A Study to Investigate the Potential Influence of Nitisinone on the Metabolism and the Transport of Other Drugs in Healthy Volunteers

NCT03103568 | Completed Phase 1

• 2 other identifiers: Sobi.NTBC-0062016-004297-17
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

An open-label, non-randomized, 2-arm, 2-period fixed sequence phase 1 study to evaluate the potential inhibition of nitisinone on cytochrome P450 2C9, 2D6, and 2E1 and the organic anion transporters OAT1 and OAT3 in healthy volunteers

Conditions

Drug Drug Interaction

Outcome Measures

Primary Outcomes (4)

• Area under the curve (AUC) infinity for CYP2C9 (tolbutamide) substrate

  The primary outcome measure is to investigate the AUC for tolbutamide taken as a single dose with and without the presence of nitisinone.

  Blood samples will be obtained the following times in relation to tolbutamide administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose.

• AUC infinity for CYP2D6 (metoprolol) substrate

  The primary outcome measure is to investigate the AUC for metoprolol taken as a single dose with and without presence of nitisinone.

  Blood samples will be obtained the following times in relation to metoprolol administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 7, 9, 11, 15 and 23 h post-dose.

• AUC infinity for CYP2E1 (chlorzoxazone) substrate

  The primary outcome measure is to investigate the AUC for chlorzoxazone taken with and without the presence of nitisinone.

  Blood samples will be obtained the following times in relation to chlorzoxazone administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 7, 9 and 11 h post-dose.

• AUC infinity for OAT1/OAT3 (furosemide) substrate

  The primary outcome measure is to investigate the AUC for furosemide with and without the presence of nitisinone.

  Blood samples will be obtained the following times in relation to furosemide administration: predose and, 5, 10, 15, 20, 30, 45 minutes, 1, 2, 3, 4, 6, and 8 hours post-dose

Secondary Outcomes (22)

• Maximum concentration (Cmax) for CYP2C9 (tolbutamide) substrate

  Blood samples will be obtained the following times in relation to tolbutamide administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose.

• Time to maximum concentration (tmax) for CYP2C9 (tolbutamide) substrate

  Blood samples will be obtained the following times in relation to tolbutamide administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose.

• AUC last for CYP2C9 (tolbutamide) substrate

  Blood samples will be obtained the following times in relation to tolbutamide administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose.

• Residual area for CYP2C9 (tolbutamide) substrate

  Blood samples will be obtained the following times in relation to tolbutamide administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose.

• terminal half-life for CYP2C9 (tolbutamide) substrate

  Blood samples will be obtained the following times in relation to tolbutamide administration: predose and, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose.

Study Arms (2)

Arm A - CYP substrates

EXPERIMENTAL

In Arm A of the clinical study the potential effect of multiple doses of nitisinone on the blood concentration of the active substances tolbutamide, metoprolol and chlorzoxazone will be investigated. These substances are metabolized by CYP2C9, CYP2D6 and CYP2E, respectively. A cocktail of the substances tolbutamide, metoprolol and chlorzoxazone will be given as a single dose at the beginning of the study and PK will be investigated. The participants will then administer nitisinone for two weeks until therapeutic serum concentrations level is reached. Serum and urine concentrations of nitisinone will then be investigated for 24 hours, followed by giving the substances tolbutamide, metoprolol and chlorzoxazone as a single dose together with nitisinone to investigate the PK during interaction.

Drug: Nitisinone in Arm A; Drug: Tolbutamide; Drug: Metoprolol; Drug: Chlorzoxazone

Arm B - OAT substrates

EXPERIMENTAL

In Arm B of the clinical study the potential effect of multiple doses of nitisinone on the blood concentration of the active substances furosemide in the blood, which is transported by the transporter proteins OAT 1 and OAT 3, will be investigated. Furosemide will be given intravenously as a single dose at the beginning of the study and PK will be investigated. The participants will then administer nitisinone for two weeks until therapeutic dose is reached. Furosemide will then be given as a single dose together with nitisinone to investigate the PK during interaction.

Drug: Furosemide; Drug: Nitisinone in Arm B

Interventions

Nitisinone in Arm A DRUG

4 capsules of 20 mg nitisinone (80 mg) is given once daily for 17 days.

Also known as: Orfadin

Arm A - CYP substrates

Tolbutamide DRUG

A 500 mg tablet is given as single oral dose 2 weeks apart.

