Drug Drug InteractionPhase 1NCT03103568
A Study to Investigate the Potential Influence of Nitisinone on the Metabolism and the Transport of Other Drugs in Healthy Volunteers
A Phase 1 study testing Nitisinone in Arm A, Tolbutamide and Metoprolol in people with Drug Drug Interaction, run by Swedish Orphan Biovitrum at 1 site in Germany.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug Drug Interaction
- What is being tested?
- Nitisinone in Arm A, Tolbutamide and Metoprolol
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 1 siteGermany
- Study dates
- 28 Mar 2017to 24 Jul 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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:
- 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).
- 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.
Who cannot join
- Any medical condition which in the opinion of the investigator makes the subject unsuitable for inclusion.
- 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.
- Poor or ultra-rapid metabolism of CYP2D6 substrates confirmed by genotyping (exclusion criteria for Arm A only).
- History of allergy, hypersensitivity or known contraindication to any of the drugs, or their excipients, used in this study.
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- 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.
- Enrollment in another concurrent clinical study, or intake of an experimental drug, within 3 months prior to inclusion in this study.
- 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.
- Inability to give written informed consent or to comply fully with the protocol.
- Vulnerable subjects, e.g., subjects kept in detention.
- Soldiers, investigator, employees of the Sponsor or CRO.
- Subject is not able to read, write and speak German.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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
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
Read the detailed description
This is an open-label, non-randomized, 2-arm, 2-period fixed-sequence drug-drug interaction study in a total of 36 (18 in each arm) male and female healthy volunteers.
The study consists of: Screening, Period 1 (substrates only), Period 2 (substrates + nitisinone) and Follow-up. In the screening period, subjects will be assessed for eligibility. Eligible subjects will be assigned to one of two treatment arms. In Arm A, the potential inhibition of nitisinone on CYP2C9, CYP2D6, and CYP2E1 will be investigated. In Arm B, the possible combined effect of nitisinone on the renal transporters OAT1 and OAT3 will be investigated.
In Period 1, the subjects will receive a single dose of a CYP cocktail of 3 substrates (Arm A) or an OAT1/OAT3 substrate (Arm B). Substrate plasma concentrations will be measured for determination of substrate PK; for up to 48 hours in Arm A and for 8 hours in Arm B.
During Period 2, the treatment and assessments will vary slightly between the 2 treatment arms. Nitisinone will be administered for 14 days, without co-administration of any substrate, in order to reach steady state and the recommended target plasma concentration, before the interaction with the substrates is studied.
In Arm A, Period 2, subjects will receive nitisinone for 16 consecutive days (14 days on nitisinone only and two days on nitisinone + substrate). Nitisinone steady state PK will be determined based on plasma and urine samples collected during one dosage interval at steady state, on the day before co-administration of the substrates. Nitisinone will then be administered together with the CYP substrates, and plasma samples for determination of their PK will be collected as in Period 1. There will be a final nitisinone dose on the day after substrate administration in order to maintain therapeutic levels throughout the 48-hour sampling period.
In Arm B, Period 2, subjects will receive nitisinone for 15 consecutive days (14 days on nitisinone only and one day on nitisinone + substrate). No nitisinone steady state PK characterization will be conducted in this arm. On the last treatment day, the subjects will receive nitisinone together with the OAT1/OAT3 substrate. This will be followed by 8 hours of blood sampling for determination of substrate PK.
- Conditions
- Drug Drug Interaction
- Being tested
- Nitisinone in Arm A, Tolbutamide, Metoprolol, Chlorzoxazone, Furosemide
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitisinone in Arm ADrug
Also called Orfadin
4 capsules of 20 mg nitisinone (80 mg) is given once daily for 17 days.
TolbutamideDrug
A 500 mg tablet is given as single oral dose 2 weeks apart.
MetoprololDrug
A 50 mg tablet of metoprolol tartrate is given as single oral dose 2 weeks apart.
ChlorzoxazoneDrug
A 250 mg tablet is given as single oral dose 2 weeks apart.
