A Study to Evaluate Drug-Drug Interaction of TAK-788 With Itraconazole and Rifampin in Healthy Adult Participants

A Phase 1 Study of Oral TAK-788 to Evaluate the Drug-Drug Interaction With Itraconazole and Rifampin in Healthy Adult Subjects

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03928327

Enrollment

Registered

2019-04-26

Start date

2019-05-02

Completion date

2019-08-16

Last updated

2020-08-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers

Keywords

Drug Therapy

Brief summary

The purpose of this study is to characterize the effect of itraconazole (Part 1) and rifampin (Part 2) on the single-dose pharmacokinetics (PK) of TAK-788 and its active metabolites (AP32960 and AP32914) in healthy adult participants.

Detailed description

The drug being tested in this study is called TAK-788 (Mobocertinib). The study assessed the drug-drug interaction of TAK-788 with either a strong cytochrome P-450 (CYP)3A inhibitor, itraconazole (Part 1) or with a strong CYP3A inducer, rifampin (Part 2) in healthy adult participants. The study enrolled 24 healthy participants. The study was designed to consist of 2 parts: Part 1- TAK-788 assessment with itraconazole Part 2- TAK-788 assessment with rifampin. Part 1 had 2 cohorts: Part 1: Participants (n = 12) received a single oral dose of 20 mg capsule of TAK-788 on Day 1 of Period 1 followed by 200 mg itraconazole oral solution once daily (QD) in Period 2 on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule were coadmistered on Day 5 of Period 2. In Part 2 participants (n = 12) received a single oral 160 mg dose of TAK-788 capsules in Period 1 of Day 1 followed by 600 mg capsules of rifampin QD in Period 2 Days 1 to Day 13 and a single dose of 160 mg TAK-788 capsules was coadministered on Day 7 of Period 1. There was a washout period of 7 days between the dose of TAK-788 on Period 1 and the first dose of rifampin in Period 2. This single-center trial was conducted in the United States. The overall time to participate in this study was approximately 120 days (including screening period). Participants were contacted by telephone 30 days after the last dose of study drug for a follow-up assessment.

Interventions

DRUGTAK-788

TAK-788 Capsules

DRUGItraconazole

Itraconazole Oral solution

DRUGRifampin

Rifampin Capsules

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

Inclusion criteria

Key Inclusion Criteria: 1. Continuous non smoker who has not used nicotine containing products for at least 3 months prior to the first dose and throughout the study based on participant self-reporting. 2. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms (ECGs), as deemed by the Investigator or designee. Has liver function tests (LFTs) including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin within the upper limit of normal at screening and at first check-in. 3. Normal baseline spirometry for forced vital capacity (FVC) and forced expiratory volume (FEV1)/FVC within 7 days prior to the first dosing based on the following normal FVC and FEV1/FVC range: a. 20 - 39 years of age: ≥ 80% and b. 40 - 55 years of age: ≥ 75% 4. Body mass index (BMI) ≥18.0 and ≤32.0 kg/m\^2, at screening. Key

Exclusion criteria

1. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing. 2. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds. 3. Presence of an acute lung infection, within 3 months of screening. 4. History or presence of any previous lung disease. 5. Part 1 only: History or presence of any of the following, deemed clinically significant by the PI or designee, and as confirmed by the Sponsor: * Ventricular dysfunction or risk factors for Torsades de Pointes (e.g., heart failure, cardiomyopathy, family history of Long QT Syndrome); * Uncorrected hypokalemia (potassium levels \<3.7) and/or hypomagnesemia (magnesium levels \<1.9); * Myasthenia gravis. 6. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV). 7. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening. 8. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. 9. QTcF interval is \>460 msec (males) or \>470 msec (females) or ECG findings are deemed abnormal with clinical significance by the Investigator or designee at screening. 10. Estimated creatinine clearance \<90 mL/min at screening 11. Unable to refrain from or anticipates the use of: * Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements within 14 days prior to the first dosing and throughout the study. Medication listed as part of acceptable birth control methods will be allowed. Thyroid hormone replacement medication may be permitted if the subject has been on the same stable dose for the immediate 3 months prior to the first dosing. Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study, only after initial dosing. * Any drugs known to be inhibitors or inducers of CYP3A enzymes and/or P-gp, including St. John's Wort, within 28 days prior to the first dosing and throughout the study. Appropriate sources (e.g., Flockhart Table™) will be consulted to confirm lack of pharmacokinetic (PK)/pharmacodynamics interaction with study drugs.

