A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of KRP-A218 in Healthy Subjects

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: Placebo
Drug: KRP-A218
Drug: itraconazole

Registration Number: NCT04908800

Lead Sponsor: Kyorin Pharmaceutical Co.,Ltd

Brief Summary: This first-in-human study has three parts. In Parts A and B, the safety, tolerability, and pharmacokinetics (PK) will be evaluated following administration of single and multiple doses of KRP-A218, including food-effect. In Part C, the drug-drug interaction (DDI) with itraconazole will be evaluated.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 99

Inclusion Criteria

Male or female adults, between 20 and 55 years of age, inclusive.
Body weight ≥50 kg, with body mass index (BMI) between 18.0 and 30.0 kg/m^2, inclusive.
In good health, at Screening or Day -1 as assessed by the Investigator.
Females will not be pregnant or lactating, and females of childbearing potential will agree to use contraception and to not donate eggs (ova, oocytes). Males will agree to use contraception and to not donate sperm.
Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions.

Key

Exclusion Criteria

Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator.
Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing.
Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to dosing.
Use or intend to use any prescription medications/products within 14 days or 5 half-lives (whichever is longer) prior to dosing, unless deemed acceptable by the Investigator.
Use or intend to use slow release medications/products considered to still be active within 14 days prior to dosing, unless deemed acceptable by the Investigator.
Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant derived preparations within 7 days prior to dosing, unless deemed acceptable by the Investigator.
Use of tobacco or nicotine-containing products within 3 months prior to Day -1, or positive cotinine test at screening or Day -1.
Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 7 days prior to Day -1.
Consumption of caffeine- or xanthine-containing foods and beverages within 36 hours prior to Day -1.
Participation in strenuous exercised within 7 days prior to Day -1.
Receipt of blood products within 2 months prior to Day -1.
Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening.
Poor peripheral venous access.
Have previously completed or withdrawn from this study or have previously received the investigational medicinal product (IMP).
Subject is, in the opinion of the Investigator, unlikely to comply with the protocol or unsuitable to participate in this study for any reason.

Other protocol defined Inclusion/Exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part A (SAD) and Part B (MAD): Placebo	Placebo	Administration Route: Oral
Part C drug-drug interaction (DDI): KRP-A218 and itraconazole	KRP-A218	Administration Route: Oral
Part A single ascending dose (SAD) and Part B multiple ascending dose (MAD): KRP-A218	KRP-A218	Administration Route: Oral
Part C drug-drug interaction (DDI): KRP-A218 and itraconazole	itraconazole	Administration Route: Oral

Primary Outcome Measures

Name	Time	Method
Part A: Number of Participants With Adverse Events	Screening to follow-up (Approximately 6 weeks)	A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.
Part B: Number of Participants With Adverse Events	Screening to follow-up (Approximately 8 weeks)	A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.
Part C: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)	Days 1 to 11	The area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity) following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Part C: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)	Days 1 to 11	The area under concentration-time curve from time 0 extrapolated to last quantifiable concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Part C: Apparent Terminal Elimination Half-life (t1/2)	Days 1 to 11	The apparent terminal elimination half-life following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Part C: Apparent Total Clearance (CL/F)	Days 1 to 11	The apparent total clearance following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Part C: Maximum Observed Concentration (Cmax)	Days 1 to 11	The maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Part C: Time of the Maximum Observed Concentration (Tmax)	Days 1 to 11	The time of the maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Part C: Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Days 1 to 11	The apparent volume of distribution during the terminal phase following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole

Secondary Outcome Measures

Name	Time	Method
Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)	Day 1	Area under concentration-time curve from time 0 extrapolated to infinity following single oral dose of KRP-A218
Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)	Day 1	Area under curve from time 0 to the time of the last quantifiable concentration following single oral dose of KRP-A218
Part A: Maximum Observed Concentration (Cmax)	Day 1	Maximum observed concentration following single oral dose of KRP-A218
Part A: Time of the Maximum Observed Concentration (Tmax)	Day 1	Time of the maximum observed concentration following single oral dose of KRP-A218
Part A: Apparent Terminal Elimination Half-life (t1/2)	Day 1	Apparent terminal elimination half-life following single oral dose of KRP-A218
Part A: Apparent Total Clearance (CL/F)	Day 1	Apparent total clearance following single oral dose of KRP-A218
Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Day 1	Apparent volume of distribution during the terminal phase following single oral dose of KRP-A218
Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ)	Days 1 and 14	Assessment of the area under the concentration-time curve over a dosing interval (AUC0-τ)
Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)	Day 1	Assessment of the area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity)
Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)	Days 1 and 14	Assessment of the area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast)
Part B: Maximum Observed Concentration (Cmax)	Days 1 and 14	Assessment of the maximum observed concentration (Cmax)
Part B: Minimum Observed Concentration (Cmin)	Day 14	Assessment of the minimum observed concentration (Cmin)
Part B: Time of the Maximum Observed Concentration (Tmax)	Days 1 and 14	Assessment of the time of the maximum observed concentration (Tmax)
Part B: Apparent Terminal Elimination Half-life (t1/2)	Days 1 and 14	Assessment of the apparent terminal elimination half-life (t1/2)
Part B: Apparent Total Clearance (CL/F)	Days 1 and 14	Assessment of the apparent total clearance (CL/F)
Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Days 1 and 14	Assessment of the apparent volume of distribution during the terminal phase (Vz/F)
Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T)	Day 14	Observed accumulation ratio based on area under the concentration-time curve over a dosing interval (ARAUC0-T) in Part B
Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax)	Day 14	Observed accumulation ratio based on maximum observed concentration during the dosing interval (ARCmax) in Part B
Part C: Number of Participants With Adverse Events	Screening to follow-up (Approximately 7 weeks)	A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.