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Clin Pharmacokinet 2001; 40 (9): 661-684 0312-5963/01/0009-0661/$22.00/0 © Adis International Limited. All rights reserved.

The Nicotine Inhaler Clinical Pharmacokinetics and Comparison with Other Nicotine Treatments Nina G. Schneider,1,2 Richard E. Olmstead,1,2 Mikael A. Franzon3 and Erik Lunell4 1 University of California-Los Angeles, School of Medicine, Los Angeles, California, USA 2 Nicotine Research Unit, VA-Greater Los Angeles Healthcare System, West Los Angeles, California, USA 3 Pharmacia Consumer Healthcare, Bridgewater, New Jersey, USA 4 Department of Clinical Pharmacology, University Hospital, Lund, Sweden

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Nicotine Treatments for Tobacco Dependence . . . . . . . . . . . . . . . . 1.1 Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2 Nicotine Delivery in Smoke . . . . . . . . . . . . . . . . . . . . . . . . . 2. Development of the Nicotine Inhaler . . . . . . . . . . . . . . . . . . . . . . 2.1 Rationale: Multiple Reinforcers in Treatment . . . . . . . . . . . . . . . 2.2 Precursors and Clinical/Approved Preparations . . . . . . . . . . . . . 3. Pharmacokinetics of Nicotine from the Inhaler . . . . . . . . . . . . . . . . 3.1 Venous Blood Nicotine Concentrations and Rise Time . . . . . . . . . 3.1.1 Temperature Dependency . . . . . . . . . . . . . . . . . . . . . 3.1.2 Inhalation Techniques . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Absorption, Deposition and Positron Emission Tomography Data 3.2 Arterio-Venous Blood Nicotine Concentrations . . . . . . . . . . . . . . 4. Comparative Pharmacokinetics Among Nicotine Systems . . . . . . . . . . 4.1 Venous Nicotine Concentrations – Single Dose . . . . . . . . . . . . . . 4.2 Venous Nicotine Concentrations – Ad Libitum Use . . . . . . . . . . . . 5. Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Efficacy Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Withdrawal and Craving . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Comparative Efficacy Among Nicotine Treatments . . . . . . . . . . . 5.4 Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Use Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6 Cotinine Concentrations . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Treatment Dependence and Abuse Liability . . . . . . . . . . . . . . . . . . 6.1 Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Clinical Indicators of Treatment Dependence . . . . . . . . . . . . . . 6.3 Abuse Liability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Tailoring Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Individual Needs and Preferences . . . . . . . . . . . . . . . . . . . . . 7.2 Combining Pharmacological Treatments . . . . . . . . . . . . . . . . . 8. Inhaler Use and Harm Reduction . . . . . . . . . . . . . . . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

Schneider et al.

Nicotine inhaled in smoke is the most rapid form of delivery of the drug. With smoking, arterial boli and high venous blood nicotine concentrations are produced within seconds and minutes, respectively. The potency of nicotine as the primary reinforcement in tobacco addiction is attributed to this rapid rate of delivery. By design, nicotine treatments reduce the rate and extent of drug delivery for weaning from nicotine during smoking cessation. Theoretically, they prevent relapse by reducing withdrawal and craving associated with the abrupt cessation of cigarettes. The nicotine inhaler treats the complexity of smoking through weaning both from the drug and from the sensory/ritual components associated with smoking. The inhaler is ‘puffed’ but not lit and there is considerable ‘puffing’ required to achieve slower rising and lower nicotine concentrations. These factors allow it to be used as a nicotine reduction treatment. One inhaler contains 10mg of nicotine (and 1mg of menthol) of which 4mg of nicotine can be extracted and 2mg are systemically available. Shallow or deep ‘puffing’ results in similar nicotine absorption. Nicotine is delivered mainly to the oral cavity, throat and upper respiratory tract with a minor fraction reaching the lungs. This was confirmed with positron emission tomography and by assessment of arterial concentrations. A single inhaler can be used for one 20-minute period of continuous puffing or periodic use of up to 400 puffs per inhaler. With controlled puffing in laboratory testing, venous plasma nicotine concentrations from a single inhaler puffed 80 times over 20 minutes averaged 8.1 μg/L at 30 minutes. Lower concentrations of 6.4 to 6.9 μg/L have been reported for self-administration under clinical conditions. The time to peak plasma concentrations varies but is always significantly longer than with cigarette delivery. Estimates of nicotine intake from cotinine concentrations were higher than expected (60 to 70% of baseline smoking concentrations). This elevation may be due to the swallowing of nicotine and subsequent first-pass biotransformation to cotinine. In general, venous blood nicotine concentrations are considerably lower than with smoking and are within the range observed for other nicotine reduction therapies. Efficacy trials show consistent superiority of the inhaler over placebo. Despite the ‘cigarette-like’ appearance of the inhaler and the associated sensory/ritual elements, little treatment dependence or abuse has been reported. This is attributed to the slow rise time and low nicotine blood concentrations. The inhaler is a valuable addition to treatment of tobacco dependence and can be used alone or with other treatments.

