Nicotine Pouch Pharmacokinetics Abuse Liability

Nicotine Pharmacokinetics and Subjective Effects of 9 Investigational Nicotine Pouch Products in Adult Cigarette Smokers: A Controlled, Randomized, Cross-over Study With a Balanced Incomplete Block Design.

Nicotine pharmacokinetics and subjective effects of Investigational Nicotine Pouch Products in adult cigarette smokers: A controlled, randomized, cross-over study with a balanced incomplete block design.

To characterize nicotine pharmacokinetic (PK) parameters following a single ad libitum administration of 9 Investigational nicotine pouches (NPs) relative to usual brand combustible cigarette (UBCC), Nicorette (NRT) gum, and a comparator NP product.

Inclusion Criteria:

1. Voluntary consent to participate in this study documented on the signed ICF.

2. Healthy adult males and females ≥22 and ≤65 years of age, at screening.

3. Smokers and smokers that use other tobacco products (i.e., snus, moist snuff, Electronic Nicotine Delivery Systems, NP) will be considered. Smoking history (self-reported at screening) of an average of at least 5 but no more than 30 factory-manufactured combustible cigarettes daily for at least 12 months prior to screening. Brief periods (i.e., up to 7 consecutive days) of nonsmoking during the 3 months prior to screening (e.g., due to illness or participation in a study where smoking was prohibited) will be permitted.

4. Participants must demonstrate the ability to use a 12-mg NP for 30 minutes.

5. Participants who use THC, must be willing to abstain from THC use for 7 days before Check-in and able to participate in the study without THC use.

6. Participants must be generally healthy, free of lifetime malignant tumors, and without clinically significant abnormalities as assessed by the Investigator based on the review of medical and surgical history, physical examination, vital signs, 12-lead ECG, and laboratory evaluations conducted at screening and Check-in, as applicable. A single repeat measurement/test may be performed to confirm vital signs, 12-lead ECG, and clinical laboratory tests abnormalities (i.e.,to confirm that a participant is eligible).

7. Screening and first Check-in blood pressure ≤150/90 mmHg measured after being in the supine position or in the most recumbent position possible for at least 5 minutes. Two rechecks may be performed at the Principal Investigator's discretion.

8. Positive urine cotinine (≥200 ng/mL) at screening.

9. Exhaled carbon monoxide ≥8 ppm at screening.

10. Male participants, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from first Check-in (Day -1) to the clinical site until 90 days after the last administration of study product. Adequate contraception for the male participant (and his female partner, if she is of childbearing potential) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence from heterosexual intercourse, in accordance with the lifestyle of the subject, is also acceptable.

11. Negative pregnancy test at screening and first Check-in (Day -1) for all female participants.

12. Female participants who are heterosexually active and of childbearing potential (e.g., neither surgically sterile at least 6 months prior to first Check-in nor postmenopausal with amenorrhea for at least 12 months prior to first Check-in with FSH levels consistent with postmenopausal status) must have been using one of the following forms of contraception for the time period indicated and agree to continue using it through completion of the study:

    • Hormonal (e.g., oral, vaginal ring, transdermal patch, implant, injection) consistently for at least 3 months prior to first Check-in, when used in combination with male condoms with spermicide (use of NuvaRing is at the Principal Investigator's discretion)
    • Double barrier (e.g., condom with spermicide or diaphragm with spermicide) consistently for at least 2 weeks prior to first Check-in
    • Intrauterine device or system (utilize Principal Investigator discretion regarding use of hormonal or nonhormonal devices) for at least 3 months prior to first Check-in
    • Exclusive partner who is clinically sterile (i.e., documented infertility or surgical sterilization; see below for additional information on sterility) or has been vasectomized for at least 6 months (inclusive) prior to first Check-in
    • Note: Sexual abstinence, defined as refraining from intercourse, is allowed when this is in line with the preferred and usual lifestyle of the participant. Female participants of childbearing potential who are not currently engaging in heterosexual intercourse must agree to use one of the above methods of birth control through completion of study, in the event that they have heterosexual intercourse during the course of the study.

13. Female participants who are of nonchildbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to first Check-in:

    • Hysteroscopic sterilization (including Essure or similar nonsurgical sterilization procedures)
    • Bilateral tubal ligation or bilateral salpingectomy
    • Hysterectomy
    • Bilateral oophorectomy
    • Or be postmenopausal with amenorrhea for at least 12 months prior to first Check-in and have FSH levels consistent with postmenopausal status.

