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PHARMACOKINETICS |
From Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan, Inc, Tokyo, Japan (Dr Sobue, Dr Sekiguchi, Dr Kikkawa) and Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan (Dr Irie).
Address for reprints: Satoshi Sobue, Department of Clinical Pharmacology, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc, Shinjuku Bunka Quint Bldg. 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan; e-mail: Satoshi.Sobue{at}pfizer.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Nicotine • transdermal • pharmacokinetics • application site • multiple dose
Nicotine, as a low-molecular weight substance with good lipid and aqueous solubility, can be absorbed from skin. The nicotine pharmacokinetic profiles after application of transdermal patches indicate the observation of 3 distinct phases: time-lag phase, which covers the period until the attainment of therapeutic concentrations; plateau phase, which has a fairly steady plasma level; and declining phase, which follows the removal of patches.8 No significant differences in the nicotine pharmacokinetics have been observed when nicotine was applied to different sites of the body.8,10,11 The percutaneous absorption, however, has been reported to vary with the application sites in addition to the variation in the physicochemical properties of drugs and chemicals.12-14 We investigated the regional variations in percutaneous absorption of nicotine when TNP was applied to 3 different skin sites (upper arm, abdomen, and back) in study 1. The pharmacokinetics and safety of nicotine during once-daily application of TNP for 5 days were also investigated in study 2.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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84 mm Hg and a pulse rate of 50 to 99 bpm, and have smoked 
15 cigarettes a day constantly for at least 1 year. Volunteers were excluded if evidence of cardiovascular disease or history of drug allergies, drug abuse, or alcohol dependence was observed at screening. In addition, volunteers were excluded if they had received any treatment or donated blood within the 2 months prior to the start of the study. The subjects had to abstain from smoking during their stay at the clinic. Subjects with an expired air carbon monoxide level above 10 ppm before each dose were excluded. These studies were conducted at the Medical Co. LTA, Kyushu Clinical Pharmacology Research Clinic (Fukuoka, Japan), in compliance with good clinical practice and the Declaration of Helsinki. The Institutional Review Board of the Medical Co. LTA provided formal approval for the studies.
Study Design
Study 1 was a single-dose, 3-period, crossover study to investigate the effect of application sites on the percutaneous nicotine absorption. Three subjects each were randomly assigned to 1 of the following 3 treatment sequences: (1) upper arm 
abdomen back, (2) abdomen back upper arm, and (3) back upper arm abdomen. The back means the lumbar portion above the waistband. Each subject received a TNP (Nicorette patch, Pfizer Health AB, Helsingborg, Sweden) for 16 hours at each treatment period with a 1-week washout between treatments. The subjects stayed at the clinic from 36 hours before application to 8 hours after completion of application in each treatment period.
Study 2 was an open, multiple-dose study in 10 subjects. A new TNP was applied to a fresh site of the upper arm for 16 hours each day for 5 days. The subjects stayed at the clinic from 36 hours before the first application to 20 hours after completion of the final application.
The patch was applied approximately at 8:00 AM and removed at 0:00 AM. Standardized breakfast, lunch, and dinner were provided approximately at 7:30 AM, 0:30 PM, and 6:30 PM, respectively. Consumption of alcohol, caffeine-containing beverages, and grapefruit-containing products was prohibited throughout the stay at the clinic.
Pharmacokinetic Sampling
For the assay of nicotine, blood samples (7 mL) were collected immediately before application (predose) and at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 17, 20, 23, and 24 hours after each application in study 1. In study 2, blood samples were collected predose and at 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 17, 20, 23, and 24 hours after applications on day 1 and day 5, as well as predose and at 6, 8, and 10 hours after applications on day 3 and day 4. Samples were centrifuged (4°C, 3000 rpm, 10 minutes), and the plasma was stored at -20°C.