1. Nicotine Treatments for Tobacco Dependence

Nicotine is now widely acknowledged as the addicting component in compulsive tobacco use.[1,2] Inhalation of nicotine in smoke is considered the most dependence-producing form of administration of the drug because of rapidly established concentrations in brain and blood.[3,4] Rapid onset is a known factor in abuse liability of drugs.[5,6] Reducing the © Adis International Limited. All rights reserved.

speed and extent of drug delivery has been central to development of nicotine treatments for tobacco dependence. Because reduction (rather than replacement) of nicotine occurs with the onset of treatment, we will use the acronym NRT for ‘nicotine reduction treatment’. Although NRT has previously been used for ‘nicotine replacement treatment’, we feel this is a misnomer. Reduction of some sort (arterial concentrations, speed of delivery) always occurs with the Clin Pharmacokinet 2001; 40 (9)

Nicotine Inhaler

switch from smoking to use of any nicotine delivery system. Thus, ‘nicotine reduction’ is more accurate than ‘nicotine replacement’. Each of several NRTs has been designed to alter reinforcement by changing the pharmacokinetic parameters of nicotine intake. The first preparation, nicotine gum,[7] produced low, slow-rising nicotine concentrations. Provision of some nicotine (for ‘weaning’) was expected to help relieve withdrawal and craving that lead to relapse with abrupt smoking cessation. After a period of time (varying by individual need), nicotine was withdrawn altogether. One additional advantage of these treatments is the instantaneous elimination of the carcinogens and gases of burned tobacco. The efficacy of nicotine gum and subsequent NRTs (patch, nasal spray and inhaler) is well established.[8,9] Findings for a new nicotine sublingual microtablet are also promising.[10,11] Despite these demonstrations of efficacy over placebo controls, there has been significant drop-out early in treatment. In a recent comparative trial of 4 treatments (patch, nasal spray, gum and inhaler), dropout rates ranged from 45 to 57% at 1 week and from 62 to 69% at 4 weeks.[12] We suggest compliance as a function of mode of delivery is essential to success with these treatments. One solution is to tailor treatment by preferences[13] related to the form of administration and pharmacokinetic profile of each drug. In general, treatment efficacy will depend upon the individual’s acceptance of each medication as well as its delivery parameters. Previously, we reviewed the clinical pharmacokinetics of a nicotine nasal spray.[14] The present paper reviews the clinical pharmacokinetics of the nicotine inhaler. Comparative pharmacokinetic data among nicotine treatments are presented. We also briefly review clinical findings including inhaler efficacy and safety, use issues, inhaler use in combination with other treatments, treatment dependence or abuse, tailoring of treatment and use of the inhaler for ‘harm reduction’. © Adis International Limited. All rights reserved.

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1.1 Nicotine

The chemical profile of nicotine has been described in numerous publications.[1,15,16] Nicotine is absorbed from many sites (with absorption influenced by pH) and has a half-life of approximately 2 hours.[16] Cotinine, its major metabolite, is essentially inactive and has a half-life of 18 to 36 hours.[16] Nicotine is the primary reinforcer in tobacco, with proposed stimulant and depressant actions.[1,17] Nicotine may affect mood, performance, cognitive function, produce pleasure, reduce hunger and relieve anxiety and depression.[1,17-19] However, whether these effects are direct actions (positive reinforcers), due to relief of withdrawal symptoms within the addiction (negative reinforcement) or are related to both is unclear. 1.2 Nicotine Delivery in Smoke

The pharmacokinetics of inhaled nicotine in smoke (rapid entry into brain, rapidly established arterial/venous concentrations) are key to nicotine addiction. Reinforcement of drug seeking is immediate and is ‘perfectly confounded’ with the sensory, ritual and psychological effects of smoking. Nicotine in smoke, with its bolus input, is regarded as the most reinforcing and dependence-producing of the commonly used forms of nicotine administration.[3,4,20] Benowitz[18] has noted that the increasing trough concentrations with repeated smoking leads to increased tolerance by brain receptors and potential withdrawal when drug intake ceases. Nicotine absorption from cigarette smoke is facilitated by a huge alveolar surface area, thin alveolar endothelial layers and an extensive capillary bed. Average trough venous blood nicotine concentrations for smoking range from 10 to 37 μg/L[21,22] and peak venous blood concentrations range from 19 to 50 μg/L.[23,24] Significant variability occurs because of individual differences in puffing (e.g. depth of inhalation, volume of puff) and nicotine metabolism.[25-27] Time of measurement is essential; Henningfield et al.[28] reported venous blood concentrations of 28.2 μg/L at 1 minute post smoking versus 21.6 μg/L at 5 minutes. Clin Pharmacokinet 2001; 40 (9)