FurosemideDrug
A single intravenous dose of 20 mg administered as an i.v. infusion is given 2 weeks apart.
Nitisinone in Arm BDrug
Also called Orfadin
4 capsules of 20 mg nitisinone (80 mg) is given once daily for 16 days.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Furosemide; Drug: Nitisinone in Arm B |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
A secondary outcome measure is to investigate Cmax for tolbutamide taken as a single dose with and without the presence of nitisinone.
Measured: 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
A secondary outcome measure is to investigate tmax for tolbutamide taken as a single dose with and without the presence of nitisinone.
Measured: 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
A secondary outcome measure is to investigate AUC last for tolbutamide taken as a single dose with and without the presence of nitisinone.
Measured: 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
A secondary outcome measure is to investigate the residual area for tolbutamide taken as a single dose with and without the presence of nitisinone.
Measured: 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
A secondary outcome measure is to investigate the terminal half-life for tolbutamide taken as a single dose with and without the presence of nitisinone.
Measured: 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.
Cmax for CYP2D6 (metoprolol) substrate
A secondary outcome measure is to investigate Cmax for metoprolol taken as a single dose with and without the presence of nitisinone.
Measured: 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.
tmax for CYP2D6 (metoprolol) substrate
A secondary outcome measure is to investigate tmax for metoprolol taken as a single dose with and without the presence of nitisinone.
Measured: 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 last for CYP2D6 (metoprolol) substrate
A secondary outcome measure is to investigate AUClast for metoprolol taken as a single dose with and without the presence of nitisinone.
Measured: 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.
Residual area for CYP2D6 (metoprolol) substrate
A secondary outcome measure is to investigate the residual area for metoprolol taken as a single dose with and without the presence of nitisinone.
Measured: 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.
terminal half-life for CYP2D6 (metoprolol) substrate
A secondary outcome measure is to investigate the terminal half-life for metoprolol taken as a single dose with and without the presence of nitisinone.
Measured: 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.
Cmax for CYP2E1 (chlorzoxazone) substrate
A secondary outcome measure is to investigate Cmax for chlorzoxazone taken as a single dose with and without the presence of nitisinone.
Measured: 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.
tmax for CYP2E1 (chlorzoxazone) substrate
A secondary outcome measure is to investigate tmax for chlorzoxazone taken as a single dose with and without the presence of nitisinone.
Measured: 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 last for CYP2E1 (chlorzoxazone) substrate
A secondary outcome measure is to investigate AUC last for chlorzoxazone taken as a single dose with and without the presence of nitisinone.
Measured: 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.
Residual area for CYP2E1 (chlorzoxazone) substrate
A secondary outcome measure is to investigate the residual area for chlorzoxazone taken as a single dose with and without the presence of nitisinone.
Measured: 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.
terminal half-life for CYP2E1 (chlorzoxazone) substrate
A secondary outcome measure is to investigate the terminal half-life for chlorzoxazone taken as a single dose with and without the presence of nitisinone.
Measured: 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.
Cmax for OAT1/OAT3 (furosemide) substrate
A secondary outcome measure is to investigate Cmax for furosemide taken as a single dose with and without the presence of nitisinone.
Measured: 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
tmax for OAT1/OAT3 (furosemide) substrate
A secondary outcome measure is to investigate tmax for furosemide taken as a single dose with and without the presence of nitisinone.
Measured: 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
AUC last for OAT1/OAT3 (furosemide) substrate
A secondary outcome measure is to investigate AUC last for furosemide taken as a single dose with and without the presence of nitisinone.
Measured: 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
Residual area for OAT1/OAT3 (furosemide) substrate
A secondary outcome measure is to investigate the residual area for furosemide taken as a single dose with and without the presence of nitisinone.
Measured: 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
terminal half-life for OAT1/OAT3 (furosemide) substrate
A secondary outcome measure is to investigate the terminal half-life for furosemide taken as a single dose with and without the presence of nitisinone.
Measured: 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
24-hour plasma concentration profile for nitisinone at steady state.
A secondary outcome measure is to investigate the plasma concentration profile for nitisinone at steady state.
