Evaluation of Bioavailability of Lidocaine Dermal Products
Phase: EARLY_PHASE1
Conditions: Heat Effect
Sponsor: University of Maryland, Baltimore

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EVALUATION OF THE BIOAVAILABILITY OF LIDOCAINE DERMAL PRODUCTS 
 
Short title: PK and DPK of lidocaine dermal products 
UMB IRB #:  HP-00067033 
 
Principal Investigator:  
Audra L. Stinchcomb (contact), PhD, RPh 
 
Medically Accountable Investigator(s): 
Jeffrey Fink, MD, MS 
Shoshana Weiner, MD, MPH 
 
 
Sponsor: 
Food and Drug Administration 
Office of Generic Drugs 
 
NCT03145207 
 
Version 13.0 
11 December 2018 
 

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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP) and the applicable Food and Drug 
Administration and other Department of Health and Human Services regulatory requirements. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 

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Protocol Summary 
Title:  
Evaluation of the bioavailability of lidocaine dermal products 
Population: 
Healthy adults age 18 - 45 years 
Number of Sites: 
Single site: University of Maryland School of Medicine 
Study Duration: 
Approximately up to 1 year 
 
Subject Participation 
Duration: 
Approximately 16-18 weeks including the screening period 
 
Description of Study 
Product: 
Lidocaine (Lidoderm® patch) 5%, Endo Pharmaceuticals; 
Lidocaine 5% patch, Mylan  
Objective: 
 
The 
present 
study 
aims 
to 
generate 
human 
dermatopharmacokinetics (DPK) and pharmacokinetic (PK) data 
in healthy subjects for the purpose of establishing a reference 
for in vitro-in vivo correlation (IVIVC) with an in vitro model 
following the application of lidocaine formulations: Lidoderm® 
(Lidocaine 5%patch) and lidocaine 5% Mylan patch with and 
without heat application.   
Description of Study 
Design: 
The study will be an open-label, study over 16-18 weeks (n=12 
healthy subjects) with one week washout period between 
procedure days. 
 
The study contains eight procedure days: 
 
Procedure Day 1:  Lidoderm® patches containing 5% 
lidocaine to be worn for 10 h. 
 
Procedure Day 2:  Mylan Lidocaine patches containing 5% 
lidocaine to be worn for 10 h. 
 
Procedure Day 3: The heating pad will be set to induce a 
skin temperature of 42.0 ± 4°C and applied for 1 hour 30 
minutes, 4 hours after application of the Lidoderm® patches. 
 
Procedure Day 4: The heating pad will be set to induce a 
skin temperature of 42.0 ± 4°C and applied for 1 hour 30 
minutes, 8.5 hours after application of the Lidoderm® 
patches. 
 
Procedure Day 5: The heating pad will be set to induce a 
skin temperature of 42.0 ± 4°C and applied for 1 hour 30 

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minutes, 4 hours after application of the Mylan (lidocaine) 
patches (5%). 
 
Procedure Day 6: The heating pad will be set to induce a 
skin temperature of 42.0 ± 4°C and applied for 1 hour 30 
minutes, 8.5 hours after application of the Mylan (lidocaine) 
patches (5%). 
 
Procedure Day 7:  Multiple applications of Lidoderm® patch 
pieces, Mylan lidocaine 5% patch pieces; Removal of patch 
pieces at 10 h, followed by tape stripping (Uptake or 
Absorption); Tape stripping at 15 h [5 h after patch piece 
removal] (Clearance) 
 
Procedure Day 8:  Tape stripping at 24 h [14 h after patch 
piece removal] (Clearance) 
A)  Pharmacokinetics (PK) 
Each subject will be his/her own control and each subject will 
sign an institutional review board–approved consent form 
explaining the purpose, nature, risks, benefits, and duration of 
the study. The study will be conducted in accordance with good 
clinical practice guidelines and with the ethical principles 
originating in the Declaration of Helsinki.  
The subject’s skin in the area of application (volar forearms and 
upper arm(s)) will be relatively free of hair before patch 
application. Blood samples (approximately 3 mL each) will be 
drawn in BD vacutainer (BD # 366668) tubes. On Procedure 
Days 1-6, blood samples will be obtained as follows: 
 
Within 60 min pre-patch application and then up to 10 hours, 
during wear and post patch removal (from 10 hours to 15 
hours).  No blood samples will be obtained during the DPK 
study (Procedure Days 7 and 8). 
 