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There are only a few studies on arterial concentrations. Rand[29] reported nicotine concentrations of 100 μg/L after 1 puff of a cigarette as measured in arterial blood within 20 seconds of use. Henningfield et al.[6,28] reported arterial nicotine concentrations for cigarettes up to 10 times higher than venous concentrations. Gourlay and Benowitz[4] reported arterial concentrations for cigarettes at least 2 times higher than venous concentrations (39.8 arterial μg/L vs 18.6 μg/L venous concentrations). In a recent study by Rose et al.,[20] testing puffby-puff arterial concentrations, concentrations of 7 μg/L were achieved after a single puff and 20.5 μg/L after smoking a cigarette. This is in contrast with the high concentrations observed in some studies[28,29] but similar to those of Gourlay and Benowitz[4] and Lunell et al.[30] where arterial concentrations were 2 to 3 times higher than venous concentrations. Rose et al.[20] attribute their low nicotine arterial concentrations to binding of nicotine in the lungs [the binding is consistent with positron emission tomography (PET) data[31]] which results in ‘slowing [nicotine’s] entry into the arterial circulation’. They propose that stimulation of lung nicotinic receptors adds to direct CNS effect for the greater reinforcing efficacy of rapid administration. They also suggest lower concentrations would be consistent with the efficacy of NRTs, i.e. the degree of change in nicotine intake would be less drastic and minimal replacement more viable. The inhaler, like the other NRTs, was designed to ‘wean’ smokers from nicotine by producing lower arterial and venous concentrations and slower rise times than cigarettes. The inhaler was to add a second and key element to the nicotine weaning, namely, to allow smokers to also ‘wean’ from the secondary reinforcers of smoking (e.g. handling and oral manipulation of the cigarette). 2. Development of the Nicotine Inhaler 2.1 Rationale: Multiple Reinforcers in Treatment

Nicotine gum (the first NRT) was shown to provide sufficient nicotine to relieve withdrawal and © Adis International Limited. All rights reserved.

Schneider et al.

improve successful outcome over placebo controls.[8] However, improper use in practice[32,33] (e.g. chewing problems leading to poor absorption and destruction of swallowed nicotine via first-pass liver metabolism) undermined its success. Consequently, a nicotine patch was developed to bypass those problems and deliver steady concentrations of the drug.[34] The patch, although much easier to use, is limited by passive administration and a very slow rise time ranging from 2 to 6 hours.[18,35,36] The patch is the antithesis of the fine ‘control’ of drug selfadministration and nicotine blood concentrations obtained by smokers with cigarettes. A nicotine nasal spray (NNS) was then devised to deliver a fixed dose of nicotine, retain the element of ad libitum self-administration and provide an even faster-acting means of delivery than nicotine gum.[37] However, success with NNS in clinical trials[38-41] has not been replicated in practice as a result of frequent, unpleasant adverse effects. A new NRT has been developed, a nicotine sublingual microtablet,[10,42] which is designed to function like nicotine gum while eliminating some of the problems with buccal administration. Thus, each therapy has its advantages and limitations. The inhaler was designed to provide nicotine in a form closer to typical intake (inhaled by mouth) and one which would address the secondary reinforcement (sensory and ritual phenomena) important to a large subset of smokers. Although nicotine is the primary reinforcer in tobacco dependence, secondary reinforcers can become ‘functionally autonomous’. Many smokers attribute withdrawal and craving and the inability to quit to such factors. An additional conditioned sensory reinforcement associated with inhalation of smoke (airway stimulation) has also been proposed to play a role in maintenance of tobacco dependence.[43] Taking these strongly conditioned phenomena into consideration, the inhaler allows weaning from both the primary reinforcement (nicotine) and secondary reinforcement (sensory/ritual) associated with smoking. The inhaler differs sufficiently from the look, feel and taste of a cigarette (as well as in rate of Clin Pharmacokinet 2001; 40 (9)

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Sharp point that breaks the seal

Air/nicotine mixture out

Cartridge Sharp point that breaks the seal

Mouthpiece

Porous plug impregnated with nicotine

Air in

Aluminium laminate sealing material

Fig. 1. Schematic of nicotine inhaler.[47]

nicotine delivery) to be used as this kind of ‘dual’ weaning treatment. 2.2 Precursors and Clinical/Approved Preparations

The oral nicotine inhaler was developed from a commercial product called ‘Favor’.[44-46] ‘Favor’ cigarettes were noncombustible nicotine ‘cigarettes’ available with and without menthol to be puffed but not lit. ‘Favor’ cigarettes were introduced as an alternative to smoking, not for smoking cessation. The US Food and Drug Administration (FDA) considered ‘Favor’ a drug delivery system requiring safety and efficacy testing and removed the product from the market. The rights for this product were then purchased by Pharmacia Corporation (Sweden) for development as a smoking cessation tool. The current and final preparation for the oral nicotine inhaler will be referred to simply as the inhaler.[47] Figure 1 shows a schematic of the final inhaler preparation. An ‘inhaler’ consists of a cartridge loaded into a plastic mouthpiece. Each cartridge contains a porous plug of nicotine 10mg and menthol 1mg. Menthol is added to decrease irritancy from nicotine. Each cartridge is sealed on both sides with foil. © Adis International Limited. All rights reserved.

