| Eligibility |
Inclusion criteria:
1. Understands the study procedures in the informed consent form (ICF), and be willing
and able to comply with the protocol.
2. Healthy, adult, male or female of non-childbearing potential, 18-55 years of age,
inclusive, at the screening visit.
3. Male participants must follow protocol specified contraception guidance.
4. Continuous non-smoker who has not used nicotine- and tobacco-containing products for
at least 3 months prior to the first dosing based on participant self-reporting.
5. Body mass index (BMI) = 18.0 and = 32.0 kg/m^2 at the screening visit.
6. Medically healthy with no clinically significant medical history, physical
examination, laboratory profiles, vital signs, and electrocardiograms (ECGs), as
deemed by the Investigator or designee, including the following:
- Seated blood pressure (BP) is = 90/40 millimeter of mercury (mmHg) and = 140/90
mmHg at the screening visit.
- Seated pulse rate is = 40 beats per minute (bpm) and = 99 bpm at the screening
visit.
- Part 1 only: QTcF interval is = 450 msec (males and females) and has ECG findings
considered normal or not clinically significant by the Investigator or designee
at the screening visit.
- Part 2 and 3: ECG findings considered normal or not clinically significant by the
Investigator or designee at the screening visit.
- Estimated glomerular filtration rate (eGFR) = 80 mL/min/1.73m^2 at the screening
visit.
- Liver function tests including Alanine aminotransferase (ALT), Aspartate
aminotransferase (AST), Alkaline phosphatase (ALP), and total bilirubin = upper
limit of normal (ULN) at the screening visit and at check-in.
- No clinically significant hypokalemia or hypomagnesemia at the screening visit.
Exclusion criteria:
1. Is mentally or legally incapacitated or has significant emotional problems at the time
of the screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or
disease in the opinion of the Investigator or designee.
3. History of any illness that, in the opinion of the Investigator or designee, might
confound the results of the study or poses an additional risk to the participant by
their participation in the study.
4. Has a history of any of the following:
- Active infection or febrile illness within 7 days prior to first dosing, as
assessed by the Investigator or designee.
- Symptoms suggestive of systemic or invasive infection requiring hospitalization
or treatment within 8 weeks prior to first dosing.
- Chronic or recurrent bacterial disease, including but not limited to chronic
pyelonephritis or cystitis, chronic bronchitis/pneumonitis, osteomyelitis, or
chronic skin ulcerations/infections or fungal infections (except superficial
nailbed mycosis).
- An infected joint prosthesis unless that prosthesis has been removed or replaced
greater than 60 days prior to first dosing.
- Opportunistic infections (eg, Pneumocystis jirovecii pneumonia, histoplasmosis,
coccidiomycosis).
- Cancer or lymphoproliferative disease within 5 years prior to first dosing, with
the exception of successfully treated nonmetastatic cutaneous squamous cell or
basal cell carcinoma and/or localized carcinoma in situ of the cervix is not
exclusionary.
- Known or suspected condition/illness that is consistent with compromised
immunity, including but not limited to any identified congenital or acquired
immunodeficiency; splenectomy.
- Liver or other solid organ transplant.
5. Has history or presence of alcoholism and/or drug abuse within the past 2 years prior
to first dosing, as determined by the Investigator or designee.
6. History or presence of hypersensitivity or idiosyncratic reaction to the study drugs,
including macrolide antibiotics (Part 1 only; eg, erythromycin) or anti-seizure agents
(Part 2 only; eg, phenytoin) or anti-viral drugs (Part 3 only; eg, efavirenz).
7. Part 2 and Part 3 only: Any positive responses on the Columbia-Suicide Severity Rating
Scale (C-SSRS) or has a risk of suicide according to the Investigator's or designee
judgment based on the assessment of the C-SSRS at the screening visit or check-in or
has made a suicide attempt within 12 months before the first dosing.
8. Part 2 only: History of seizure (excluding simple febrile seizure), epilepsy, severe
head injury, multiple sclerosis, or other known neurological conditions which the
Investigator or designee considers to be clinically significant.
