Nicotine Pharmacokinetics:

Comparison of a cigarette,

loose snus, pouched snus

and nicotine gum

ST14 - 2011 CORESTA – Smoke Science/ Product Technology

9 – 13 October 2011 – Graz, Austria

H. Digarda, C. Proctora, U. Malmqvistb, A.

Richtera

aBritish American Tobacco, Group R&D,

Regents Park Road, Southampton, SO15 8TL,

UK bClinical Research and Trial Centre, Lund

University Hospital, SE-221 85 Lund, Sweden

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Background

Swedish-style snus is available in pouched and loose form

Consumption survey of Swedish snus users †: - users of loose snus consumed a greater weight of

tobacco each day than users of pouched snus

† Patterns and Behaviors of Snus Consumption In Sweden. H. Digard, et al. 2009, Nic. & Tob.Res., 11: 1175-1181

§ Oral mucosal changes and nicotine disposition in users of Swedish smokeless tobacco products: a comparative study. G.

Andersson, et al. (1994). J.Oral Pathol.Med., 23: 161-167

*Effect of Smokeless Tobacco (Snus) on Smoking and Public Health in Sweden. J. Foulds, et al. 2003, Tob. Cont., 12: 349-

359

Average systemic doses of nicotine from loose and pouched snus reportedly similar, based on nicotine equivalents in 24 hour urine §

Rate of uptake & max. plasma nicotine from snus intermediate between those for cigarettes and nicotine gum or dermal patches*

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Study Objective

Conducted: - A randomised, pharmacokinetic study of multiple tobacco

products and an OTC nicotine product in healthy subjects

Study Objectives: - To investigate how product type (pouched versus loose) and

nicotine content affects nicotine absorption kinetics

- To compare nicotine absorption kinetics for different snus products against those for a cigarette and a nicotine replacement product

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Study Details

Country: Sweden (one site)

Approvals: - Independent Ethics Committee

- Swedish Medical Products Agency

- Required due to inclusion of the nicotine gum

- Trial Registration Number: ISRCTN11703777

Number of Subjects: - 20 daily snus users who occasionally smoke

- Aged between 19 and 55 years

Single Product Use

Use of tobacco restrictions - Subjects asked to refrain from using tobacco or nicotine products for 12 hours

prior to visit

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Study Test Products

The five tobacco products were manufactured by British American Tobacco and

commercially available in Sweden at the time of the study

The nicotine gum was purchased in a Swedish pharmacy

Product Target

Weight

Measured Nicotine

per product

Cigarette NA 0.9 mg*

Loose snus 1g 10.8 mg

Loose snus 2.5g 27.1 mg

Pouched snus 1g† 10.7 mg

Pouched snus 1g† 14.7 mg

Nicotine gum (Nicorette®) NA 4.2 mg

*Nicotine in smoke, ISO method

†Total weight including that of the pouch.

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Study Product Administration

SNUS: - Snus portion placed under upper lip

- Product used for 1 hour

CIGARETTE: - Smoked naturally for 5 minutes or until cigarette had been

smoked to 30mm from the filter tip end

- Cigarette extinguished

NICOTINE GUM: - Product used for 30 minutes

- Gum chewed every 2 seconds in time with a metronome

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Study Design

One test product administered to each subject at each visit (Visits 1 to 6)

- Products randomised

For each visit: - Administration of product

- Blood samples taken at set times for nicotine analysis

- 10 samples were taken at specific times over 2 hours

- An extra sample taken for the cigarette product

- Samples were taken before, during and after use

Analysis of nicotine in plasma was performed by LC-MS/MS

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Nic

otine P

lasm

a c

oncentr

ation (

ng/m

L)

Time post-administration (min)

Geometric Mean of Plasma Nicotine

Concentrations

Loose Snus

(27.1mg nicotine)

Pouched Snus

(14.7mg nicotine)

Cigarette

(0.9mg nicotine)

Nicotine Gum

(4.2mg nicotine)

Pouched Snus

(10.7mg nicotine)

Loose Snus

(10.8mg nicotine)

--- Lower limit of quantification (0.5ng/ml)

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Nic

otine P

lasm

a c

oncentr

ation (

ng/m

L)

Time post-administration (min)

Median time to maximum concentration of

nicotine (Tmax)

Loose Snus

(27.1mg nicotine)

Pouched Snus

(14.7mg nicotine)