Subjects emptied their bladders immediately prior to each application in study 1 and prior to the application on day 1 in study 2. A 20-mL aliquot of this sample was retained for pharmacokinetic analysis. Urine collections were then made from 0 to 4, 4 to 8, 8 to 16, and 16 to 24 hours following the start of each application in study 1 and following the start of the applications on day 1 and day 5 in study 2. Samples within a collection period were well mixed, their volumes were measured, and a 20-mL aliquot was stored at -20°C for nicotine assay.
Drug Assay
Plasma and urine samples were analyzed for nicotine using a modification of the validated high-performance liquid chromatographic (HPLC) method of Pacifici et al.15 Nicotine and internal standard (IS), N-ethylnorcotinine, were extracted from plasma and urine samples using solid-phase extraction cartridges (Bond Elut C2, Varian, Harbor City, Calif), which were initially preconditioned by 2 mL of methanol and 2 mL of 30 mM K2HPO4.
A 1.0-mL aliquot of plasma sample spiked with IS was loaded on the conditioned cartridge and washed with 1 mL of 30 mM K2HPO4, 3 mL of water, and 1 mL of 2% acetonitrile. The analytes were eluted with 0.5 mL of methanol, and 20 µL of 0.1 M HCl was added to the eluate. The resulting acid solution was evaporated to dryness under a stream of nitrogen, reconstituted with 200 µL of mobile phase, and then centrifuged at 12 000 rpm for 10 minutes to remove any precipitation. Then, 100 µL of the supernatant was injected onto the HPLC system.
A 0.5-mL aliquot of a urine sample spiked with 0.5 mL of 100 mM K2HPO4 and IS was loaded on the conditioned cartridge and washed with 1 mL of 4% acetonitrile in 30 mM K2HPO4, 1 mL of 2% acetonitrile in 30 mM K2HPO4, and 1 mL of 2% acetonitrile. Following elution with methanol, acidification with 0.1 M HCl, evaporation to dryness, reconstitution with mobile phase, and centrifugation, 100 µL of yielded extract was injected onto the HPLC system.
Residual content of nicotine in recovered patches was analyzed using a modification of the HPLC method of Kochak et al.16 In brief, the nicotine in each patch sample was extracted by shaking in a flask containing 50 mL of n-heptane and then mixed with 100 mL of 25 mM HCl for back-extraction. The HCl phase obtained was diluted and mixed with IS (ethyl p-aminobenzoate) solution and then filtered to remove insoluble materials. Then, 25 µL of the sample was injected onto the HPLC system.
Chromatography was performed at ambient temperature on an Inertsil ODS3 column (5 µm, 150 x 4.6 mm, GL Science, Tokyo, Japan) at a flow rate of 1.0 mL/min. The mobile phase consisted of 30 mM citric acid monohydrate-K2HPO4 buffer (pH 6.0)/acetonitrile (90:10, v/v), which contained 100 mM sodium heptane sulfonate for plasma and urine samples, as well as 0.25 M sodium dodecyl sulfate solution/1M sodium acetate solution/water/acetonitrile (8:10:612:370, v/v) for patch samples. The analytes were monitored by UV detection with 256 nm for plasma and urine samples and 254 nm for patch samples.
During analysis, calibration standards demonstrated acceptable linearity (r2 > 0.99). The accuracy of the method was demonstrated by comparing the measured concentration of the calibration standards and quality control samples with their theoretical values to be <20%, expressed as a percentage of deviation from theoretical values. The intra- and interassay precisions were 12%, expressed as a percentage coefficient of variation. The lower limit of quantification for the assay was 1 ng/mL for plasma and 25 ng/mL for urine, respectively.
