Pharmacokinetics of Lidocaine in Healthy Adults

Topical drug delivery systems in the form of patches are convenient, attractive, and easy to
use. Lidocaine is a very popular patch available on the United States market today. Accurate
determination of the rate and extent of drug release and absorption is crucial to ensure the
safety of individuals using these and other types of patches. The drug delivery rate can be
determined early in the development process by using in vitro skin flux permeation studies,
and later in humans by accurately quantifying residual drug from patches post-wear and in
pharmacokinetic studies. In this study the investigators will employ two types of evaluation
to determine the rate and extent of drug release and absorption from lidocaine patches,
namely residual drug analysis post-wear and pharmacokinetic analysis in healthy adult
volunteers. In addition, the investigators will compare the serum drug concentrations
following patch and intravenous administration in order to determine the absolute
bioavailability of these patches. Positive outcomes of this project will identify appropriate
methods to determine the rate and extent of drug release and absorption from topical patches,
and will help regulatory agencies in the development of Guidances for Industry regarding the
characterization of drug release and absorption kinetics to ensure the safety of individuals
utilizing these types of products.

Inclusion Criteria:

1. Men or non-pregnant women, of any ethnic background, between the age of 18 and 65
years old.

2. Provide written informed consent before initiation of any study procedures.

3. Available for follow-up for the planned duration of the study.

4. Able to communicate well with the investigators.

5. Demonstrate comprehension of the protocol procedures and knowledge of study, as
demonstrated by a study member filling out a consent checklist form to verify that the
subject understands all aspects of the study including the purpose, procedures, risks
and benefits.

6. Able to adhere to the study protocol schedule, study restrictions and examination
schedule.

7. Subjects must be non-smokers and not regular users of tobacco. They must have
refrained from regular and habitual use of nicotine-containing substances, including
tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, patch or electronic
cigarettes) over the previous 12 months and must have not used any nicotine-containing
products in the previous 30 days.

8. Subjects who are within their ideal body weight (BMI between 18-29.9 kg/m2).

9. Subjects deemed to be healthy as judged by the Medically Accountable Investigator
(MAI), as determined by medical history, physical examination, and medication history.

10. Negative urine drug screening test.

11. Have a normal blood pressure (systolic: 90-139 mmHg; diastolic: 60-89 mmHg) and heart
rate (55-100 bpm).

12. Have normal screening laboratories for WBC, Hgb, Hct, platelets, sodium, potassium,
chloride, bicarbonate, BUN, creatinine, ALT, AST.

13. Female subjects must be of non-childbearing potential. This is defined as surgically
sterile (i.e. history of hysterectomy or tubal ligation), or postmenopausal for more
than 1 year (no bleeding for 12 consecutive months). If the person is of childbearing
potential they must be non-pregnant at the time of enrollment and on the morning of
the first day of each study treatment procedure day (a urine pregnancy test will be
administered if it has been >30 days since serum pregnancy test for enrollment). The
person must also agree to use hormonal or barrier birth control such as implants,
injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual
abstinence, or a vasectomized partner.

14. Agrees not to participate in another clinical study during the study period unless the
study is in the follow-up phase and it has been one month since the subject received
any experimental agents or treatments. The subject also agrees not to participate in
an investigational drug study for at least 30 days after last procedure day.

15. Agrees not to donate blood to a blood bank throughout participation in the study and
for at least 60 days after last procedure day.

16. Have a normal ECG; must not have any of the following: pathologic Q wave
abnormalities, significant ST-T wave changes, left ventricular hypertrophy, right
bundle branch block, left bundle branch block, advanced A-V heart block, non-sinus
rhythm, excluding isolated premature atrial contractions (sinus rhythm is not between
55-100 beats per minute), or any other abnormality that, in the opinion of the MAI,
makes it unsafe for the subject to participate in the study.

Exclusion Criteria:

1. Women who are pregnant or lactating or have a positive serum pregnancy test at
enrollment or positive urine pregnancy test at any time during the study.

2. Smokers. A "smoker", for the purposes of the study, will be defined as an individual
who has regularly and habitually used nicotine-containing substances, including
tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, patch or electronic
cigarettes) over the past 12 months. Occasional recreational use (less than once
monthly) will not warrant exclusion unless the individual has used nicotine-containing
substances in the previous 30 days before study enrollment.

3. Participation in any ongoing investigational drug trial or clinical drug trial period
unless the study is in the follow-up phase and it has been ≥ one month since the
subject received any experimental agents or treatments.

4. Abnormal vital signs, defined as:

- Hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90
mmHg) at rest on two separate days.

- Heart rate <55 at rest on two separate days

- Respiratory rate ≤ 11 to ≥ 18 breaths per minute

5. Temperature >38.0ºC (100.4ºF) or symptoms of an acute self-limited illness such as an
upper respiratory infection or gastroenteritis within seven days of administration of
a study product.

6. History of chronic obstructive pulmonary disease.

7. Positive urine drug screening test.

8. Use of any prescription medication during the period 0 to 30 days or over-the counter
medication during the period 0 to 3 days before entry to the study (vitamins, herbal
supplements and birth control medications will be allowed).

9. Use of medications or treatments that would significantly influence or exaggerate
responses to the test product or that would alter inflammatory or immune response to
the product. This includes antihistamines (within 72 hours prior to dosing), systemic
or topical corticosteroids within four weeks prior to dosing, use of monoamine oxidase
inhibitors 21 days prior to study, cyclosporine, tacrolimus, cytotoxic drugs, immune
globulin, Bacillus Calmette-Guerin [BCG], monoclonal antibodies, or radiation therapy.

10. Donation or loss of greater than one pint of blood within 60 days of entry to the
study.

11. Any prior serious adverse reaction or hypersensitivity to lidocaine administered by
any route.

12. Current diagnosis of any major psychiatric illness.

13. Received an experimental agent (vaccine, drug, biologic, device, blood product or
medication) within 30 days before enrollment in this study or expects to receive an
experimental agent during the study.

14. Medical history of a serious chronic condition, including (but not limited to):
allergic conditions such as anaphylaxis to food or drugs; asthma; generalized drug
reactions; any seizure disorder; any central nervous system disorder; glaucoma (open
or closed angle); history of pyloric or urinary bladder neck obstruction; intestinal
obstruction; difficulty swallowing; stomach or bowel problems (e.g, blockage, muscle
weakness, ulcerative colitis, Crohn's disease); bleeding disorders; acid reflux
disease; myasthenia gravis; allergy to belladonna alkaloids; impaired hepatic or renal
function.

15. Any condition that would, in the opinion of the Principal Investigator (PI) or MAI,
place the subject at an unacceptable risk of injury or render the subject unable to
meet the requirements of the protocol.

16. Inability to communicate or cooperate with the investigators.

17. Medical history of significant dermatologic diseases or conditions, such as atopy,
psoriasis, vitiligo or conditions known to alter skin appearance or physiologic
response (e.g. diabetes, porphyria).

18. History of significant dermatologic cancers (e.g. melanoma, squamous cell carcinoma),
except basal cell carcinomas that were superficial and did not involve the
investigative site.

19. History of consumption of alcohol within 24 hours prior to dose administration.

20. Subject has an obvious difference in skin color at patch sites (compared to
neighboring skin), or the presence of a skin condition, excessive hair at the
application site, sunburn, raised moles and scars, open sores at application site,
scar tissue, tattoo, or coloration that would interfere with placement of test
articles, or the assessment of the skin and/or reactions to drug.