Multiple dose pharmacokinetics of caffeine administered in chewing gum to normal healthy volunteers

BIOPHARMACEUTICS & DRUG DISPOSITIONBiopharm. Drug Dispos. 26: 403–409 (2005)Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdd.469 Multiple Dose Pharmacokinetics of Caffeine Administeredin Chewing Gum to Normal Healthy Volunteers Shariq A. Syeda, Gary H. Kamimorib, William Kellyb and Natalie D. Eddingtona,*a Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy,University of Maryland at Baltimore, AHB 540A, 100 Penn Street, Baltimore, MD 21201, USAb Department of Neurobiology and Behavior, Walter Reed Army Institute of Research, 503 Robert Grant Road, 2W 97 Silver Spring,MD 20910-7500, USA ABSTRACT: The purpose of this study was to examine the pharmacokinetics of three doses ofcaffeine administered as Stay Alert1 chewing gum in a multiple dose regimen.
Methods: A double-blind, parallel randomized, four-treatment study design was employed. The treatment groups were: 50, 100 and 200 mg caffeine and placebo. Subjects were 48 (n ¼ 12 pergroup), healthy, non-smoking, males and females who had abstained from caffeine ingestion for atleast 20 h prior to dosing, who were randomly assigned to the treatment groups. Caffeine wasadministered at 2400, 0200 and 0400 h depending on the treatment group. Blood samples werecollected pre-dose and at 5, 15, 30, 45, 60, 75, 90 and 105 min after each caffeine dose. Samples werealso collected at 7.5, 8.5 and 18 h after the last dose of caffeine. Plasma caffeine levels were analysedby a validated UV-HPLC method.
Result: The mean Tmax after the third dosing ranged from 0.37 to 1.12 h. Cmax for 50, 100 and 200 mg was 2.69, 3.45 and 6.33 mg/l, respectively. AUCinf for 50, 100 and 200 mg group was 33.2,46.94 and 86:94 mg=l à h, respectively. AUCinf values suggested a dose proportionate increase. Dosenormalized Cmax and AUC0Àt values across doses were not significantly different, suggestinglinearity was maintained after multiple doses of the Stay Alert1 chewing gum. There were no grouprelated differences in elimination.
Conclusions: The results suggest that caffeine administered in the gum formulation (Stay Alert1 chewing gum) via a multiple dosing regimen provides an effective and convenient means ofmaintaining effective concentrations of caffeine that would in some operational scenariosbe desirable for maintaining alertness and performance in sleep deprived individuals. Copyright# 2005 John Wiley & Sons, Ltd.
Key words: caffeine chewing gum; caffeine multiple dose; pharmacokinetics; buccal absorption is a commonly used stimulant, known to alle-viate the effects of sleep deprivation and fatigue.
Sleep loss and fatigue are associated with The pharmacodynamics and pharmacokinetics of degraded physical performance, cognitive im- caffeine have been well characterized [3]. It is pairment and disturbance of mood [1,2]. Caffeine rapidly absorbed after oral dosing, and exten-sively metabolized by the liver (99%) to formthree major metabolites 3,7-dimethylxanthine, *Correspondence to: Department of Pharmacokinetics-Biophar- 1,7-dimethylxanthine and 1,3-dimethylxanthine.
maceutics Laboratory, Department of Pharmaceutical Sciences, At typical dose levels (e.g. 1 cup of coffee/ School of Pharmacy, University of Maryland at Baltimore, AHB 70–100 mg), caffeine exhibits dose-independent 540A, 100 Penn Street, Baltimore, MD 21201, USA.
E-mail: [email protected] or linear pharmacokinetics [3]. However, at Copyright # 2005 John Wiley & Sons, Ltd.
higher doses (e.g. 250–500 mg single dose), the who habitually consumed less than 300 mg of clearance of caffeine is significantly reduced and caffeine per day volunteered for this study.
its elimination half-life is prolonged, indicating Females were not using nor had used any form of hormonal contraceptives in the 3 months prior Caffeine has also been used to counteract the to the study (such contraceptives are known to effects of sleep deprivation. Penetar et al. [4] modify the metabolism of caffeine [10]). After showed that caffeine is effective for reversing signing an informed consent, the health status of performance, alertness and mood deficits pro- the subjects was determined on the basis of duced by prolonged sleep deprivation. Other medical history, physical examination and rou- studies have demonstrated that the pharmaco- tine laboratory tests. The study was conducted at dynamic properties of caffeine are dose depen- the Walter Reed Army Institute of Research dent [1]. Over the past few years, there has been (WRAIR) and the protocol for the study was increased interest in the pharmacodynamic ef- fects of caffeine during sleep deprivation, reflect- Review Board of the Office of the Surgeon ing concerns surrounding the ubiquitous and pervasive problem of sleep loss in military andother operational environments. Thus, studies have been conducted to compare various caffeinedoses and modes of delivery (capsule, oral Subjects were randomly assigned to one of four solution, gum), with the aim of determining treatment groups as follows: placebo, 50, 100 or which is the safest, most reliable and most 200 mg of caffeine as Stay Alert1 chewing gum.