Measured: Blood samples will be collected during 24 hours when steady state has been reached during the following time points: pre-dose and, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16 and 24 h postdose.
24 hour renal excretion for nitisinone at steady state.
A secondary outcome measure is to investigate the urine excretion of nitisinone at steady state.
Measured: Urine will be collected for 24 hours post nitisinone dosing and during the following time intervals: 0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours and 12-24 hours.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Apr 2017
- Study start28 Mar 2017
- Primary completion10 Jun 2017
- Study completion24 Jul 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Drug Drug InteractionStudies of the same condition, open and under way.
- More trials run by Swedish Orphan BiovitrumThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- Swedish Orphan Biovitrum
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Parexel
- Responsible party
- Sponsor
- Investigators
- Anders Bröijersén, MD, PhD, Study director, Swedish Orphan Biovitrum
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03103568
- Sponsor's protocol ID
- Sobi.NTBC-006
- Other IDs
- 2016-004297-17, 2016
- Status last verified
- Aug 2017
- First submitted
- 27 Mar 2017
- Last updated
- 10 Aug 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03103568
- Acronym / sponsor ID
- Sobi.NTBC-006
- Conditions
- Drug Drug Interaction
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- Swedish Orphan BiovitrumIndustry (pharma, biotech, devices)
- Collaborators
- Parexel
- Study start
- 28 Mar 2017 (actual)
- Primary completion
- 10 Jun 2017 (actual)
- Study completion
- 24 Jul 2017 (actual)
- First posted
- 6 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
This is an open-label, non-randomized, 2-arm, 2-period fixed-sequence drug-drug interaction study in a total of 36 (18 in each arm) male and female healthy volunteers.
The study consists of: Screening, Period 1 (substrates only), Period 2 (substrates + nitisinone) and Follow-up. In the screening period, subjects will be assessed for eligibility. Eligible subjects will be assigned to one of two treatment arms. In Arm A, the potential inhibition of nitisinone on CYP2C9, CYP2D6, and CYP2E1 will be investigated. In Arm B, the possible combined effect of nitisinone on the renal transporters OAT1 and OAT3 will be investigated.
In Period 1, the subjects will receive a single dose of a CYP cocktail of 3 substrates (Arm A) or an OAT1/OAT3 substrate (Arm B). Substrate plasma concentrations will be measured for determination of substrate PK; for up to 48 hours in Arm A and for 8 hours in Arm B.
During Period 2, the treatment and assessments will vary slightly between the 2 treatment arms. Nitisinone will be administered for 14 days, without co-administration of any substrate, in order to reach steady state and the recommended target plasma concentration, before the interaction with the substrates is studied.
In Arm A, Period 2, subjects will receive nitisinone for 16 consecutive days (14 days on nitisinone only and two days on nitisinone + substrate). Nitisinone steady state PK will be determined based on plasma and urine samples collected during one dosage interval at steady state, on the day before co-administration of the substrates. Nitisinone will then be administered together with the CYP substrates, and plasma samples for determination of their PK will be collected as in Period 1. There will be a final nitisinone dose on the day after substrate administration in order to maintain therapeutic levels throughout the 48-hour sampling period.
In Arm B, Period 2, subjects will receive nitisinone for 15 consecutive days (14 days on nitisinone only and one day on nitisinone + substrate). No nitisinone steady state PK characterization will be conducted in this arm. On the last treatment day, the subjects will receive nitisinone together with the OAT1/OAT3 substrate. This will be followed by 8 hours of blood sampling for determination of substrate PK.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A - CYP substrates | Experimental | Drug: Nitisinone in Arm A, Drug: Tolbutamide, Drug: Metoprolol, Drug: ChlorzoxazoneIn 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. |
| Arm B - OAT substrates | Experimental | Drug: Furosemide, Drug: Nitisinone in Arm BIn 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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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:
- 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
Key exclusion criteria (22 listed)
- Any medical condition which in the opinion of the investigator makes the subject unsuitable for inclusion.
- 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.