Built-in spikes in the tray and/or mouthpiece are used to activate a cartridge; the user punctures both sides of foil and inserts the cartridge into the mouthpiece. With the foil seals broken, nicotine vapour is released by drawing air through the mouthpiece. A box of inhalers comes with 7 plastic trays, 6 nicotine cartridges per tray and a reusable mouthpiece yielding 42 active ‘inhalers’. The total available nicotine from a single active inhaler, at ambient room temperature, is approximately 4mg of nicotine. One puff from the inhaler provides approximately 13μg of nicotine at room temperature. Eighty to 100 puffs from the inhaler over 20 minutes had been expected to partially replace (about 30%) venous nicotine concentrations attained with 10 puffs from a cigarette smoked over 5 minutes. This was based on calculations from the microgram per puff data. However, actual nicotine extraction and resulting blood concentrations for the inhaler are both temperature- and puff-dependent (see sections 3.1.1 and 3.1.2). The vapourised nicotine from the inhaler is delivered to the oral cavity for absorption (vs alveolar absorption with cigarettes). Initially, this was inferred from low venous blood nicotine concentrations and slow rise times (see section 3.1); confirmation of site of absorption was attained directly Clin Pharmacokinet 2001; 40 (9)

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using PET techniques (section 3.1.3) and by assessment of arterial nicotine concentrations (section 3.2).

3.1 Venous Blood Nicotine Concentrations and Rise Time

Venous nicotine blood concentrations for an aerosol device were first established with testing of the original ‘Favor’ vapour cigarette.[48] In that trial, smokers puffed at exceedingly frequent intervals for 20 minutes with change to a fresh device every 5 minutes. Prior to that trial, Sepkovic et al.[49] tested the preparation and found no nicotine in the plasma or urine of 7 participants; this is probably attributable to insufficient puffing (3 puffs every 2 minutes for 6 minutes). In a trial of 24 hour ad libitum use in the Russell laboratory, Hajek et al.[50] found the ‘Favor’ cigarettes produced average blood nicotine concentrations of 6.3 μg/L, corresponding to approximately 30% of smoking concentrations at 24 hours. The slow increase of venous plasma concentrations in the Russell laboratory trials[48,50] provided indirect evidence that a major part of the nicotine ‘puffed’ was deposited in the mouth as opposed to deposition into the lungs. In an early investigation of the redesigned and current inhaler preparation,[51] strict inhalation procedures were instituted with 80 deep inhalations over a 20-minute period constituting a ‘single dose’. The mean maximum venous plasma nicotine concentrations achieved after the first single dose for the inhaler were 7.1 ± 3.5 μg/L at 20 minutes, 8.1 ± 2.5 μg/L at 30 minutes (the peak) and 8.1 ± 2.2 μg/L at 60 minutes.[51] Figure 2 shows the course of nicotine in venous blood for 3 delivery systems: a cigarette,[52] the original ‘Favor’ vapour cigarette[48] and for 3 test points for the current inhaler preparation.[51] With the inhaler, mean plasma concentrations were also obtained after 8 hours of ad libitum use (including the ‘strict puffing’ initial single dose) with resultant blood concentrations of 8.4 ± 5.9 © Adis International Limited. All rights reserved.

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3. Pharmacokinetics of Nicotine from the Inhaler

Cigarette Favor® Inhaler

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Fig. 2. Nicotine plasma concentrations achieved after 1 cigarette smoked over 5 minutes,[52] after ‘Favor’ cigarettes puffed 10 times in 6 minutes followed by rapid puffing for 20 minutes[48] and after a single nicotine inhaler puffed 80 times over 20 minutes.[51]

μg/L.[51] In an ad libitum crossover trial of inhaler vs cigarette smoking,[22] venous blood nicotine concentrations of 6.4 to 6.9 μg/L were observed for the inhaler. These concentrations were approximately 50 to 70% lower than those obtained after cigarette smoking (19.2 to 21.6 μg/L).1 3.1.1 Temperature Dependency

In addition to puff topography, the release of nicotine from the porous plug depends on the vapour pressure of nicotine which is dependent on the temperature of the air passing through the plug. In vitro and in vivo experiments[53] demonstrate the relationship between air temperature and release of nicotine. Figure 3 shows area under the concentrationtime curve (AUC) in vivo results as a function of temperature. In vitro, the average nicotine dose released to a 15L air volume, forced through the inhaler at 10°C, 22°C, 29°C and 40°C, was 1.44, 3.49, 4.80 and 6.99mg, respectively.[53] 1 Nicotine is a high clearance drug and, consistent with such drugs, actual plasma concentrations will vary widely for nicotine in all forms.