rapidly absorbed. Gum formulations have been The subjects were restricted from using caffeine, a particular focus, since such formulations have alcohol or any medications for 32 h prior to been used to enhance the rate of absorption for dosing. An indwelling catheter was inserted into various other agents including aspirin [5,6], the forearm vein of each subject and maintained with a saline drip prior to dosing. Each subject In order to determine if caffeine is also more was administered two sticks of gum and was rapidly absorbed from gum (Stay Alert1 chewing instructed to chew the gum for 5 min. Previous gum) vs an immediate release capsule, the work has demonstrated that approximately 85% pharmacokinetics of these two formulations of the caffeine is delivered by 5 min of chewing were recently compared in a single dose study [11]. Subjects were administered the Stay Alert1 [9]. A significantly faster absorption rate was gum at 2400, 0200 and 0400 h, and after chewing evident for the gum formulation, as evidenced by for 5 min the subjects expectorated the gum.
its higher absorption rate constant (ka), higher Blood samples were collected at the following times: pre- dose and at 5, 15, 30, 45, 60, 75, 90 and of absorption (AUCinf) for both formulations 105 min after each dose. In addition, blood samples were collected at 7.5, 8.5 and 18 h after The present study constitutes the next step in the first dose of caffeine. Plasma was immedi- determining the operational usefulness of caffei- ately separated by centrifugation and stored at nated chewing gum}determination of whether À708C until analysed. The subjects received a enhanced absorption is also evident across a standardized lunch and dinner, and water was multiple dosing regimen, and characterization of other aspect of the pharmacokinetics of caffeinein Stay Alert1 chewing gum.
A valid specific high-performance liquid chro- matography method was used to quantify caf-feine in the plasma samples [12]. To 250 ml of Forty-eight young (18–35 years), healthy, non- plasma, 250 ml of 0.8 m perchloric acid containing smoking males ðn ¼ 28Þ and females ðn ¼ 20Þ 8 mg/ml of the internal standard, 8-chlorotheo- Copyright # 2005 John Wiley & Sons, Ltd.
Biopharm. Drug Dispos. 26: 403–409 (2005) phylline was added. The resulting solution was mental modeling. Additional pharmacokinetic vortexed for 10 s and centrifuged at 6000 rpm parameters determined by compartmental mod- for 5 min. Fifty ml of the supernatant was injected eling were Vd/F, Cl/F. The accumulation factor onto the chromatographic system. The analyte was determined by comparison of the third was eluted with a Phenomenex C18 analytical dose vs the first dose as defined below in the column (Phenomenex, CA) (15 cm  4.6 mm). The mobile phase consisted of acetonitrile/tetrahy- drofuran/acetic acid/H2O (50:30:5:915 v:v:v:v) and pumped at a flow rate of 1 ml/min. Caffeine was detected using UV absorption at a wave- where n is the number of doses, t is the dosing length of 274 nm. The LOQ was 100 ng/ml with interval and lz is the terminal elimination rate a within-day variation of less than 5% and a constant. A parametric general linear model was between-day variation of less than 10%.
applied to each of the aforementioned pharma-cokinetic parameters. Inferential statistical ana- lyses consisted of one-way ANOVA with aTukey’s post-hoc test. The significance level was Non-compartmental and compartmental model- ing was used to estimate caffeine pharmacoki-netic parameters after multiple dose adminis-tration. The caffeine concentration-time datawere evaluated using Winnonlin1 Professional (Pharsight Inc., Cary, NC, v 3.1). The maximumcaffeine concentration measured for each subject Forty-eight normal healthy volunteers completed was Cmax. The time that Cmax occurred was Tmax.
the study with no serious adverse effects.