B)  Dermatopharmacokinetics (DPK) of Lidocaine Patches  
 
Lidocaine products (6 sites/product, 3 sites/arm/product) will 
be applied to each arm.  All of the patchpieces will be 
removed at 10 h.  Four patch sites will be tape stripped 
(uptake or absorption) at 10 h, four patch sites (two 
sites/product/time point) will be tape stripped (clearance) at 
15 and 24 h.    

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 
Tape strips applied and removed after patch piece removal 
to determine the drug concentration in stratum corneum, 
which is the outer barrier layer of the epidermis.  
C)  Residual Drug Analysis of Lidocaine Patches  
In conjunction with the above described study, residual drug 
analysis will also be conducted for the used patches described 
in Part A.    
 
Prior to administration to the Subject as described in Part A, 
patches will be weighed and the weight recorded. 
 
The pouch, release liner and all items coming into contact 
with the patches (gloves, forceps, etc..) applied in Part A will 
be retained for analysis. 
 
The used patches will be retained for drug content analysis. 
 
All items coming into contact with the patches during 
removal from the Subject will be stored in a separate labeled 
Ziploc bag until analyzed for drug content. 
 
 
 

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1 KEY ROLES 
U01 Principal Investigator: 
 
 
Audra L. Stinchcomb (contact), PhD, RPh  
Professor 
Department of Pharmaceutical Sciences 
University of Maryland School of Pharmacy 
20 N Pine St, Room PHN521 
Baltimore, MD 21201 
Phone: 410-706-2646 
Fax: 410-706-0886 
Email: astinchc@rx.umaryland.edu  
 
 
 
 
 
 
 
Medically Accountable 
Investigator(s) 
 
 
Jeffrey C Fink M.D., M.S. 
Professor 
Department of Medicine and Epidemiology (secondary) 
University of Maryland School of Medicine 
UMMC, Room NN3E03 
Baltimore, MD 21201 
Phone: 410-328-4822 
Fax: 410-328-5685 
Email:  jfink@medicine.umaryland.edu 
 
Shoshana Weiner, M.D., MPH 
 
Associate Professor 
Department of Medicine 
UMMC, Room N3E10 
Baltimore, MD 21201 
Phone : 667-214-1500 
Cell : 443-799-001 
Email : ssnitker@medicine.umaryland.edu 
 
 

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2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
The purpose of this project is to investigate the development of appropriate methods to 
determine the in vitro/in vivo correlation (IVIVC) of drug absorption from dermal 
products, which has represented a longstanding challenge. The model drug for this 
study is lidocaine, which is available in two different patch formulations approved by the 
United States FDA.  This healthy human subject study will provide the carefully designed 
protocols and data for direct comparison (IVIVC) with an in vitro human skin diffusion 
study model.  Generic drugs are approved based upon bioequivalence (BE) testing, and 
with respect to oral drug delivery, the accepted BE approach is relatively straightforward 
and is principally based on matching blood level profiles. In some cases, in vitro 
dissolution tests can be done to help determine the bioequivalence of an oral dosage 
form.  For topical drug products in the United States, with the exception of the 
corticosteroids and a few other products, a comparative clinical endpoint study is often 
necessary for approval of a generic product or for replacement of an approved 
dermatological drug product with one that has major changes. Comparative clinical trials 
are relatively insensitive, time-consuming and costly.  It is especially difficult to gain the 
adequate statistical power needed to evaluate bioequivalence in some dermatological 
conditions, and can require a large number (i.e., hundreds1,2) of subjects. 
This study supports FDA’s continuing effort to identify the most accurate, sensitive, 
reproducible and efficient methods to evaluate topical dermatological drug products.  
2.2 
Rationale 
The goal of this study is to help establish more efficient pathways for approval of topical 
generic drug products by developing better tools to assess bioavailability. This study with 
the reference listed drug (RLD) Lidoderm® (lidocaine 5%) topical patch and its approved 
generic product marketed by Mylan will provide sufficient systemic concentrations of 
lidocaine to characterize the systemic bioavailability. The systemic concentration will be 
compared with the local bioavailability of lidocaine in the skin using the same products, 
measured by tape-stripping the skin to measure the concentrations of lidocaine in the 
stratum corneum. The same RLD and generic topical patches will also be studied (under 
a parallel but separate in vitro study protocol) using an in vitro permeation test (IVPT) 
model with excised human skin which has demonstrated IVIVC in previous studies. This 
research will help establish whether the IVPT model correlates with and is predictive of 
in vivo bioavailability, and whether IVPT and/or in vivo tape-stripping can be utilized as 
part of a collective weight-of-evidence approach to support an approval pathway for 
generic topical drug products.  In addition, in vivo studies will be conducted to compare 