Cigarette

(0.9mg nicotine)

Nicotine Gum

(4.2mg nicotine)

Pouched Snus

(10.7mg nicotine)

Loose Snus

(10.8mg nicotine)

Snus: 60 minutes

Nicotine Gum: 45 minutes

Cigarette: 7 minutes

--- Lower limit of quantification (0.5ng/ml)

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Summary of PK Parameters for Nicotine

Cigarette

(0.9 mg)

Loose

snus

(10.8 mg)

Loose

snus

(27.1 mg)

Pouched

snus

(10.7 mg)

Pouched

snus

(14.7 mg)

Nicotine

gum

(4.2 mg)

AUC0-120 ng.h/ml Geometric Mean*

CV%

14.8 30.4

16.0 31.2

26.9 23.8

16.8 39.6

20.4 37.6

13.1 28.3

Cmax ng/ml Geometric Mean*

CV%

12.8 41.3

10.8 34.4

17.9 22.8

10.8 41.4

13.4 39.0

9.1 28.6

tmax h

Median*

Range: min,max

0.117 0.083, 0.517

1.00 0.75, 1.50

1.00 0.75, 1.50

1.00 0.33, 1.50

1.00 0.75, 1.50

0.75 0.33, 1.50

*N = 20

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Loose and Pouched Snus with the same

nicotine content

Cigarette

(0.9 mg)

Loose

snus

(10.8 mg)

Loose

snus

(27.1 mg)

Pouched

snus

(10.7 mg)

Pouched

snus

(14.7 mg)

Nicotine

gum

(4.2 mg)

AUC0-120 ng.h/ml Geometric Mean

14.8

16.0

26.9

16.8

20.4

13.1

Cmax ng/ml Geometric Mean

12.8

10.8

17.9

10.8

13.4

9.1

tmax h

Median

0.117

1.00

1.00

1.00

1.00

0.75

Systemic nicotine exposure is similar for

loose and pouched snus products with

approximately the same nicotine content

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Systemic nicotine exposure increased with

increasing nicotine content

This increase appeared to be

smaller than the increase in

nicotine content for both types of

snus

The highest

exposures were

seen for the

products with the

highest nicotine

contents

Measured Nicotine

Content

Loose Snus Pouched

Snus

27.1 mg 14.7 mg

Nicotine content increment

2.6 1.4

Increase in AUC0-tlast 1.7 1.2

Increase in Cmax 1.7 1.2

Cigarette Loose

snus

Loose

snus

Pouched

snus

Pouched

snus

Nicotine

gum

Nicotine

mg 0.9 10.8 27.1 10.7 14.7 4.2

AUC0-120

ng.h/ml

14.8

16.0

26.9

16.8

20.4

13.1

Cmax

ng/ml 12.8 10.8 17.9 10.8 13.4 9.1

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Systemic Exposure of Tobacco Products

compared to the Nicotine Gum

All of the tobacco products gave higher

systemic nicotine exposure than the nicotine

gum

Cigarette

(0.9 mg)

Loose

snus

(10.8 mg)

Loose

snus

(27.1 mg)

Pouched

snus

(10.7 mg)

Pouched

snus

(14.7 mg)

Nicotine

gum

(4.2 mg)

AUC0-120 ng.h/ml

Geometric Mean

14.8

16.0

26.9

16.8

20.4

13.1

Cmax ng/ml

Geometric Mean

12.8

10.8

17.9

10.8

13.4

9.1

tmax h

Median

0.117

1.00

1.00

1.00

1.00

0.75

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Summary

The nicotine exposure was similar for the 10.7mg nicotine pouched snus compared to the 10.8mg loose snus portions, suggesting that product form had no effect on the absorption kinetics of nicotine

Systemic nicotine exposure increased with increasing nicotine content for both types of snus, although increases in exposure were sub-proportional to the increases in nicotine content

All of the tobacco products gave higher systemic nicotine exposure than the nicotine gum

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Acknowledgements

The authors thank the following for invaluable input and assistance:

- Graham Errington, Karsta Luettich, Oscar Camacho and Nathan Gale of GR&D, British American Tobacco

- Covance Clinical Research Unit, Leeds, U.K.

- Fiedler & Lundgren, Malmo, Sweden

- British American Tobacco Regional Product Centre Europe, Bayreuth, Germany

Thank you for Listening

Any questions

This presentation is available on bat-science.com

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