The area under the curve (AUC) from time 0 to The mean (Æ SD) age, weight and height of the end of the dosing interval (t), AUC0Àt, the subjects were 25 (Æ 5.1) years, 158.45 (Æ 27.39) AUC from 0 to the last concentration time point lbs and 58 (Æ 4.25), respectively. The first pre- (AUCcplast) was determined by the trapezoidal dose concentrations of caffeine were below the LOQ of the assay. This indicates that the subjects did not take caffeine prior to the start of the study. Figure 1 depicts the geometric mean The elimination rate constant (lz) was deter- profile after the 50, 100 and 200 mg multiple mined by linear regression of the linear portion dose gum treatments obtained after dosing at of the ln (conc) vs time profile. Typically, four to 2400, 0200 and 0400 h. As expected, the plasma five time points were used to determine the caffeine concentrations displayed a rapid rise terminal elimination rate constant. A one-com- after each administration and Cmax levels were partment model assuming first-order oral ab- achieved within 15 min after administration.
sorption and first-order elimination provided Furthermore, the pharmacokinetic profile of the best fit for individual patient concentration- the three-dosage groups appears to be mono- time data. The choice of PK model was based on exponential. Figure 2 illustrates the mean the standard goodness of fit criteria which (Æ SD) Cmax and AUC0Àt for the three dosing included weighted sum of squares of residuals intervals. In general, this shows a steady (WSSR), Akaike’s information criteria (AIC), increase in both the Cmax and AUC with each Schwarz criteria (SC), residual plots, and plots of observed and model-predicted concentration As stated, the subjects were randomly assigned vs time. The model with the smallest values to one of the four groups: placebo, 50, 100 or for AIC, SC and WSSR was chosen as the best 200 mg of caffeine as Stay Alert1 chewing gum.
model. Absorption rate constant (Ka) was esti- Subjects were administered the 50 mg dose of the mated from the absorption phase by compart- gum at time 2400, 0200 and 0400 h. Samples were Copyright # 2005 John Wiley & Sons, Ltd.
Biopharm. Drug Dispos. 26: 403–409 (2005) also collected at 7.5, 8.5 and 18 h after the first dose. The pharmacokinetic parameters obtained after administration of caffeine are summarizedin Tables 1 and 2. After the third 50 mg dose of the chewing gum, the mean Cmax associated withthe 50 mg dose group was 2.609 (+1.481) mg/l.
The time to reach peak concentration (Tmax) was consistent across dosings, suggesting that the rapid absorption seen with the previous single dose study is maintained after successive doses.
The extent of absorption, AUCinf over the threedoses was found to be 33:2 mg=l à h. The mean AUC(4–6) after the third dose ð4:66 mg=l à hÞdisplayed an accumulation of 2.308 compared Figure 1. Mean ( Æ SD) caffeine plasma concentration profiles with the first dose ð1:88 mg=l à hÞ. Figure 2A, B following a 50, 100 and 200 mg multiple dose of caffeine as displays the Cmax and AUC0Àt observed with gum formulation to healthy volunteers. Caffeine was admi-nistered at 0, 2 and 4 h. Twelve subjects were enrolled in each tion achieved with multiple doses of theStay Alert1 gum.
The 100 mg treatment group also displayed accumulation after the second and third doses.
Caffeine plasma concentrations displayed anincrease in Cmax with every subsequent dose as illustrated in Figure 2A. The Cmax after the third dose (3.46 mg/l) was significantly higher (p5 0.05) than the first dose (1.25 mg/l). Tmax values max1: 0.937, Tmax2: 2.781, Tmax3: 4.841 h) at each dosing interval indicate rapid caffeine absorption after each dosing. The extent of caffeine absorp-tion 46:95 mg=l à h. Again as was evident with Cmax, the AUC4–6 ð5:73 mg=l à hÞ displayed an accumu- lation ratio of 2.467 compared with the first dose The plasma concentration profile of subjects in the highest dose group showed a similar pattern of drug accumulation, with Cmax for the thirddosing interval being the highest at 6.24 mg/l.
The mean Cmax associated with three dosing intervals were 2.14 (Cmax1), 4.37 (Cmax2) and 6.24 (Cmax3) mg/l (Figure 2). Tmax values (Tmax1:1.028, Tmax2: 2.77, Tmax3: 5.125 h) for the highest dosing group continued to show a similar pattern of rapid caffeine absorption after each dosing.
The mean AUCinf was 86:93 mg=l à h (Table 2)and partial AUC for the three dosing intervals Figure 2. Mean ( Æ SD) Cmax (A) and AUC (B) following were AUC0–2: 3.11, AUC2–4: 6.45 and AUC4–6: 9:2 a 50, 100 and 200 mg multiple dose of caffeine as gum 9 mg=l à h (Figure 2). Partial areas in this max- formulation to healthy volunteers. Caffeine was adminis- imum dose group also displayed a consistent tered at 0, 2 and 4 h. Twelve subjects were enrolled in eachtreatment group Copyright # 2005 John Wiley & Sons, Ltd.