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the influence of heat on patch products (RLD e.g. Lidoderm® versus generic product 
e.g. Mylan lidocaine 5% patch) that have different inactive ingredients.  
 
Lidoderm® patch and Mylan lidocaine 5% patch  
  
Lidoderm® 5% patch 
Lidocaine 5% 
patch 
 
Inactive 
ingredients 
dihydroxyaluminum 
aminoacetate, disodium 
edetate, gelatin, glycerin, 
kaolin, methylparaben, 
polyacrylic acid, polyvinyl 
alcohol, propylene glycol, 
propylparaben, sodium  
carboxymethylcellulose, 
sodium polyacrylate, D-
sorbitol, tartaric acid, and 
urea 
polyisobutylene 
adhesive matrix 
 
  
 
 
 
Formulation 
Patch 
Patch 
 
  
  
 
 
Manufacturer 
Endo Pharmaceuticals 
Mylan 
 
 
 
 

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3 OBJECTIVES 
3.1 
Study Objectives 
The present study aims to: 
 
1)  Generate human PK data for the purpose of establishing an IVIVC model by 
collecting data following the application of two lidocaine formulations: Lidoderm® 
(lidocaine 5% patches) and Mylan lidocaine 5% patches. 
2)  Generate DPK data for the purpose of establishing a fundamental IVIVC model by 
collecting skin concentration data following the application of two lidocaine formulations: 
Lidoderm® (lidocaine 5% patches) and Mylan lidocaine 5% patches. 
3)  Determine serum lidocaine levels after using RLD (Lidoderm®, matrix type patch, 
Endo Pharmaceuticals) and generic lidocaine (Mylan) patch with and without 
standardized heat application in healthy adult subjects.  The influence of heat on RLD 
vs. generic product that are formulated differently impose critical safety issue for users 
of generic patches. 
 
3.2 
Study Outcome Measures 
For the DPK study the main outcome measure is the ratio of clearance and uptake of 
lidocaine drug concentrations for each lidocaine formulation. For the PK study the main 
outcome measure is the maximum serum concentration (Cmax); time of maximum serum 
concentration (Tmax) of lidocaine and area under the curve (AUC) attained with and 
without heating for Lidoderm® patch and Mylan lidocaine 5% patch.  In addition, we will 
determine residual drug content from worn Lidoderm® patches and Mylan lidocaine 5% 
patches to estimate total amount of absorbed lidocaine from each.     
 
 

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4   STUDY DESIGN 
This is designed as an open-label, non-placebo controlled study. The products tested 
are already FDA approved; however, the products are used outside of the approved 
indications by using healthy subjects.  The products being tested are for research 
purposes only; this is not a treatment study.  The study is not blinded because PK and 
DPK assessment is not subject to participant and/or observer bias.  The study will 
consist of seven Study Sessions (12 healthy subjects).  Each of the 12 subjects will be 
enrolled to complete seven study sessions (eight procedure days).   There will be no 
overnight stays during the study.  There will be at least a one week washout period 
between each study session.  
 
The studies are as follows: 
 
STUDY SESSION 1 
(Procedure Day 1):  Lidoderm® patches [140 cm2 each] will be applied for 10 h and 
removed.  Blood samples will be collected at specified times over a 16 hour period of the 
clinical study.  There will be at least a one week washout period before proceeding to the 
next Study Session.   
 