14. Able to communicate effectively with the study personnel and willing to comply with the requirements of the study.

15. Willing and able to use all of the study products in-confinement and product use sessions

Exclusion Criteria:

1. Self-reported puffers (i.e., adult smokers who draw smoke from the cigarette into the mouth and throat but do not inhale).
2. Any postponement of a quit attempt to participate in the study; or any attempts to quit smoking in the 3 months prior to Check-in).
3. Poor dentition that prevents participant from using nicotine gum.
4. History or presence of any type of malignant tumor or clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, urologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, or any other condition that, in the opinion of the Investigator, would interfere with the absorption, distribution, metabolism, or excretion of nicotine or jeopardize the safety of the participant or impact the validity of the study results.
5. Current evidence or any history of congestive heart failure.
6. Any other condition or prior therapy that, in the Investigator's opinion, would make the participant unsuitable for the study, or unable or unwilling to comply with the study procedures.
7. All prescribed medication must have been stopped at least 14 days prior to (first) admission to the clinical site. An exception is made for hormonal contraceptives that may be used throughout the study.
8. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (eg, St. John's wort) must have been stopped at least 14 days prior to (first) admission to the clinical site. An exception is made for acetaminophen that is allowed up to admission to the clinical site.
9. Clinically significant abnormal vital sign, physical examination (including oral cavity and oropharynx), medical history, or clinical laboratory finding(s), in the opinion of the Investigator.
10. Positive test for HIV-1 or HIV-2; or HBsAg or HCV consistent with current infection at screening.
11. Diabetes mellitus that is not controlled by diet/exercise alone, in the opinion of the Investigator. Fasting plasma glucose >126 mg/dL (7 mmol/L) is exclusionary. One recheck may be performed for fasting plasma glucose values >126 mg/dL but <200 mg/dL.
12. An acute illness (e.g., upper respiratory infection, viral infection) requiring treatment with prescribed medicines within 2 weeks prior to Check-in.
13. History of surgery or major trauma within 12 weeks of screening, or surgery planned during the study through EOS.
14. History of alcohol abuse or drug abuse within 24 months prior to Check-in.
15. Consumption of alcohol-containing food or beverages within 48 hours prior to Check-in.
16. Positive screen for alcohol (breath or urine) or drugs of abuse (urine), regardless of the reason of use at screening or Check-in, with the exception of positive results for THC. If positive for THC at check-in (Day -1), a cannabis intoxication evaluation will be performed, and inclusion will be at the discretion of the Investigator.
17. Fever (i.e., body temperature >100.5°F) at screening or Check-in; 1 recheck may be performed at the Investigator's discretion.
18. BMI <18.0 kg/m2 or >40.0 kg/m2 at screening.
19. Estimated glomerular filtration rate <80 mL/minute using the CKD-EPI formula (Medscape) at screening.
20. Serum alanine aminotransferase ≥1.5 times the upper limit of normal and/or aspartate aminotransferase ≥2.0 times the upper limit of normal at screening; 1 recheck may be performed at the Investigator's discretion.
21. Female participants who are pregnant (positive pregnancy test at screening or Check-in), lactating, or intend to become pregnant from screening through EOS.
22. Use of prescription or OTC bronchodilator medication (e.g., inhaled or oral β-agonists) for treatment of any illness within 12 months prior to Check-in.
23. Use of antibiotics within 2 weeks prior to Check-in.
24. Use of medications known or suspected to interact with cytochrome P450 2A6 (including, but not limited to, amiodarone, amlodipine, amobarbital, buprenorphine, clofibrate, clotrimazole, desipramine, disulfiram, entacapone, fenofibrate, isoniazid, ketoconazole, letrozole, methimazole, methoxsalen, metyrapone, miconazole, modafinil, orphenadrine, pentobarbital, phenobarbital, pilocarpine, primidone, propoxyphene, quinidine, rifampicin, rifampin, secobarbital, selegiline, sulconazole, and tioconazole, tranylcypromine) within 14 days or 5 half lives of the medication, whichever is longer, prior to Check-in.
25. Has taken other investigational drugs/products or participated in any clinical study for an investigational drug, device, biologic, or for a tobacco product within 30 days or 5 half-lives (if known) of the investigational product's PK, PD, or biological activity (if known), whichever is longer, prior to first administration of study product in this study or is currently participating in another clinical study prior to Check-in.
26. Has received a vaccination within 14 days prior to Check-in.
27. Plasma donation within 7 days prior to Day 1.
28. Donation of ≥1 unit of blood or blood products (with the exception of plasma as noted), had significant blood loss >450 mL, or received whole blood or a blood product transfusion within 56 days prior to Check-in.
29. Strenuous activity (as assessed by the Investigator) within 48 hours prior to Check-in.
30. Participant or a first-degree relative (i.e., parent, sibling, child, spouse) is a current or former employee of the tobacco industry, or a named party or class representative in litigation with any tobacco company.
31. Participant or a first-degree relative (i.e., parent, sibling, child, spouse) is a current employee of the study site or service provider.
32. Unwilling or unlikely to comply with the requirements of the study