Biopharm. Drug Dispos. 26: 403–409 (2005) Table 1. Mean (Æ SD) pharmacokinetic parameters following multiple doses of 50, 100 and 200 mg of StayAlert1 gum to normalhealthy volunteers using compartmental analysis To determine if multiple dosing altered the similar to levels achieved in the previous study pharmacokinetics of caffeine, dose normalized for each caffeine gum group. The elimination rate values of Cmax and AUC were also examined.
constants obtained in that prior single dose study Neither the dose-normalized values for Cmax nor ranged over 0.144–0.17 for the 50–200 mg dose the AUCinf differed across the treatment groups.
groups, and were not significantly different from The mean volume of distribution ranged over those obtained in the present study.
0.82–1.27 l/kg, consistent with earlier observa- These findings suggest that the faster rate and tions that caffeine distributes rapidly with no extent of absorption seen with the single dose specific binding to tissues [10]. Likewise, elim- study is essentially maintained across repeated ination parameters lz and Cl/F did not differ doses. Also, the pharmacokinetic parameters across the treatment groups. This suggests that at seem to be dose independent. These findings higher treatment doses there is no saturation of suggest that both the physical and mental metabolic pathways, i.e. pharmacokinetics in performance deficits that result from sleep loss humans at levels of normal exposure (5250 mg) or fatigue could be reversed quickly by caffeine are not dose dependent. The elimination rate administered in a gum formulation, and benefits constant and Cl/F values showed no statistical might be maintained over an extended period of differences across the treatment groups. These results suggest that linearity is maintained in a In a gum formulation, caffeine absorption occurs primarily through the buccal mucosa}asite at which drug absorption is known to berapid [13]. The buccal mucosa has a rich vascularsupply resulting in a favorable rate of absorption for many drugs, especially for lipophilic agentssuch as caffeine. However, it is likely that with The objective of this study was to evaluate the the gum formulation some portion of the caffeine pharmacokinetics of caffeine extruded from a was also swallowed with saliva, and absorbed in gum, across multiple doses. A steady accumula- the gastrointestinal tract. The likelihood of this is tion of drug after each dosing interval was supported by that fact that multiple peaks in the evident, and linear kinetics was suggested by plasma profiles were evident for a number of the dose normalized AUC and Cmax values. In a subjects, suggesting multiple sites of absorption previous study the rate of absorption and relative (i.e. buccal mucosa for the early peak, and GI bioavailablity of caffeine administered were tract for the later peak). This most likely compared in chewing gum versus capsules [9].
contributed to the high variability of the phar- The Cmax levels achieved were 0.7, 1.2 and macokinetic parameters, indicated by high stan- 3.7 mg/l for the 50, 100 and 200 mg caffeine gum groups. The Cmax levels achieved in the Another potential source of increased varia- present study for the first dosing interval are bility was the ‘mastication rate.’ Differential Copyright # 2005 John Wiley & Sons, Ltd.
Biopharm. Drug Dispos. 26: 403–409 (2005) mastication rates, both within and between subjects, could have contributed to variability in the data, by affecting the rate at which the caffeine was extruded from the gum. Varia-bility resulting from this and other factors may have been reduced had the study utilized The pharmacodynamic effects of caffeine are dependent on its pharmacokinetic properties.
Caffeine improves performance and alertness insleep-deprived subjects, and in individuals who are required to work long hours. With caffeine administered in a gum formulation, a quick onsetof action is obtained (within 5–10 min of admin- istration). The dose can be repeated every 2 h or as needed to have sustained levels of caffeine, and thus sustained performance for extended In summary, caffeine administered in the gum formulation (Stay Alert1 chewing gum) via a repeated dosing regimen provides a viable means of sustaining blood concentrations of caffeine for prolonged periods, i.e. at levels necessary to achieve continuous, effective phar- macodynamic responses in sleep deprived in- dividuals. Further studies are underway to We would like to acknowledge the assistance of the staff of the Division of Neuropsychiatry,Walter Reed Army Institute of Research for their assistance and support in the completion of this study and the preparation of this manu- script. Human volunteers participated after giv- ing their free and informed written consent. This research was conducted in conformity with AR 70-25 and USAMRDC Reg 70-25 on the useof human volunteers in research and the Guiding and Human Beings. Use of trade names does not constitute endorsement of product. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the opinions of the Department of the Army or the Depart- Copyright # 2005 John Wiley & Sons, Ltd.
Biopharm. Drug Dispos. 26: 403–409 (2005) hydrochloride administered in chewing gum and tablets.
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