STUDY SESSION 2  
(Procedure Day 2):  Mylan lidocaine 5% patches [140 cm2 each] will be applied for 10 h 
and removed.  Blood samples will be collected at specified times over a 16 hour period 
of the clinical study.  There will be at least a one week washout period before proceeding 
to the next Study Session. 
 
STUDY SESSION 3  
(Procedure Day 3): Lidoderm® (lidocaine) [140 cm2 each] will be applied without heat for 
4 hours, then heating pad(s) will be applied over each patch (see details in Manual of 
Procedures (MOP)) and set to induce a skin temperature of 42.0 ± 4°C for 1 hour 30 
minutes then heating pad(s) are removed, and the patches will be kept on, then removed 
(patches applied for a total of 10 hours).  Blood samples will be collected at specified 
times over a 16 hour period of the clinical study.  There will be at least a one week 
washout period before proceeding to the next Study Session.   
 
 
 

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STUDY SESSION 4 
(Procedure Day 4):    Lidoderm® (lidocaine) patches [140 cm2 each] will be applied 
without heat for 8.5 hours, then heating pad(s) will be applied over each patch and set to 
induce a skin temperature of 42.0 ± 4°C for 1 hour 30 minutes, then the patches and 
heating pad(s) will both be removed (patches applied for a total of 10 hours).  Blood 
samples will be collected at specified times over a 16 hour period of the clinical study.  
There will be at least a one week washout period before proceeding to the next Study 
Session.   
 
STUDY SESSION 5 
(Procedure Day 5):   Mylan 5% lidocaine patches [140 cm2 each] will be applied without 
heat for 4 hours, then theratherm® heating pad(s) will be applied over each patch and 
set to induce a skin temperature of 42.0 ± 4°C for 1 hour 30 minutes, then removed 
(patches applied for a total of 10 hours).  Blood samples will be collected at specified 
times over a 16 hour period of the clinical study.  There will be at least a one week 
washout period before proceeding to the next Study Session.   
 
STUDY SESSION 6 
(Procedure Day 6):    Mylan 5% lidocaine patches [140 cm2 each] will be applied without 
heat for 8.5 hours, then heating pad(s) will be applied over each patch and set to induce 
a skin temperature of 42.0 ± 4°C for 1 hour 30 minutes, then the patches and the heating 
pad(s) will both be removed (patches applied for a total of 10 hours).  Blood samples will 
be collected at specified times over a 16 hour period of the clinical study.  There will be 
at least a one week washout period before proceeding to the next Study Session.     
 
STUDY SESSION 7 
(Procedure Day 7): Six sites (3 sites/arm) will be designated on the volar forearms for 
each lidocaine formulation and 1 site for a negative control. Lidoderm® 5% patch pieces 
and Mylan lidocaine 5% patch pieces will be applied.   At 10 h post application, all 
formulations will be removed from their respective sites.  Two sites for each patch 
product will be tape stripped at the designated uptake (absorption) time.    Two sites for 
each formulation will be tape stripped at the designated clearance period. 
 
(Procedure Day 8):  The remaining two sites for each formulation will be tape stripped 
at the designated clearance period.   
 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Only adult healthy volunteers who meet the inclusion/exclusion criteria will be eligible for 
enrollment into this study.  Twelve subjects will be recruited as well as at least another 
five alternates who could replace subjects who drop out from the study for any 
unforeseen reason.  The study population selected for this study includes healthy adult 
men and women without other comorbidities ages 18-45, inclusive.  The selection 
criteria are designed to exclude people who might have medical conditions that could 
pose a safety risk and people whose medical conditions might interfere with the 
objectives and results of the study.   
Subjects will be recruited by local advertisements to the study center.  Potential subjects 
who are interested in the study will be informed of the study and if they wish to 
participate, will receive additional study information, including a screening and informed 
consent form.  Each of the 12 subjects enrolled will be expected to complete all study 
sessions.   
We aim to target at least 40% participants of each gender. There are no specific 
ethnicity/race categories recruitment targets although such information will be recorded 
by the researchers.  
5.1 
Subject Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below: 
1. Men or non-pregnant, women who are of any ethnic background between the 
age of 18 and 45 years old. 
2. Subjects must be non-smokers (must have refrained from the use of nicotine-
containing substances, including tobacco products (e.g., cigarettes, cigars, 
chewing tobacco, snuff, gum, patches or electronic cigarettes) over the previous 
2 months and are not currently using tobacco products. 
3. Provide written informed consent before initiation of any of the study procedures. 
4. Agrees not to participate in another clinical trial/study or to participate in an 
investigational drug study for at least 1 month after the last study session. 
5. Able to adhere to the study restrictions and protocol schedule. 
6. Able to participate in all study sessions. 

