A Phase 1 Study to Evaluate the Effects of Fluconazole and Atorvastatin on the Pharmacokinetics of TAK-385 in Healthy Subjects

Study Overview
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Brief Summary
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This is a nonrandomized, open-label, fixed-sequence, 2-arm study designed to assess the effect of multiple doses of fluconazole or atorvastatin on the single-dose pharmacokinetics of TAK-385 in healthy adult subjects.

Detailed Description
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The drug being tested in this study is called TAK-385. TAK-385 was being tested to assess if the way it is processed the body changes when it administered with other medications (fluconazole or atorvastatin). This study looked at lab results in people who took TAK-385. The study enrolled 40 patients. Participants were assigned to one of the two treatment groups: TAK-385 40 mg and fluconazole 400 mg on Day 6 and 200 mg on Days 7 to 14 TAK-385 40 mg and atorvastatin 80 mg on Days 6-14 Participants in the fluconazole arm were administered TAK-385 on Days 1 and 10 and fluconazole on Days 6 through 14. Participants in the atorvastatin arm were administered TAK-385 on Days 1 and 10 and atorvastatin on Days 6 through 14. This single-center trial was conducted in the United States. The overall time to participate in this study was 4 weeks. Participants made multiple visits to the clinic, including one 16-day period of confinement to the clinic, and a final visit 7 days after last dose of study drug for a follow-up assessment.

Official Title
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A Phase 1, Open-Label, Drug-Drug Interaction Study to Evaluate the Effects of Multiple Oral Doses of Fluconazole and Atorvastatin on the Pharmacokinetics of a Single Oral Dose of TAK-385 in Healthy Subjects

Conditions
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Prostate Cancer, Endometriosis

