected at pre-specified time points and AUC0-24 was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, and 24 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: Ceoi of Plasma MK-3866	Plasma samples were collected at pre-specified time points and Ceoi was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	At the end of the infusion (0.5 hours after infusion start) on Day 1 of Period 1 and Period 2
Primary	Part 2: Cmax of Plasma MK-3866	Plasma samples were collected at pre-specified time points and Cmax was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: CL of Plasma MK-3866	Plasma samples were collected at pre-specified time points and CL was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: Tmax of Plasma MK-3866	Plasma samples were collected at pre-specified time points and Tmax was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: t1/2 of Plasma MK-3866	Plasma samples were collected at pre-specified time points and t1/2 was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1. Method of dispersion used for these data is geometric %CV.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Primary	Part 2: Vz of Plasma MK-3866	Plasma samples were collected at pre-specified time points and Vz was assessed. Plasma concentrations of MK-3866 were determined using HPLC-MS/MS. For ESRD participants, hemodialysis took place predose in Period 1 and from 0.5 to 4.5 hours after dosing in Period 2. Data for healthy participants are from Part 1. Method of dispersion used for these data is geometric %CV.	Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Secondary	Part 1: Total Amount of MK-3866 Excreted in the Urine Over 24 Hours (Ae0-24)	Urine samples were collected at pre-specified intervals and Ae0-24 was assessed. Ae0-24 was obtained by adding the amounts excreted over each collection interval. Urine concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1
Secondary	Part 1: Renal Clearance (CLr) of MK-3866	Urine samples were collected at pre-specified intervals and CLr was assessed. CLr was calculated as AE(t'-t")/AUC(t'-t"), where t'-t" is the longest interval of time during which AE and AUC are both obtained. Urine concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1
Secondary	Part 1: Fraction of MK-3866 Excretion (Urine) During Each Collection Interval (Fe0-24)	Urine samples were collected at pre-specified intervals and Fe0-24 was assessed. Fe0-24 was obtained by dividing the amount of MK-3866 excreted in each collection interval by the dose. Urine concentrations of MK-3866 were determined using HPLC-MS/MS.	Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1
Secondary	Part 2: Total Amount of MK-3866 Excreted Unchanged in the Urine Over the Period of 24 Hours (Ae0-24)	Urine samples were collected at pre-specified intervals and Ae0-24 was assessed. Ae0-24 was obtained by adding the amounts excreted over each collection interval. Urine concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1 of Period 1 and Period 2
Secondary	Part 2: Renal Clearance (CLr) of MK-3866	Urine samples were collected at pre-specified intervals and CLr was assessed. CLr was calculated as AE(t'-t")/AUC(t'-t"), where t'-t" is the longest interval of time during which AE and AUC are both obtained. Urine concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1 of Period 1 and Period 2
Secondary	Part 2: Fraction of MK-3866 Excretion (Urine) During Each Collection Interval (Fe0-24)	Urine samples were collected at pre-specified intervals and Fe0-24 was assessed. Fe0-24 was obtained by dividing the amount of MK-3866 excreted in each collection interval by the dose. Urine concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1 of Period 1 and Period 2
Secondary	Part 2: Concentration of MK-3866 in Plasma Entering the Dialyzer Line (Ca)	Plasma samples entering the dialyzer line were collected at pre-specified time points and Ca was assessed. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Concentration of MK-3866 in Plasma Exiting the Dialyzer Line (Cv)	Plasma samples exiting the dialyzer line were collected at pre-specified time points and Cv was assessed. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Area Under the Concentration-time Curve of MK-3866 in Plasma Entering the Dialyzer Line During the Dialysis Period (AUCD)	Plasma samples entering the dialyzer line were collected at pre-specified time points and AUCD was assessed. AUCD values were determined from the Ca versus time profile during the HD period, using the 'linear up, log down' calculation method. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Area Under the Concentration-time Curve of MK-3866 in Plasma Entering the Dialyzer Line From 0.75 to 4.5 Hours During the Dialysis Period (AUC[0.75-4.5]Ca)	Plasma samples entering the dialyzer line were collected at pre-specified time points and AUC[0.75-4.5]Ca was assessed. AUC[0.75-4.5]Ca values were determined from the Ca versus time profile from 0.75 to 4.5 hours during the HD period, using the 'linear up, log down' calculation method. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Area Under the Concentration-time Curve of MK-3866 in Plasma Entering the Dialyzer Line From 0.75 to 4.5 Hours During the Dialysis Period (AUC[0.75-4.5]Cv)	Plasma samples entering the dialyzer line were collected at pre-specified time points and AUC[0.75-4.5]Cv was assessed. AUC[0.75-4.5]Cv values were determined from the Cv versus time profile from 0.75 to 4.5 hours during the HD period, using the 'linear up, log down' calculation method. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Dialysis Clearance of MK-3866 Based on Plasma (CLD,Plasma)	Plasma dialysis samples were collected at pre-specified time points and CLD was assessed. CLD was calculated as Q x R x (AUC[1-4.5]Ca - AUC[1-4.5]Cv) / AUC[1-4.5]Ca, where Q is the flow rate of blood through the dialyzer, and R is the ratio of blood drug concentration to plasma drug concentration. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Concentration of MK-3866 in Dialysate Samples (CD)	Plasma dialysis samples were collected at pre-specified time points and CD was assessed. Concentrations of MK-3866 were determined using HPLC-MS/MS.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Amount of MK-3866 Recovered From Each Dialysate Sample (AD)	Plasma dialysis samples were collected at pre-specified time points and AD was assessed. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Rate of Removal of MK-3866 From the Dialysate (rr)	Plasma dialysis samples were collected at pre-specified time points and rr was assessed. rr was calculated as CD x dialysate flow rate. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Cumulative Amount of MK-3866 Recovered From the Dialysate (AD,Total)	Plasma dialysis samples were collected at pre-specified time points and AD,total was assessed. AD,total was obtained by integrating the rr versus time profile over the dialysis session duration, using actual times relative to the start time of dialysis. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Part 2: Hemodialysis Clearance of MK-3866 Based on the Dialysate(CLD,Dialysate)	Plasma dialysis samples were collected at pre-specified time points and CLD,dialysate was assessed. CLD,dialysate was calculated as AD.total / AUCD. Concentrations of MK-3866 were determined using HPLC-MS/MS. Method of dispersion used for these data is geometric %CV.	0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
Secondary	Number of Participants With at Least One Adverse Event (AE)	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.	Part 1: up to Day 14 after dosing; Part 2, Period 1: up to Day 14 after dosing (including =6 day washout period); Part 2, Period 2: up to Day 14 after dosing
Secondary	Number of Participants Discontinuing the Study Due to an Adverse Event	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.	Part 1: up to Day 14 after dosing; Part 2, Period 1: up to Day 14 after dosing (including =6 day washout period); Part 2, Period 2: up to Day 14 after dosing