OATP1B-mediated drug-drug interaction study with cyclosporin A

JRCT ID: jRCTs031200012

Registered date:13/04/2020

Basic Information

• Recruitment status: Complete
• Health condition(s) or Problem(s) studied: None
• Date of first enrollment: 03/06/2020
• Target sample size: 10
• Study type: Interventional

Intervention(s)

Period I: On the day before study drug administration, placebo (excipient: lactose) administration is used to obtain endogenous substrate baseline data. On the day of dosing, pitavastatin, rosuvastatin, and valsartan (3 drugs in total) are orally administered at the doses shown below.
Cyclosporin A dosages are 20, and 75 mg, and subjects are divided into one of the following two administration orders.
Order of administration 1: Phase II 20mg Phase III 75mg (administration interval 1 hour) Phase IV 75mg (administration interval 3 hours)
Order of administration 2: Phase II 20mg Phase III 75mg (dose interval 3 hours) Phase IV 75mg (dose interval 1 hour)
Phase II: Phase I drug + cyclosporine A 20 mg orally with an interval of 1 hour.
Phase III, Phase IV: Oral administration of Phase I drug + cyclosporin A 75 mg at 1-hour or 3-hour intervals.

Drug dosage
Pitavastatin 0.2 mg
Rosuvastatin 1 mg
Valsartan 2 mg
Cyclosporin A 20 mg, 75 mg

Outcome(s)

Primary Outcome

Of endogenous substrate when combined with probe cocktail and cyclosporin A Kinetic parameters
Measurement target: plasma / serum coproporphyrin I, total and direct bilirubin, bile acids (sulfate conjugates and glucuronide conjugates), 7a-hydroxy-4-cholesten-3-one, OATP1B and other transporters Endogenous substrates that may be other candidates for metabolic enzymes. For some endogenous substrates, urinary excretion may be measured.
Pitavastatin, rosuvastatin, valsartan, cyclosporin A
Evaluation of pharmacokinetics
Measurement target: unchanged drug concentration in plasma
Analysis using PBPK model
Least sum of squares and AIC of calculated results and measured values using PBPK model

• Secondary Outcome: Pitavastatin, rosuvastatin, valsartan, cyclosporin A, genotypes of genes related to pharmacokinetics of endogenous substrates (OATP1B1, BCRP and drug transporters and drug metabolizing enzymes related to pharmacokinetics (ADME))

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: <= 40age old
• Gender: Male

Include criteria

a) Healthy Japanese men at >=20 but <40 years of age when the consent was obtained.
b) Persons who were judged appropriate as subjects by the investigator (sub-investigator) based on medical history and physical exam and laboratory tests at screening.
c) Persons whose body mass index (BMI) is >=18.5 but <25.0 at screening.
d) Subjects who can understand and comply with the protocol and from whom the written consent based on his or her own free will can be obtained.

Exclude criteria

a) Persons with a history of hypersensitivity to the probe drugs, and cyclosporin A
b) Persons with lactose intolerance
c) Persons with hypotension (systolic blood pressure: <90 mmHg) or hypertension (systolic blood pressure: >=160 mmHg)
d) Persons who donated or lost 200 mL (1 unit) of blood within 4 weeks before administration of study drugs or 400 mL (2 units) of blood within 3 months before administration of study drugs.
e) Persons with a medical history/complication of severe nerve disease, cerebrovascular disease, liver disease, kidney disease, endocrine disease, cardiovascular disease, gastrointestinal disease (including digestive system disease which is considered to affect the absorption of study drugs), respiratory disease, metabolic disease, and anemia.
f) Persons diagnosed as Rotor syndrome or Gilbert syndrome
g) Persons who have been confirmed of a clinically severe abnormality based on medical examination or physical examination by the investigator or subinvestigator.
h) Persons with a clinically severe disease within 30 days before administration of study drugs.
i) Persons who took drugs, health food including St. Johns wort, food 14 days prior to dosing and beverages including grapefruit, orange and apple (including food containing them), and nutritional supplements 7 days prior to dosing and cannot comply with prohibition of taking them during the study.
j) Persons who are smoking or taking nicotine within 30 days before administration of study drugs and who cannot comply with smoking cessation during the study period.
k) Persons who took alcohol/caffeine-containing food on the day before hospitalization in each study period and cannot comply with prohibition of taking them until the day of discharge in each study period.
l) Persons who tested positive in an alcohol breathe test/urine drug test at screening.
m) Persons who cannot discontinue the use of drugs other than study drugs from 2 weeks before administration of study drugs until the study completion.
n) Persons who are positive to hepatitis B surface (HBs) antigens, hepatitis C (HCV) antibodies, or human immunodeficiency virus (HIV) antigens/antibodies.
o) Other persons who were judged inappropriate by the investigator or subinvestigator.

Related Information

• Primary Sponsor: Furihata Kenichi
• Source(s) of Monetary Support: RESEARCH COLLABORATION CONSORTIUM