9. Part 2 only: Participant is known to be a CYP2C9 and/or CYP2C19 poor metabolizer based
on genotyping prior to screening or is determined to be a CYP2C9 and/or CYP2C19 poor
metabolizer at the screening visit.
10. History or presence of ventricular dysfunction or risk factors for Torsades de Pointes
(eg, heart failure, cardiomyopathy, family history of Long QT Syndrome).
11. Female participant of childbearing potential.
12. Female participant with a positive pregnancy test at the screening visit or at
check-in or who is lactating.
13. Positive urine drug or alcohol results at the screening visit or check-in.
14. Unable to refrain from or anticipates the use of:
- Any drugs, including prescription and non-prescription medications, herbal
remedies, or vitamin supplements beginning 14 days prior to the first dosing.
- Any drugs known to be moderate or strong inducers of CYP3A4 enzymes and/or
P-glycoprotein (P-gp), including St. John's Wort, for 28 days prior to the first
dosing. Appropriate sources (eg, Flockhart Table™) including the product label
for erythromycin (Erythromycin Tablets USP 2018), phenytoin (DILANTIN (extended
phenytoin sodium capsules) 2022), and efavirenz (SUSTIVA (efavirenz) capsules and
tablets 2019) will be consulted to confirm lack of pharmacokinetic
(PK)/pharmacodynamic interaction with the study drugs.
15. Has been on a diet incompatible with the on study diet, in the opinion of the
Investigator or designee, within the 30 days prior to first dosing and throughout the
study.
16. Has made a donation of blood or had significant blood loss within 56 days prior to
first dosing.
17. Has made a plasma donation within 7 days prior to first dosing.
18. Participated in another clinical study within 30 days prior to first dosing. The 30
day window will be derived from the date of the last dosing in the previous study to
Day 1 of Period 1 of the current study.
19. Herpes infections:
- Participant has active herpes virus infection, including herpes zoster or herpes
simplex 1 and 2 (demonstrated on physical examination and/or medical history) at
screening or Day 1 of Period 1.
- Participant has history of serious herpetic infection that includes any episode
of disseminated disease, multidermatomal herpes simplex virus, herpes
encephalitis, ophthalmic herpes, or recurrent herpes zoster (defined as 2
episodes within 2 years).
20. Positive results for non-herpetic viral diseases at the screening visit:
- Hepatitis C virus (HCV) antibody and a positive confirmatory test result for HCV
ribonucleic acid (RNA) (nucleic acid test or polymerase chain reaction [PCR]);
- Hepatitis B surface antigen (HBsAg)+, hepatitis B virus deoxyribonucleic acid
(DNA), or HBcAb+ with positive hepatitis B virus DNA;
- Human immunodeficiency virus (HIV).
21. Positive results for tuberculosis (TB) at the screening visit or has the following:
- Has history of active TB infection, regardless of treatment status.
- Has signs or symptoms of active TB (including but not limited to chronic fever,
chronic productive cough, night sweats, or weight loss) as judged by the
investigator or designee.
- Has evidence of latent tuberculosis infection (LTBI) as evidenced by a positive
QFT result OR 2 indeterminant Quantiferon TB Gold (QFT) results and does not have
documentation of appropriate LTBI prophylaxis. Participant remains eligible if he
or she can provide documentation of prior and complete treatment for LTBI
(appropriate in duration and type per current local country guidelines).
- Has had any imaging study during or 6 months prior to screening, including x-ray,
chest computed tomography, magnetic resonance imaging, or other chest imaging
suggesting evidence of current active or a history of active TB.
22. Part 3 only: History of amphetamine and methylphenidate use; history or presence of
sleeping disorders or sleeping irregularities, or any significant cardiac abnormality
in the opinion of the Investigator or designee.
23. Part 2 and Part 3 only: History or presence of Stevens-Johnson Syndrome and/or
seizures.
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