Sublingual vs IV Atropine Bioavailability Study
Condition: Toxic Effect of Organophosphate and Carbamate Insecticides
Intervention: Atropine Sulfate Ophthalmic Solution; Atropine Sulphate Injection
Intervention description: Atropine sulfate ophthalmic solution, USP 1% is a sterile topical anti-muscarinic indicated for cyclopegia, mydriasis, and penalization of the healthy eye in the treatment of amblyopia. Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains active ingredient: atropine sulfate 10 mg equivalent to 8.3 mg of atropine. Inactive ingredients include benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910), monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be added to adjust pH (3.5 to 6.0), and water for injection, USP.; Atropine sulfate injection, USP, 8mg/20mL (0.4 mg per mL) is a sterile, nonpyrogenic, isotonic, clear solution of atropine sulfate in water for injection with sodium chloride sufficient to render the solution isotonic. Each mL contains atropine sulfate, 0.4 mg; benzyl alcohol, 9 mg; sodium chloride 9 mg; and may contain sulfuric acid for pH adjustment, pH 3.5 (3.0 to 3.8).
Intervention MeSH terms: Atropine; Ophthalmic Solutions
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This randomized, three-sequence, three-period, phase 1 study is designed to assess the
      bioavailability and pharmacokinetics (PK) of sublingually administered atropine sulfate
      ophthalmic solution 1% USP (at 0.5 mg and 1.0 mg; test) compared to atropine sulfate
      injection administered IV (1.0 mg; reference).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Healthy male and nonpregnant female volunteers between the ages of 18 and 55 years at
             time of randomization

          2. Willing and able to provide written informed consent

          3. Females who are of childbearing potential and are sexually active with a male partner
             must have used an acceptable method of birth control for at least 2 months prior to
             Screening, and must agree to continue using an acceptable method of birth control from
             Screening to Follow-up (Day 21).

             A female of childbearing potential is defined as postonset menarche and premenopausal
             female capable of becoming pregnant. This does not include females who meet any of the
             following conditions: menopausal > 2 years, tubal ligation > 1 year, bilateral
             salpingo-oophorectomy, or hysterectomy.

             Adequate contraception is defined as a contraceptive method with a failure rate of
             less than 1% per year when used consistently and correctly and when applicable, in
             accordance with the product label. Examples include oral contraceptives, injectable
             progestogen, implants of etonogestrel or levonorgestrel, estrogenic vaginal ring,
             percutaneous contraceptive patches, intrauterine device or intrauterine system, or
             male partner sterilization at least 6 months prior to the female subject's Screening
             Visit.

          4. In the judgment of the investigator, the subject is in good health, based on review of
             medical history and the results of screening evaluation (including vital signs,
             physical examination, 12-lead ECG, and routine clinical laboratory testing, performed
             no more than 14 days prior to randomization into the study)

          5. Able to comply with the dosing instructions and available to complete the study
             Schedule of Events

        Exclusion Criteria:

          1. Females who have a positive pregnancy test or who are breastfeeding

          2. Subjects with thyroid disease as evidenced by a thyroid-stimulating hormone (TSH) <
             0.9 × lower limit of normal (LLN) or > 1.2 × upper limit of normal (ULN) at screening.
             (This test will not be repeated prior to subsequent dosing.)

          3. Subjects with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or
             serum creatinine > 1.5 × ULN at screening. (These tests will not be repeated prior to
             subsequent dosing.)

          4. Have known human immunodeficiency virus (HIV), or acute or chronic hepatitis B or
             hepatitis C infection based on medical history; or test positive for any of these at
             Screening. Subjects who have been effectively treated for hepatitis C, as evidenced by
             a negative hepatitis C ribonucleic acid (RNA) confirmation test and who no longer
             require antiviral therapy, are eligible for participation. (Screening tests will not
             be repeated prior to subsequent dosing.)

          5. Subjects who took any prescription medications (with the exception of oral
             contraceptives or hormone replacement therapy) within 30 days of screening. Prior to
             each dose, the investigator will review prohibited medication use and determine
             whether the subject should be terminated from further dosing.

          6. Subjects who took any over-the-counter medication/vitamins/herbal supplements in the
             last 72 hours prior to screening. Prior to each dose, the investigator will review
             prohibited medication use and determine whether the subject should be terminated from
             further dosing.

          7. Subjects with glaucoma and/or history of ocular surgery (including Lasik), ocular
             trauma, or congenital ocular disorder

          8. Subjects with any history of heart disease including but not limited to coronary
             artery disease, arrhythmia (treated or untreated), congestive heart failure,
             pacemaker, history of vasovagal syncope, peripheral vascular disease, or claudication

          9. Subjects with clinically significant arrhythmias or abnormal conduction; abnormal
             conduction is defined as a prolonged PR or QRS, or a QTc ≥ 450 msec for males or ≥ 470
             msec for females

         10. Subjects with a history of partial organic pyloric stenosis, chronic constipation, or
             other gastrointestinal motility issue

         11. Subjects with a history of xerostomia due to an underlying disease or previous
             radiation therapy to the head and neck

         12. Males with history of symptomatic prostatic hypertrophy; males or females with a
             history of hesitancy or retention

         13. Subjects with a blood pressure > 140/90 mm Hg taken after the subject has been seated
             and resting for at least five minutes

         14. Subjects with a history or current diagnosis of myasthenia gravis

         15. Subjects with a history of drug or alcohol abuse in the last two years or evidence of
             a positive urine drug test at screening. (This screening test will not be repeated
             prior to subsequent dosing.)

         16. Subjects with a known sensitivity or prior adverse reaction to atropine

        Subjects cannot be rescreened for exclusionary laboratory test results. Potentially
        exclusionary vital sign results may be repeated once. If a subject's repeat vitals remain
        exclusionary or the investigator determines that the repeat vital signs could pose a risk
        to the subject participating in the study, then the subject will be excluded.