Pharmacokinetic Analysis
The pharmacokinetic analysis of nicotine concentrations was performed by noncompartmental methods using the computer program WinNonlin Professional (version 3.1). The concentrations below the lower limit of quantification were treated as missing. The maximum observed plasma concentration (Cmax), the first time to Cmax (tmax), and the concentration at 24 hours after application (C24) were taken directly from the recorded plasma concentration-time data. The apparent terminal phase half-life (t1/2) was calculated as ln2/kel, where kel was the terminal phase rate constant, which was estimated by linear regression of the log concentration versus time profile. The area under the plasma concentration-time curve from time 0 to infinity (AUC) was calculated as AUCt +(Ct/kel), where Ct was the concentration at the last measurable time (t), and AUCt was the area under the plasma concentration-time curve from time 0 to the time (t) by the linear trapezoidal method. The amount of nicotine delivered from each patch (dose) was determined from the labeled content and residual content in each recovered patch. The transdermal clearance (CL/F) was calculated as dose/AUC, where AUC24 was substituted for AUC on day 5 in study 2. Dose-normalized Cmax, AUC, and AUC24 were also calculated by dividing by dose. The percentage of the dose excreted in the urine up to 24 hours after application [Ae24 (%)] was calculated as 
(concentration x volume)/dose, where summation () was over the urine collection intervals.
Safety Assessments
The investigator recorded all observed or volunteered adverse events. Application sites were examined for local irritation predose of each patch and immediately and at 1 hour (on days 1 and 5 in study 2) and 8 hours (in study 1 and on day 5 in study 2) after each patch removal in both studies. Laboratory safety tests, including urinalysis, hematology, clinical chemistry (total protein, albumin, albumin/globulin ratio, total bilirubin, blood urea nitrogen, serum creatinine, uric acid, Na+, K+, Cl-, total cholesterol, triglyceride, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, leucine aminopeptidase, lactate dehydrogenase, 
-glutamyltranspeptidase), blood pressure, pulse rate, respiration rate, body temperature, and 12-lead electrocardiogram (ECG) measurements, were performed at screening, throughout the stay at the clinic, and at follow-up (7 days after final dosing).
Statistical Analyses
In study 1, AUC, Cmax, dose, and CL/F were subjected to an analysis of variance (ANOVA) for crossover study design, which allowed for variation due to sequence, subject, application site, and period. Prior to analysis, AUC and Cmax were log transformed according to US Food and Drug Administration guidance.17 For AUC and Cmax, the ratio of the antilogged treatment means and the corresponding antilogged 90% confidence interval (CI) were determined and expressed as a percentage of the mean value for upper arm. In study 2, log-transformed AUC24, log-transformed Cmax, log-transformed AUC (day 1, AUC; day 5, AUC24), dose, and CL/F were assessed for significant differences between day 1 and day 5 using the paired t test. Dose-normalized AUC, Cmax, and AUC24 were also subjected to the same statistical analyses.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacokinetics
Mean plasma concentration profiles and pharmacokinetic parameters of nicotine are shown in Figure 1 and Table I for study 1 and in Figure 2 and Table II for study 2.
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Study 1
Mean plasma concentrations of nicotine increased gradually and reached a broad peak at 8 to 10 hours after TNP application to any body site (Figure 1). After removal of patch, the plasma concentrations exhibited a transient maintenance, which dissipated within 1 hour and then declined with a mean t1/2 of approximately 4 to 5 hours. The plasma concentrations after application to the upper arm were similar to those to the back but higher compared with the abdomen. The results of ANOVA for AUC, Cmax, and CL/F showed the statistically significant effects of application sites (P < .01). The ratios (90% CIs) of AUC and Cmax for comparison to the upper arm were 102% (88, 117%) and 106% (95, 119%) for the back and 75% (65, 87%) and 75% (66, 84%) for the abdomen (Table I). These suggest that systemic exposure of nicotine after application to the upper arm was greater compared with the abdomen but equivalent to the back. There was no statistically significant effect of application sites on dose (P = .09). Similar results were obtained when AUC and Cmax were dose normalized. There was comparatively high intersubject variability in pharmacokinetic parameters, and no significant difference was observed in tmax, t1/2, and Ae24 among the 3 application sites.