Arm A - CYP substrates

Metoprolol DRUG

A 50 mg tablet of metoprolol tartrate is given as single oral dose 2 weeks apart.

Arm A - CYP substrates

Chlorzoxazone DRUG

A 250 mg tablet is given as single oral dose 2 weeks apart.

Arm A - CYP substrates

Furosemide DRUG

A single intravenous dose of 20 mg administered as an i.v. infusion is given 2 weeks apart.

Arm B - OAT substrates

Nitisinone in Arm B DRUG

4 capsules of 20 mg nitisinone (80 mg) is given once daily for 16 days.

Also known as: Orfadin

Arm B - OAT substrates

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy male and female volunteers, 18 - 55 years of age inclusive, who are judged by the investigator to be healthy on the basis of a pre-study physical examination, which includes clinical chemistry, hematology and urinalysis, vital signs (pulse and blood pressure), and ECG.
• Female subject must be either:
• a. Of none childbearing potential: i. post-menopausal (defined as at least 1 year without any menstruation without an alternative medical cause) , prior to Screening, or ii. documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening).
• b. Or, if of childbearing potential, i. must have a negative urine/serum pregnancy test at Screening, and ii. must be using highly effective methods of birth control \[Acceptable forms of birth control include: 1) Placement of an intrauterine device (IUD) or intrauterine system (IUS). The devices must not release any hormones. (Note: The IUD must have a failure rate \< 1 %) 2) the subject's male partner has undergone effective surgical sterilization before the female subject entered the clinical trial and he is the sole sexual partner of the female subject during the clinical trial. 3) Observe abstinence (acceptable only if it is the subject's usual lifestyle). \] (failure rate \< 1% per year when used consistently and correctly) at least 3 months prior to Screening until 4 weeks after study termination in combination with an approved barrier method \[Approved barrier methods of contraception include: condom (without spermicidal foam/gel/film/cream/suppository or fat- or oil-containing lubricants), or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.\]. Women should be informed of the potential risks associated with becoming pregnant while enrolled.
• Male subjects must agree to use a condom when having sexual intercourse with female partners of childbearing potential during treatment and up to 4 weeks after the last dose of study treatment.
• Body weight 64 to 100 kg.
• Body mass index (BMI) 18 - 30 kg/m2
• Signed informed consent.

You may not qualify if:

• Recent history or presence of clinically significant gastrointestinal, hepatic, renal, cardiovascular, hematological, metabolic, urological, pulmonary, neurological or psychiatric disorder.
• History of hypoglycemia.
• Current keratopathy, or other clinically relevant abnormalities, found by ophthalmologic slit-lamp examination.
• History of allergy, hypersensitivity or known contraindication to any of the drugs, or their excipients, used in this study.
• History of sulfonamide allergy.
• Continuous use of any non-topical medication within 1 month, over-the-counter preparations, herbal remedies , and all other medication within 14 days or less than 5 times the half-life of that medication, whichever is the longer, prior to first intake of an IMP.
• Daily smoking \> 10 cigarettes.
• Daily consumption of more than 5 cups of coffee.
• History of drug and/or alcohol abuse.
• Positive drug screen or alcohol test.
• Positive screens for HBsAg, anti-HCV, anti-HBc Ab, HepC, HIV 1 2 antibodies.
• Pregnancy or breast feeding.
• Female subjects using hormonal contraceptives.
• Donation of more than 400 mL of blood within 90 days prior to drug administration or donation of more than 1.5 liters of blood in the 10 months prior to first intake of an IMP.
• Foreseeable inability to cooperate with given instructions or study procedures.

Sponsors & Collaborators

• Swedish Orphan Biovitrum: lead
• Parexel: collaborator

Study Sites (1)

PAREXEL EPCU Berlin

Berlin, 14050, Germany

Location

MeSH Terms

Interventions

nitisinone; Tolbutamide; Metoprolol; Chlorzoxazone; Furosemide

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Benzoxazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Sulfanilamides; Aniline Compounds

Study Officials

• Anders Bröijersén, MD, PhD

  Swedish Orphan Biovitrum

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 27, 2017
• First Posted: April 6, 2017
• Study Start: March 28, 2017
• Primary Completion: June 10, 2017
• Study Completion: July 24, 2017
• Last Updated: August 10, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)