- Poor or ultra-rapid metabolism of CYP2D6 substrates confirmed by genotyping (exclusion criteria for Arm A only).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitisinone in Arm AAlso: Orfadin4 capsules of 20 mg nitisinone (80 mg) is given once daily for 17 days. | Drug | Arm A - CYP substrates |
| TolbutamideA 500 mg tablet is given as single oral dose 2 weeks apart. | Drug | Arm A - CYP substrates |
| MetoprololA 50 mg tablet of metoprolol tartrate is given as single oral dose 2 weeks apart. | Drug | Arm A - CYP substrates |
| ChlorzoxazoneA 250 mg tablet is given as single oral dose 2 weeks apart. | Drug | Arm A - CYP substrates |
| FurosemideA single intravenous dose of 20 mg administered as an i.v. infusion is given 2 weeks apart. | Drug | Arm B - OAT substrates |
| Nitisinone in Arm BAlso: Orfadin4 capsules of 20 mg nitisinone (80 mg) is given once daily for 16 days. | Drug | Arm B - OAT substrates |
Primary outcome
Area under the curve (AUC) infinity for CYP2C9 (tolbutamide) substrate
Time frame: 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.
The primary outcome measure is to investigate the AUC for tolbutamide taken as a single dose with and without the presence of nitisinone.
AUC infinity for CYP2D6 (metoprolol) substrate
Time frame: 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.
The primary outcome measure is to investigate the AUC for metoprolol taken as a single dose with and without presence of nitisinone.
AUC infinity for CYP2E1 (chlorzoxazone) substrate
Time frame: 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.
The primary outcome measure is to investigate the AUC for chlorzoxazone taken with and without the presence of nitisinone.
AUC infinity for OAT1/OAT3 (furosemide) substrate
Time frame: 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
The primary outcome measure is to investigate the AUC for furosemide with and without the presence of nitisinone.
22 secondary outcomes
Maximum concentration (Cmax) for CYP2C9 (tolbutamide) substrate
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
Cmax for CYP2D6 (metoprolol) substrate
Time frame: 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.
tmax for CYP2D6 (metoprolol) substrate
Time frame: 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 last for CYP2D6 (metoprolol) substrate
Time frame: 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.
Residual area for CYP2D6 (metoprolol) substrate
Time frame: 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.
terminal half-life for CYP2D6 (metoprolol) substrate
Time frame: 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.
Cmax for CYP2E1 (chlorzoxazone) substrate
Time frame: 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.
tmax for CYP2E1 (chlorzoxazone) substrate
Time frame: 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 last for CYP2E1 (chlorzoxazone) substrate
Time frame: 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.
Residual area for CYP2E1 (chlorzoxazone) substrate
Time frame: 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.
terminal half-life for CYP2E1 (chlorzoxazone) substrate
Time frame: 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.
Cmax for OAT1/OAT3 (furosemide) substrate
Time frame: 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
tmax for OAT1/OAT3 (furosemide) substrate
Time frame: 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
AUC last for OAT1/OAT3 (furosemide) substrate
Time frame: 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
Residual area for OAT1/OAT3 (furosemide) substrate
Time frame: 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
terminal half-life for OAT1/OAT3 (furosemide) substrate
Time frame: 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
24-hour plasma concentration profile for nitisinone at steady state.
Time frame: Blood samples will be collected during 24 hours when steady state has been reached during the following time points: pre-dose and, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16 and 24 h postdose.
24 hour renal excretion for nitisinone at steady state.
Time frame: Urine will be collected for 24 hours post nitisinone dosing and during the following time intervals: 0-3 hours, 3-6 hours, 6-9 hours, 9-12 hours and 12-24 hours.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Aug 2017.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anders Bröijersén, MD, PhD study director
Swedish Orphan Biovitrum
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Nitisinone in Arm A, Tolbutamide and Metoprolol in people with Drug Drug Interaction, run by Swedish Orphan Biovitrum at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area under the curve (AUC) infinity for CYP2C9 (tolbutamide) substrate (time frame: 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.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Aug 2017.