Study 2
Mean plasma concentration profiles of nicotine following multiple doses of TNP were similar across days 1, 3, 4, and 5, and a mean Cmax of approximately 11 to 13 ng/mL was achieved at 8 to 10 hours after application (Figure 2). The mean t1/2 values were approximately 4 hours on both day 1 and day 5 (Table II). No statistically significant differences between day 1 and day 5 were observed for AUC24, Cmax, AUC (day 1, AUC; day 5, AUC24), and CL/F (P = .13, P = .15, P = .94, and P = .24, respectively). These suggest no significant accumulation and the linear pharmacokinetics of nicotine following multiple doses. Mean values of dose were almost similar among days 1 to 5 (range, 14.25-16.29 mg). However, there was a statistically significant difference in dose between day 1 and day 5 (P < .01). Statistically significant differences were observed in dose-normalized AUC24 and Cmax (P < .05) but not observed in dose-normalized AUC (P = .13). Mean C24 values on days 1 to 5 were almost the same (range, 2.32-2.52 ng/mL), suggesting that steady-state conditions were rapidly reached (as early as day 2) using this dosage regimen. Only a minor amount of nicotine was excreted in the urine on both day 1 and day 5 (5% of the dose).
Safety
There were no serious adverse events in both studies. Two subjects reported mild itching at the application sites on day 5 in study 2. These symptoms disappeared within 1.5 and 1.75 hours, respectively, and were considered to be probably related to the treatment. In study 1, mild erythema was observed in 3, 7, and 3 subjects immediately after completion of the application to the upper arm, abdomen, and back, respectively. In study 2, mild erythema appeared on the application sites of 4 subjects immediately after patch removal (2 subjects on days 1, 3, 4 and 5 and 3 subjects on day 2).
No changes were considered to be treatment related, and there were no abnormal changes of clinical concern in blood pressure, pulse rate, respiration rate, body temperature, 12-lead ECG, and laboratory safety tests. There was no application site effect on blood pressure and pulse rate in study 1. There was a slight trend toward an increase in systolic blood pressure and pulse rate with the repeating dose in study 2, but these were considered not clinically significant.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Regarding the skin blood flow, some reports have demonstrated that the plasma concentrations of transdermally delivered nicotine are increased during physical exercise or heat exposure in a sauna bath.18-20 This increase was considered to be related to an increase in blood flow at the application site. Coadministration of intravenous nicotine decreased the transdermal absorption of nicotine, and this resulted from a lowered cutaneous blood flow by nicotine itself.21 Tsuchida22 has reported a tendency for the skin blood flow to decrease gradually from the upper body to the lower body. Park et al23 have demonstrated that blood flow measurements were 6.6, 6.7, 7.1, 6.3, 5.3, 4.8, and 4.6 perfusion units for the upper arm, forearm, thorax, flank, abdomen, thigh, and lower leg, respectively. These results suggest that lower skin blood flow at the abdomen site may be ascribed as one cause of lower nicotine exposure after TNP application to the abdomen compared with the upper arm and back.
With respect to the SC lipid content, the sequestration of lipids to intercellular domains and their organization into a unique multilamellar system of the SC have broad implications for the permeability barrier function, water retention, and percutaneous drug delivery.24 Tsai et al25 have investigated the regional variations in drug transport into human SC of 4-cyanophenol and cimetidine. The rank order of regional variation in permeability coefficients was similar for both drugs and decreased in the order of back > forearm > thigh > leg abdomen. This variation was influenced by variation in the SC lipid content among different body sites. Elias et al26 correlated the lipid composition of leg versus abdominal SC samples with the penetration of water and salicylic acid and concluded that total lipid concentration may be the critical factor governing skin permeability. Schwindt et al27 have also demonstrated that the diffusion coefficient of water was significantly lower for the abdomen compared with the back, forearm, and thigh and suggested that intercellular lipids are a rate-determining component of the SC barrier. These data agree well with our results and suggest that the lower permeability at the abdomen site is caused by lower SC lipid content. In addition, it has also been reported that skin hydration is capable of increasing skin permeability.28,29 A measure of capacitance as a parameter of SC hydration has shown a higher state of hydration on the upper back, lower back, and upper arm compared with the abdomen.30 Based on these data, it is considered that the regional differences in the lipid content and hydration of SC may influence the lower skin permeability and percutaneous absorption after TNP application to the abdomen.