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Nicotine Inhaler

Figure 4 shows in vivo results using a crossover design; temperature dependency of the bioavailability of nicotine from the inhaler was investigated.[53] Participants inhaled deeply every 15 seconds for 20 minutes per hour over 10 hours (11 inhalers total). Inhaler use occurred in rooms at the following temperatures: 20°C, 30°C and 40°C. In between puffing sessions, participants waited in areas at ambient room temperature. Blood draws occurred hourly for the first 10 hours followed by blood draws at 10-minute intervals for the last ‘dose’. The mean peak venous plasma nicotine concentrations achieved, during the last dosage interval, were 22.5 ± 7.9 μg/L at 20°C, 29.7 ± 8.3 μg/L at 30°C and 34.0 ± 6.9 μg/L at 40°C. In summary, each inhaler, under ambient room temperature conditions, can deliver approximately 4mg of nicotine. In vivo data show temperature elevation can result in the release of more nicotine; conversely, inhaler use below 59°F (15°C) can result in reduced nicotine delivery per puff.[53] The authors concluded the inhaler, although temperature dependent, would not produce nicotine plasma concentrations exceeding those achieved with smoking even after a day’s maximal puffing in a hot climate (an important safety concern).

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use, was 3.87 ± 0.75mg (pulmonary) and 4.00 ± 0.60mg (buccal). In addition to the 2 puffing modes tested, participants were given nicotine 2mg intravenously, permitting absolute bioavailability to be estimated; the absolute bioavailability was 57 ± 16% for the pulmonary mode and 54 ± 19% for the buccal mode. Based on similar plasma concentrations, nicotine dose released and absolute bioavailability, it was concluded that the 2 modes of inhalation can produce equivalent levels. It should be noted that the concentrations reported above, 28 to 30 μg/L,[54] are related to the strict puff procedures of the trial; such elevated plasma nicotine concentrations are not anticipated with ad libitum inhaler use during smoking cessation. 3.1.3 Absorption, Deposition and Positron Emission Tomography Data

Although temperature is a factor in use of the inhaler, a key variable for blood nicotine concentrations is the site of absorption (fig. 5). The nature of absorption is essential to how the inhaler works,

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AUC Dose released

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3.1.2 Inhalation Techniques

© Adis International Limited. All rights reserved.

100

Increase (%)

Another variable potentially relevant to nicotine concentrations was inhalation technique (deep vs shallow puffing). Inhalation technique was closely supervised in a protocol requiring intense use once hourly over 12 hours.[54] Venous nicotine blood samples were collected prior to each hourly self-administered dose and up to 60 minutes after the last (12th) dose. Two inhalation techniques, 80 deep inhalations (pulmonary mode) versus 600 shallow puffs (buccal mode) over 20 minutes, were tested using a crossover design. Both inhalation techniques resulted in similar total inhalation volume, 15 L/h. Results showed the mean steady state plasma nicotine concentrations were 28.06 ± 7.9 and 30.0 ± 9.5 μg/L for the buccal and pulmonary mode, respectively. In Molander et al.,[54] the mean dose released, estimated by weighing the unit before and after

80 60 40 20 0 20˚C (68˚F)

30˚C (86˚F)

40˚C (104˚F)

Temperature

Fig. 3. Dose released in vitro and area under the concentrationtime curve (AUC) in vivo of the nicotine inhaler under varying temperatures. The percentage increase shows that the functional relationship is linear in both cases. Room temperature provides the reference for changes (reproduced from Lunell et al.,[53] with permission).

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20˚C 30˚C 40˚C

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Fig. 4. Plasma nicotine concentrations over time and as a function of temperature,[53] with (left) hourly nicotine plasma concentrations with use of the inhaler and (right) the concentrations measured at six 10-minute intervals for the last hour of inhaler use (reproduced from Lunell et al.,[53] with permission).

as the inhaler is designed to wean smokers from high nicotine concentrations achieved via alveolar absorption with smoking. Deposition of nicotine with inhaler use was demonstrated in an experiment by means of inhalers prepared with [11C]nicotine and PET imaging following 5 minutes of deep inhalations and shallow puffing from the inhaler.[55] Figure 5 (top) illustrates the deposition of nicotine in the oral cavity with inhaler use.[55] Approximately 45% of the radioactivity released was recovered in the oral cavity; 10% was deposited in the oesophagus, suggesting transfer of a considerable fraction of the dose to the stomach (the stomach was not covered by the PET camera). Only 5% of the dose was recovered in the lungs. However, given the time period since the start of inhalation, the main portion (of the 5%) could have reached the lungs via systemic circulation after absorption from the oral cavity. Radioactivity disappeared from the oral cavity with a halflife of 20 minutes; radioactivity of peripheral © Adis International Limited. All rights reserved.