Intervention / Treatment
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* Drug: TAK-385
* Drug: Fluconazole
* Drug: Atorvastatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Each subject must meet all the following inclusion criteria to be enrolled in the study: Age 18 to 55 years, inclusive, at the time of consent. Healthy adult male or female in good health, as determined by a physician evaluation Weight ≥ 45 kg and body mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive, at screening. Nonsmoker and does not use tobacco-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, or nicotine patch or gum). Exclusion Criteria Subjects meeting any of the following exclusion criteria are not to be enrolled in the study. The subject has a history of drug abuse (defined as any illicit drug use) within 1 year before screening or is unwilling to abstain from drugs throughout the study. The subject is unwilling to agree to abstain from caffeine and alcohol-containing products from 72 hours before check-in (Day -1) to completion of the final assessment. The subject has taken any prescription medicine or herbal preparations (eg, St John's wort) or received any immunizations within 30 days before check-in (Day -1). The subject has taken any over the counter (OTC) medications or vitamin supplements within 14 days before check-in (Day -1). The subject is unwilling to agree to abstain from consumption of grapefruit or grapefruit-containing products from 72 hours before check-in (Day -1) to completion of the final assessment. The subject has current or recent (within 6 months) history of gastrointestinal disease that would be expected to influence the absorption of drugs. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody or antigen, or serological reactions for syphilis at screening. The subject has a clinically significant ECG abnormality at screening or check-in (Day -1) or a QTc interval (by Fridericia's correction) of 450 msec or greater, or the subject has a history of cardiac disease. The subject has abnormal laboratory values suggesting a clinically significant disease at screening or check-in (Day -1) . Female subjects who are lactating and breastfeeding or pregnant before the first dose of study drug. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-385 + fluconazole<br>TAK-385 40 mg, tablet, orally once on Day 1 and fluconazole 400 mg, tablet, orally on Day 6 then 200 mg, tablet, orally once daily on Days 7 to 9 followed by a single dose of TAK-385 in combination with fluconazole 200 mg on Day 10 then fluconazole 200 mg, tablet, orally once daily alone on Days 11 to 14. | Drug: TAK-385<br>* TAK-385 tablets<br>Drug: Fluconazole<br>* Fluconazole tablets<br>|
| Experimental: TAK-385 + atorvastatin<br>TAK-385 40 mg, tablet, orally once on Day 1 and atorvastatin 80 mg, tablet, orally once daily on Days 6 to 9 followed by a single dose of TAK-385 in combination with atorvastatin 80 mg on Day 10 then atorvastatin 80 mg, tablet, orally once daily alone on Days 11 to 14. | Drug: TAK-385<br>* TAK-385 tablets<br>Drug: Atorvastatin<br>* Atorvastatin tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration of TAK-385 on Day 1 | Cmax is the peak concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Day 1 (Predose and multiple time points up to 120 hours postdose) | 
| Cmax: Maximum Observed Plasma Concentration of TAK-385 on Day 10 | Cmax is the peak concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Day 10 (Predose and multiple time points up to 120 hours postdose) | 
| AUC(0-tlast): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of TAK-385 on Day 1 | Area under the plasma concentration versus time curve from zero to the time of the last quantifiable concentration. | Day 1 (Predose and multiple time points up to 120 hours postdose) | 
| AUC(0-tlast): Area Under the Plasma Concentration Curve From Time Zero to the Time of the Last Quantifiable Concentration of TAK-385 on Day 10 | Area under the plasma concentration versus time curve from zero to the time of the last quantifiable concentration. | Day 10 (Predose and multiple time points up to 120 hours postdose) | 
| AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of TAK-385 on Day 1 | Area under the plasma concentration-time curve from time 0 to infinity. | Day 1 (Predose and multiple time points up to 120 hours postdose) | 
| AUC(0-inf): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of TAK-385 on Day 10 | Area under the plasma concentration-time curve from time 0 to infinity. | Day 10 (Predose and multiple time points up to 120 hours postdose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least 1 Treatment Emergent Adverse Event (AE) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | First dose of study drug through the end of the study (22 days ± 3 days) | 
| Number of Participants With Clinical Significant Changes in Vital Signs | Vital sign measurements included oral temperature, heart rate, supine (after 3 to 5 minutes in this position) and standing (after 3 to 5 minutes in this position) measurements of diastolic and systolic blood pressure. | Baseline and First dose of study drug through the end of the study (22 days ± 3 days) | 
| Number of Participants With Clinical Significant Changes in Electrocardiogram (ECG) Findings | A 12-lead ECG was administered on Days 1,9,10,11,15. | Baseline and First dose of study drug through Day 15 | 
| Number of Participants With Clinical Significant Changes in Laboratory Tests | Blood samples were collected for analysis of clinical chemistry and hematological parameters and urine samples were obtained for urinalysis. Clinical laboratory evaluations were performed at central and /local laboratories. | Baseline and First dose of study drug through the end of the study (22 days ± 3 days) | 
| Tmax: Time to Reach the Maximum Plasma Concentration of TAK-385 | Tmax is the time to reach the maximum concentrations (Cmax), equal to time (hours) to Cmax. | Days 1 and 10 (Predose and multiple time points up to 120 hours postdose) | 
| AUC (0-120): Area Under the Plasma Concentration-Time Curve From Time 0 to 120 Hours of TAK-385 | Area under the plasma concentration versus time curve from 0 to 120 hours after study drug administration. | Days 1 and 10 (Predose and multiple time points up to 120 hours postdose) | 
| Terminal Disposition Half-life (t1/2) of TAK-385 | Terminal disposition half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. | Days 1 and 10 (Predose and multiple time points up to 120 hours postdose) | 
| Apparent Total Body Clearance (CL/F) of TAK-385 |  | Days 1 and 10 (Predose and multiple time points up to 120 hours postdose) | 
| Fraction Excreted Unchanged (Fe) of TAK-385 | Fraction of TAK-385 excreted in the urine unchanged. | Days 1 and 10 (Predose and multiple time points up to 120 hours postdose) | 
| Plasma Trough Concentrations for Fluconazole | Blood samples for fluconazole trough levels were collected predose (before dosing with fluconazole and before breakfast) on Days 8 through 12. | Days 8 to 12 Predose | 
| Plasma Trough Concentrations for Atorvastatin | Blood samples for atorvastatin trough levels were collected predose (before dosing with atorvastatin and before breakfast) on Days 8 through 12. | Days 8 to 12 Predose |