On the other hand, Urae et al31 have reported that AUC and Cmax of nicotine were equivalent after a single application of other nicotine patches to the upper arm, back, and abdomen. The rate of skin permeability is proportional to the drug concentration in the vehicle. The rate of nicotine release from the nicotine patches into the skin is controlled not only by the skin permeability but also by the rate of diffusion through a polymer matrix and/or the rate of passage through a membrane. The total content and concentration of nicotine, as well as the system, duration, and rate of nicotine delivery, vary between TNP and the patch used by Urae et al.31 Their patch contains 35 mg nicotine per 20 cm2 drug dispersion-type transdermal delivery system, where nicotine is dispersed in a copolymer solution, is designed to deliver approximately 14 mg nicotine for 24 hours of application, and releases nicotine in a biphasic pattern in vitro with a much higher flux rate compared with TNP.8 The TNP is a polymer-matrix drug dispersion-type transdermal delivery system in which the nicotine is dispersed in an adhesive and produces a monophasic release pattern with a substantially lower flux rate in vitro.8 These differences may affect the skin permeability rate of nicotine and cause the different effect of application sites on the nicotine percutaneous absorption.
In study 2, although there were statistically significant differences in dose, dose-normalized AUC24, and dose-normalized Cmax between day 1 and day 5, the plasma concentration profiles and dose were similar across days 1 to 5 and showed no tendency to change with repeating dose. The pharmacokinetic parameters were similar between day 1 and day 5. These indicate no significant accumulation of nicotine concentrations after multiple applications of TNP. Only slight or almost no accumulation of nicotine has also been reported for other nicotine patches after multiple applications.4,32-37 Mean t1/2 values of nicotine after application were approximately 4 to 5 hours, which coincides with no significant accumulation and the attainment of steady state by day 2. These t1/2 values were greater than the 2 to 2.5 hours found after intravenous administration.3,4,21 This could be caused by the nicotine input rate and prolonged absorption from a skin compartment. Plasma nicotine concentrations were maintained during application, and TNP is considered to be suitable for use once daily. After removal of the patch, plasma concentrations exhibited a transient maintenance. This is attributed to a disturbance of the nicotine dermal depot caused by the mechanical distortion of the skin when the patch was removed.16
Comparatively high intersubject variability was observed in nicotine pharmacokinetics. Prather et al38 have reported that nicotine AUC was strongly correlated to body weight and body mass index when another nicotine patch was applied to normal-size men, obese men, and women. However, body weight or body mass index is unlikely to be a major source of the intersubject variability in our studies because only normal-size subjects were enrolled. One of the possible reasons for intersubject variability is the polymorphism in metabolic enzymes (eg, CYP2A6).3
Varying results from previous studies comparing nicotine clearance in men and women have been reported.3 Prather et al38 have also reported that women eliminated nicotine significantly more quickly than men, but there were no significant differences between these groups in mean nicotine concentrations, AUC, Cmax, or tmax. There is no significant difference in blood flow measurements between men and women.23 The SC hydration parameter does not vary significantly between sex groups.30 These results suggest that similarities to our studies' results will be expected when these studies are conducted in women.
In conclusion, there was a statistically significant effect of application sites on percutaneous nicotine absorption after TNP application, and systemic exposure after application to the upper arm was greater compared with the abdomen but equivalent to the back. The most probable explanation for this finding is the regional variation of the skin permeability of nicotine caused by the skin blood flow, lipid content and hydration of SC, and so on. Given comparatively high intersubject variability in nicotine pharmacokinetics, the clinical importance of 25% lower bioavailability is uncertain. Following multiple doses, linear pharmacokinetics and no significant accumulation of nicotine concentrations were observed, and the steady-state conditions were rapidly reached (as early as day 2).
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REFERENCES |
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