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7. Has a volar forearm of either at least 24 cm (9.45 inches) in length or of sufficient 
size that can accommodate the formulations to be tested in a study area that 
begins at least 5 cm (1.97 inches) above the wrist and ends a minimum of 0.5 cm 
(0.197 inches) below the antecubital fossa (i.e., the bend in the arm at the 
elbow). 
8. Subjects have upper arms (minimum 28 cm (11 inch) circumference) large 
enough to allow for the placement of two 140 cm2 patches on one upper arm or 
one 140 cm2 patch on each upper arm.   
9. Subjects deemed to be healthy as judged by the MAI and determined by medical 
history, physical examination and medication history. 
10. Negative urine drug screening test. 
11. Have normal screening laboratories for WBC, CBC, Hgb, platelets, sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, ALT and AST. 
12. Have normal screening laboratories for urine protein and urine glucose.  
13. Female subjects must be of non-childbearing potential (as defined as surgically 
sterile [i.e., history of hysterectomy or tubal ligation] or postmenopausal for more 
than 1 year), or if of childbearing potential must be non-pregnant at the time of 
enrollment and on the morning of each procedure day, and must 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 donate blood to a blood bank throughout participation in the study 
and at least 3 months after the last procedure day. 
15. Have a normal ECG; must not have the following to be acceptable: pathologic Q 
wave abnormalities, significant ST–T wave changes, left ventricular hypertrophy, 
right bundle branch block, left bundle branch block. (sinus rhythm is between 55–
100 beats per minute). 
 
16. Have normal vital signs: 
 
Temperature 35-37.9°C (95-100.3°F) 
 
Systolic blood pressure 90-140 mmHg 
 
Diastolic blood pressure 60-90 mmHg 
 
Heart rate 55-100 beats per minute 
 
Respiration rate 12-20 breaths per minute 
 
5.2 
Subject Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 

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1. Women who are pregnant, lactating, breast feeding or have a positive serum 
pregnancy test at enrollment or positive urine pregnancy test on the morning of 
each study session. 
2. Smokers (current use or use over the previous 2 months of nicotine-containing 
substances, including tobacco products (e.g., cigarettes, cigars, chewing 
tobacco, snuff, gum, patches or electronic cigarettes). 
3. Participation in any ongoing investigational drug trial/study or clinical drug 
trial/study. 
4. History of chronic obstructive pulmonary disease or cor pulmonale, or 
substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing 
respiratory depression. 
5. Active positive Hepatitis B, C and/or HIV serologies (see Appendix B). 
6. Known anemia. 
7. Positive urine drug screening test. 
8. Use of any prescription medication during the period 0 to 30 days; or over-the 
counter medication (e.g. antihistamines or topical corticosteroids) and short term 
(<30 days) prescription medications during the period 0 to 3 days before a study 
session (vitamin, herbal supplements and birth control medications not included). 
9. Donation or loss of greater than one pint of blood within 60 days of entry to the 
study. 
10. Any prior adverse reaction to lidocaine. Hypersensitivity to lidocaine, known 
history of hypersensitivity to local anesthetics of the amide type, other excipients 
in the patches tested or to adhesives on tapes used to cover or tape strip 
treatment sites. 
11. Received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within 1 month before enrollment in this study or expects to 
receive an experimental agent during the study. 
12. Any condition that would, in the opinion of the Medically Accountable Investigator 
(MAI), place the subject at an unacceptable risk of injury or render the subject 
unable to meet the requirements of the protocol. 
13. Consumption of alcohol within 24 h prior to dose administration. 