Design outcomes

Primary

Measure	Time frame	Description
Treatment B vs Treatment A (Part 1), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose	The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.
Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for Cmax: Maximum Observed Plasma Concentration of TAK-788, AP32960, and AP32914	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose	The combined molar exposure Cmax for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar Cmax which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in nanomolar.
Treatment B Vs Treatment A (Part 1), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose	The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour\*nanomolar.
Treatment D Vs Treatment C (Part 2), Combined Molar Exposure for AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration of TAK-788, AP32960, and AP32914	Day 1 pre-dose and at multiple time points (up to 168 hours) post-dose	The combined molar exposure AUC∞ for TAK-788 and its metabolites AP32960 and AP3914 value was calculated as the sum of each molar AUC∞ which was multiplied by 1000 and divided by molecular weight of each analyte, TAK-788, AP32960, and AP32914 respectively. The combined molar exposure was presented in hour\*nanomolar.
Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of TAK-788	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose	—
Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32960	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose	—
Tmax - Time to Reach the Maximum Plasma Concentration (Cmax) of AP32914	Day 1 pre-dose and at multiple time points (up to 240 hours) post-dose	—

Countries

United States

Participant flow

Recruitment details

Participants took part in the study in the United States from 02 May 2019 to 16 August 2019.

Pre-assignment details

Healthy participants were enrolled in this 2-period study to receive: TAK-788 20 mg (Treatment A) along with itraconazole 200 mg (Treatment B) and TAK-788 160 mg (Treatment C) with rifampin 600 mg (Treatment D) in sequential manner to evaluate drug-drug interaction.

Participants by arm

Arm	Count
Part 1, Treatment Sequence AB TAK-788 20 mg, capsule, at Hour 0 on Day 1 followed by an overnight fast (Treatment A). Following Treatment A, participants received itraconazole 200 mg solution, orally, once daily (QD) on Days 1 to Day 14 and a single oral dose of TAK-788 20 mg capsule was coadministered on Day 5 (Treatment B). There was a washout period of 7 days between the two treatments.	12
Part 2, Treatment Sequence CD TAK-788 160 mg, orally, at Hour 0 on Day 1 following an overnight fast (Treatment C). Following Treatment C, participants received rifampin 600 mg as capsules, orally, once daily (QD) on Days 1 to 13 and TAK-788 160 mg as capsules, orally was coadministered on Day 7 (Treatment D). There was a washout period of 7 days between the two treatments.	12
Total	24

Baseline characteristics

Characteristic	Part 1, Treatment Sequence AB	Part 2, Treatment Sequence CD	Total
Age, Continuous	37.7 years	40.3 years	39 years
Body Mass Index (BMI)	28.573 kg/m^2	28.955 kg/m^2	28.764 kg/m^2
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants	10 Participants	19 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants	2 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Height	172.8 cm	165.8 cm	169.3 cm
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	10 Participants	12 Participants	22 Participants
Region of Enrollment United States	12 Participants	12 Participants	24 Participants
Sex: Female, Male Female	4 Participants	8 Participants	12 Participants
Sex: Female, Male Male	8 Participants	4 Participants	12 Participants
Weight	85.53 Kg	79.78 Kg	82.65 Kg

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 12	0 / 12	0 / 12
other Total, other adverse events	1 / 12	4 / 12	9 / 12	10 / 12
serious Total, serious adverse events	0 / 12	0 / 12	0 / 12	0 / 12