muscle tissue increased correspondingly, reflecting slow absorption to the body circulation. With respect to inhalation mode, there were no differences between deep inhalations and shallow puffing.[55] In another crossover comparison, PET was used to compare deep inhalation from the inhaler with inhalation from a cigarette prepared with [11C]nicotine.[31] As may be seen in the cross-sectional image of the chest at coronary level [fig. 5 (bottom left)], there is no apparent deposition in the lungs after deep inhalations from the inhaler. Deposition is mainly restricted to the trachea and 2 main bronchi. Note the radioactivity in the oesophagus demonstrates nicotine being swallowed following use of the inhaler. By contrast, the cigarette yielded a significant pulmonary deposition of radioactivity in the lungs [fig. 5 (bottom right)], with only minor amounts appearing in the upper airways, oesophagus and stomach.[31] The authors concluded that the most plausible explanation for the large deposition of nicotine vapour in the upper airways is its high Clin Pharmacokinet 2001; 40 (9)

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water solubility in combination with the absence of the carbon particles and droplets that carry nicotine to the lungs in cigarette smoke. 3.2 Arterio-Venous Blood Nicotine Concentrations

The high arterial nicotine concentrations associated with smoking[4,20,28,29] are not believed to occur with the inhaler because of the differing routes of absorption. In a recent study by Lunell et al.,[30] intravascular catheterisation was used to compare nicotine plasma concentration-time profiles in arterial blood (brachial artery) with blood from the jugular vein, the main vein that drains the

oral cavity. The aim was to determine the main sites of nicotine absorption after use of the inhaler and after smoking a cigarette. Figure 6 shows the course of arterial and venous blood nicotine for both. As seen in figure 6, after use of the inhaler, arterial nicotine concentrations rose slowly to a mean maximum value (Cmax) of 5.8 ± 1.5 μg/L at a time to reach peak concentration (tmax) of approximately 10 minutes; mean jugular venous nicotine concentrations for the inhaler peaked at 24.1 ± 6.0 μg/L at approximately 7 minutes after start of inhalation. This arterio-venous difference indicates slow absorption from the inhaler, to a major extent from the oral cavity, without the arterial spike

Deposition of [C11] nicotine in the lung

Vapour inhaler

Cigarette

Fig. 5. (top) Positron emission tomography (PET) image of the deposition of [11C]nicotine in the oral cavity after the pulmonary mode of inhalation. Sagittal slice with the mouth and nose to the left. High uptake is observed in the oral mucosa and diminishes rapidly toward the larynx.[55] The lower images are the cross-sectional tomographic view of the chest at heart level obtained after inhalation of [11C]nicotine, average of the first 15 minutes.[31] The radioactivity distribution after inhalation from the vapour inhaler ( bottom left) and after smoking a cigarette (bottom right). With the vapour inhaler only deposition in the large bronchi and oesophagus (red/yellow colour) can be identified, whereas with the cigarette a uniform distribution over the lungs is seen (blue colour) [produced from Bergström et al.[55] and Lunell et al.,[31] with permission].

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Inhaler: venous (jugular) Inhaler: arterial (brachial) Cigarette: venous (jugular) Cigarette: arterial (brachial)

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Concentration (µg/L)

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Fig. 6. Mean arterial (brachial) and venous (jugular) nicotine concentrations for a cigarette smoked over 5 minutes and for a nicotine inhaler used over 5 minutes (n = 7).[30] Note that the arteriovenous difference is reversed for the inhaler relative to the cigarette (reproduced from Lunell et al.,[30] with permission).

typical of cigarette smoking. Cigarette arterial nicotine plasma concentrations rose quickly to a Cmax of 38.9 ± 4.7 μg/L at a tmax of 5 minutes after the start of smoking, indicating rapid absorption of nicotine from the cigarette. Mean nicotine Cmax in the jugular vein for the cigarette was 21.6 ± 3.5 μg/L at 7 minutes after the start of smoking, i.e. similar to that of the inhaler. The relatively high Cmax in the jugular vein reflects the generally high systemic venous Cmax achieved after smoking a cigarette. The above findings are largely in agreement with previous research[4,28] and a recent study by Rose et al.[20] For example, for cigarette smoking, Gourlay and Benowitz[4] reported 2 to 3 (median) times higher arterial vs venous plasma nicotine concentrations at the time of arterial Cmax after smoking. Gourlay and Benowitz[4] also tested the NNS. The transnasal nicotine results also differed from the inhaler concentrations described above.[30] The tmax for the NNS was reached quickly: after 5 minutes in arterial versus 18 minutes in venous plasma. The median arterio-venous concentration ratio at the time of arterial Cmax was 4.6. A second study by © Adis International Limited. All rights reserved.