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14. History as either reported by the subject or evident to the investigator of 
infectious disease or skin infection or of chronic skin disease (e.g., diabetes, 
psoriasis, atopic dermatitis).  
15. Hereditary skin disorders or any skin inflammatory conditions as reported by the 
research participant or evident to the MAI. 
16. History of significant dermatologic cancers (e.g., melanoma, squamous cell 
carcinoma) except basal cell carcinomas that were superficial and did not involve 
the investigative sites. 
17. Subject has an obvious difference in skin color between arms or the presence of 
a skin condition, excessive hair at application site (volar forearms/upper arms), 
sunburn, raised moles and scars, open sores at application site (volar 
forearms/upper arms), scar tissue, tattoo or coloration that would interfere with 
placement of formulations, skin assessment or reactions to lidocaine. 
18. BMI  30 kg/m2. 

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6 STUDY PRODUCT 
6.1 
Study Product Description 
6.1.1 Lidoderm® (lidocaine 5%) patch [140 cm2] 
Lidoderm® is a prescription lidocaine-containing patch that releases lidocaine through 
the skin into the body.  The patch releases lidocaine over a 12 h period, the 
recommended duration of patch application. The patch is indicated to relieve the pain of 
post-herpetic neuralgia [after-shingles pain]. 
6.1.2 Mylan (lidocaine 5%) patch [140 cm2] 
Mylan lidocaine 5% patch is a prescription lidocaine-containing patch that releases 
lidocaine through the skin into the body.  The patch releases lidocaine over a 12 h 
period, the recommended duration of patch application. The patch is indicated to relieve 
the pain of post-herpetic neuralgia [after-shingles pain]. 
6.2 
Formulation, Packaging, and Labeling 
6.2.1 Lidoderm® (5% lidocaine) patch [140 cm2] 
Active ingredient (in each patch): Lidocaine, 700 mg (50 mg per gram adhesive) in an 
aqueous base.  In addition to the active ingredient (lidocaine), the following inactive 
ingredients are present in the patch: dihydroxyaluminum aminoacetate, disodium edetate, 
gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, 
propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, D-sorbitol, tartaric 
acid, and urea. This patch is manufactured by Endo Pharmaceuticals Inc. This product 
should be stored at room temperature. 

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6.2.2 Mylan 5% lidocaine patch [140 cm2] 
Active ingredient (in each patch): Lidocaine, 140 mg USP (50 mg per gram adhesive) in a 
polyisobutylene adhesive matrix.  This patch is manufactured by Mylan Pharmaceuticals Inc. 
This product should be stored at room temperature. 
 

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7 
PHARMACOKINETICS AND STATISTICAL 
CONSIDERATIONS 
7.1 
Study Hypothesis 
DPK and PK 
We will test the null hypothesis (H0) that the mean clearance/uptake lidocaine amount 
ratio, and the PK parameters (Cmax and AUC) between the lidocaine patch products 
are different (i.e., outside the 80–125% range). 
 
Heat  
Due to differences in inactive ingredients between RLD and generic lidocaine 
patches, the release rate of lidocaine may differ from these patches upon exposure to 
heat. As a result, in this study the influence of standardized heat application (two heat 
periods) on the pharmacokinetics (PK) parameters of lidocaine will be studied after 
using Lidoderm® (reference) and Mylan lidocaine (generic) patches. Analysis will be to 
determine whether heat differentially impacts lidocaine serum concentrations between 
Lidoderm® (reference) and Mylan (lidocaine) patches. We will test the null hypothesis 
(H0) that the coefficient for the patch-by-heat interaction equals zero, adjusting for 
time. 
7.2 
Analyses 
Lidocaine concentrations will be measured in serum samples collected from each 
subject. Blood samples (approximately 3 mL (0.6 tsp)) will be collected during the Study 
Sessions 1, 2, 3, 4, 5 and 6.  During Study Session 1 and 2 within 60 min before dosing 
and then at 2 hours, 3 hours, 3 hours 55 minutes, 4 hours 50 minutes, 5 hours 30 
minutes, 6 hours, 6 hours 30 minutes, 7 hours, 8 hours 25 minutes, 9 hours 20 minutes, 
10 hours, 10 hours 30 minutes, 11 hours, 11 hours 30 minutes, 12 hours, 13 hours, 14 
hours and 15 hours post-patch application. Blood samples (approximately 3 mL (0.6 
tsp)) will be collected during Study Sessions 3 and 5 within 60 min before dosing and 
then at 2 hours, 3 hours, 3 hours 55 minutes, 4 hours 5 minutes, 4 hours 20 minutes, 4 
hours 35 minutes, 4 hours 50 minutes, 5 hours 5 minutes, 5 hours 30 minutes, 6 hours, 
6 hours 30 minutes, 7 hours, 8 hours 25 minutes, 9 hours 20 minutes, 10 hours, 10 
hours 30 minutes, 11 hours, 11 hours 30 minutes, 12 hours, 13 hours, 14 hours and 15 
hours post-patch application.  Blood samples (approximately 3 mL (0.6 tsp)) will be 
collected during Study Sessions 4 and 6 within 60 min before dosing and then at 2 
hours, 3 hours, 3 hours 55 minutes, 4 hours 50 minutes, 5 hours 30 minutes, 6 hours, 6 
hours 30 minutes, 7 hours, 8 hours 25 minutes, 8 hours 35 minutes, 8 hours 50 minutes, 
9 hours 5 minutes, 9 hours 20 minutes, 9 hours 35 minutes, 10 hours, 10 hours 30 