Guthrie et al.,[56] using NNS at doses of 1 to 2.5mg, showed arterio-venous differences in agreement with the Gourlay and Benowitz[4] study. The disparity between arterial tmax for nasal spray and inhaler may be due to the following differences in nasal and oral cavity absorption described by Lunell et al.:[30] ‘from the nasal spray, nicotine is absorbed through a loose epithelium into a rich submucosal venous plexus, while from the inhaler the absorption is through a tighter, squamous epithelium and less vascularised mucosa.’ The findings suggest differing pharmacokinetic profiles of NNS and the inhaler due to the sites of absorption. One caveat to these observations is that the experimental design differed between the 2 studies. Gourlay and Benowitz[4] measured plasma nicotine concentrations in peripheral venous blood, that is, after passage through the systemic circulation. As they point out: ‘after a single dose, tissues extract substantial amounts of drug with each passage of arterial blood reducing the amount reaching venous plasma’. Considerable arterio-venous differences in drug concentration may result. Lunell et al.[30] measured drug concentration in the jugular vein that drains the site of absorption, the oral cavity, before any dilution in the superior vena cava occurred, resulting in high regional venous nicotine concentrations after use of the inhaler. Another possible explanation could be the difference in intensity of administration, as NNS is administered in one concentrated dose of nicotine 1mg whereas the inhaler was used over a 5-minute period. That is, the entire dose of the NNS is applied instantaneously on the well-vascularised nasal mucosa. However, Lunell et al.[30] claim not to have seen any steep rise in venous nicotine with an oral spray applied instantaneously in the mouth or with a nicotine sublingual microtablet chewed quickly and the content kept in the mouth. The most probable explanation is that there may be effects due to differences in both the site of absorption and period of absorption. Clin Pharmacokinet 2001; 40 (9)

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4. Comparative Pharmacokinetics Among Nicotine Systems 4.1 Venous Nicotine Concentrations – Single Dose

Plasma nicotine (µg/L)

Figure 7 shows the available comparative data on rise time and course of venous nicotine concentrations for a cigarette versus other NRT delivery systems. The data are for single administration of the first dose of the drug after overnight abstinence (for the inhaler, single administration is equal to approximately 80 to 100 puffs). We have included patch data although those data cover a full treatment course of 16 and 24 hours. The inhaler and all ‘acute’ NRT systems are self-titrated and fasteracting by design.

30

25

In figure 7, peak venous concentrations for the inhaler are similar to NNS and 2mg gum; the cigarette and 4mg gum are higher.[14,18,51,52,57,58] Inhaler concentrations are approximately one-third of those produced by smoking. tmax for the inhaler is delayed in contrast to a cigarette and nasal spray. tmax values are consistent with administration times. For example, a cigarette is smoked in a 5minute period, nasal spray administration occurs within seconds, nicotine gum is chewed for 20 to 30 minutes and the inhaler puffed for 20 to 30 minutes. The data in figure 7 were gathered under vastly different conditions and over decades; however, no equivalent newer data have been reported. The variability with a high clearance drug must also be considered (see footnote in section 3.1).

20

16h 24h

15

Cigarette[52] NNS[14,57] Gum 2mg[52] Gum 4mg[58] Inhaler[51] Patch[18]

10 5 0 0

4

8

12

16

20

24

Time (h) Plasma nicotine (µg/L)

20

15

10

5

0 0

10

20

30

40

50

60

Time (min)

Fig. 7. Venous plasma nicotine concentrations for a single cigarette[52] and single doses of the following ‘acute’ nicotine delivery systems: nicotine nasal spray (NNS),[14,57] nicotine 2mg gum,[52] nicotine 4mg gum[58] and nicotine inhaler.[51] The course of the first hour of transdermal administration is also represented.[18] There are only 3 time-points for the inhaler preparation. Intake time varies with the cigarette smoked over 5 minutes, gum chewed over 30 minutes, inhaler used over 20 minutes (80 puffs). (insert) The course of 2 nicotine patches (16 and 24 hours) represented in hours over a 24-hour period.[18]

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Schneider et al.

Table I. Use profiles for cigarettes and nicotine treatments Device

Unit

Typical recommended use per day

Observed use per day

Typical plasma concentrations (μg/L) trough

peak

Cigarette

Each (8mg)

0

15-25[1]

10-37[21-23,27,61,67,70]

19-50[23,24,52,61,62,66,70,71]

Inhaler

Cartridge (10mg)

6-16[69]

2-10[12,60,63,72,73]

2-12[22,54]

15-38[69]

Gum

Piece (2mg)

9-24a[69]

6-13[12,60,65,70,71]

4-15[21,42,52,66,67,70,71]

10-16[43]

Piece (4mg)

9-24a[69]

4-12[66]

7-34[21,23,66,67]

9-43[23]

[69]

[12,39-41,60,74]

[14,27,40,64,69]

Nasal spray

2 sprays (1mg)

8-40

4-36

3-20

6-14[14,69]

Sublingual tablet

Each (2mg)

8-12/16-24b[42]

7-30[10,11,42,60]

8-15[42]

10-16[42]

Transdermal

21mg/24h (114mg)

1[68]

1

13-21[68]

18-28[68]

15mg/16h (24.9mg)

[68]

[27,68]

1

1

6-13

10-18[61]

22mg/24h (30mg)

1[68]

1

8-14[68]

10-22[68]

a

2mg is recommended for those smoking 20 cigarettes/day.