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minutes, 11 hours, 11 hours 30 minutes, 12 hours, 13 hours, 14 hours and 15 hours 
post-patch application.  DPK will be conducted at 10 h (skin drug uptake) or 5 h and 14 h 
(skin drug clearance) post patch application.  Non compartmental analyses (NCA) will be 
conducted to estimate the  PK parameters such as: maximum serum concentration 
(Cmax); apparent elimination rate constant (k); apparent half-life (t1/2), calculated as 
0.693/k; AUC0-last of the serum concentration–time determined by the linear trapezoidal 
method; and AUC value extrapolated to infinity (AUCinf), calculated as the sum of AUC0-
last and the area extrapolated to infinity: AUCinf = AUC0-last + Clast/k where Clast would be 
the last quantifiable concentration. All NCA analyses will be conducted using Phoenix® 
WinNonlin® 6.4 (Pharsight, a Certara Company, CA). 
7.3 
Final Analysis Plan 
An objective of this study is to determine PK parameters (Cmax, AUC and ratio of stratum 
corneum drug concentration during uptake and clearance) of lidocaine in healthy adults 
and DPK data after using Lidoderm® (lidocaine 5% patches) and Mylan 5% lidocaine 
patches for the purpose of IVIVC by collecting data over two separate periods. 
Complimentary in vitro data will be collected using human skin. 
Secondly the objective is to investigate the influence of heat application on the PK 
parameters of lidocaine after using a RLD and generic patches along with no heat 
application.  The primary PK parameters to be compared are 1) Cmax, before and after 
heat application and 2) AUC before and after heat application consistent with similar PK 
studies13-23. Analysis of variance (ANOVA) followed by post-hoc Bonferroni test will be 
used for comparing the differences in the means of the PK parameters and significant 
differences will be declared at p<0.05. The statistical comparisons will be conducted as 
follow: 
 
If lidocaine PK concentrations are found to be non-normally distributed, then we will 
examine Box-Cox transformations (e.g., log, square-root, etc.) that can achieve 
normality. If no transformation can achieve normality, then will use permutation tests to 
compute empirical p-values, and will use the bootstrap to compute standard errors and 
confidence intervals that account for within-person correlation.  
 
IVIVC will be conducted comparing PK parameters and profiles to predicted PK 
parameters and profiles using IVPT and in vitro DPK results.  Multiple methods will be 
implemented to develop an IVIVC.  The first method is to compare the steady state 
concentrations.  The predicted steady state concentration using our current IVPT data 
will employ the following formula: 
          
  
 
 

PK and DPK of Lidocaine 
Version 13; 11 December 2018 
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The second method will compare the PK profiles of the clinical and IVPT study by 
predicting lidocaine concentrations at each time point in the IVPT study and comparing it 
to the clinical PK profile.  The third method will be to determine and compare residual 
patch analysis between in vitro and in vivo.     
 
In terms of developing an IVIVC for the DPK study a comparison will be made between 
in vitro and in vivo uptake and clearance lidocaine amounts.  The second method is to 
compare the clearance to uptake lidocaine amount ratio between in vitro and in vivo.