There is clearly a need for systematic testing of all medications within one laboratory for a true comparison. The data in figure 7 (and fig. 3) should be considered illustrative of the venous blood concentrations of the medications and the rationale for the development of NRT products (namely, lower levels for the ‘acute’ NRTs vs cigarettes). The reported ‘boost’ of nicotine for a subsequent cigarette, after an initial cigarette, has been reported to be only 10 to 15 μg/L in 1 trial.[59] After hourly inhaler use, the mean ‘boost’ of nicotine for 20 minutes of subsequent inhaler use was small: 1.9 μg/L at 20°C, 3.4 μg/L at 30°C and 3.3 μg/L at 40°C; results were calculated from the data in figure 4.[53] 4.2 Venous Nicotine Concentrations – Ad Libitum Use

The differences among NRTs in pharmacokinetics may affect efficacy differences among treatments and decisions for matching smokers to a treatment. Table I profiles the differences in ad libitum or repeated use of different nicotine delivery systems.[12,21-24,27,39-42,54,60-74] The values represent a range of minimum and maximum values of intervals derived from the means ± 1 standard deviation from multiple studies. Note that cigarettes are highly effective in terms of speed of nicotine delivery but not particularly efficient in terms of total nicotine delivery. © Adis International Limited. All rights reserved.

With an ‘acute’ system, at least half a dozen uses per day are recommended; however, usage below this threshold is often observed. With typical ad libitum use, nicotine blood concentrations equivalent to smoking values are rarely achieved, neither in terms of peak nor steady-state values. The transdermal systems only provide about one-third to half of the nicotine commonly obtained via smoking. The ‘acute’ systems provide amounts of nicotine similar to patches when used ad libitum, although users of 4mg nicotine gum have more frequently approached 100% replacement of venous concentrations.[66,67] The table allows for an overview of differences among NRTs although it should be kept in mind the findings are from various independent trials. Nicotine concentrations also vary as a function of other factors, for example, individual differences in intake, time-point of blood sampling, pharmacokinetics and metabolism. In general, it is not yet known how these differences affect outcome. 5. Clinical Findings 5.1 Efficacy Data

The inhaler was first tested as a cessation aid in a nonblind study in Sweden in 1988/1989, with encouraging results [Agneta Hjalmarson (Sahlgrenska University Hospital, Sweden), personal communication]. Eighty percent continuous abstinence was reported at 3 weeks with biochemical validaClin Pharmacokinet 2001; 40 (9)

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tion. In the next stage of development, 3 large placebo-controlled trials were completed. In those trials, the manufacturer assumed a large portion of the absorption of nicotine to be pulmonary; hence, use of the inhaler was restricted to 2 to 10 inhalers/day for safety purposes. The restriction of use resulted in reduced self-administration of the medication in the 2 US trials – one unpublished study reported in Leischow[45] in which Leischow was a co-investigator and the other by Glover et al.[46] In the third trial in Denmark, Tønnesen et al.[73] reported significant results (active over placebo) at all assessment points to 1 year. For the active group, this was associated with a higher use rate (mean = 5.3 inhalers/day) by successful participants. In Tønnesen et al.[73] and Glover et al.,[46] the success rate at 6 weeks was significantly correlated with number of inhalers/day. Lack of sufficient use was the rationale for setting a dosage level of at least 4 inhalers per day for the next series of trials. Subsequently, 3 additional clinical trials (2 in the US, 1 in Europe) were undertaken. In the US trials, maximum use was increased from 10 to 20 inhalers/day,[72,75] with no maximum usage specified in the European trial.[63] A comparison of the demographics for the 4 published placebo-controlled trials appears in table II.

Nearly 1000 participants have been followed. The majority of participants were ≥1 pack/day smokers. In all trials, participants were allowed ad libitum use of the inhalers for 3 months. After 1 week, participants averaged 5 to 10 inhalers/day. Consumption was slightly lower by 6 weeks. If necessary, those still using inhalers at the end of 3 months underwent an enforced tapering over the next 3 months. Tapering consisted of slow reduction by 25% each month with no further medication dispensed after 6 months. Less than 10% of participants given the active inhaler were still using the product (average 1 to 2 inhalers) at the dispensing limit. Figure 8 shows the efficacy results across these trials. For all studies, efficacy was defined by selfreported abstinence and confirmed by carbon monoxide testing. In Schneider et al.,[72] results were based on criteria of strict abstinence from day 1 of treatment and carbon monoxide (CO) levels ≤8 ppm. In the other 3 trials, a grace period of early ‘slipping’ (occasional cigarette use in the first 2 weeks) was allowed with CO levels ≤10 ppm. The effect of the difference in abstinence criteria can be seen in figure 8. Within 3 weeks in Schneider et al.,[72]