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Pharmacokinetic Profile of Rizatriptan 10-mg Tablet and 10-mg Orally Disintegrating Tablet Administered With or Without Water in Healthy Subjects: An Open-Label, Randomized, Single-Dose, 3-Period Crossover Study

From DaVita Clinical Research, Minneapolis, Minnesota (Dr Swan, Dr Alcorn); Hennepin County Medical Center, Minneapolis, Minnesota (Dr Swan); and Merck & Co, Inc, West Point, Pennsylvania (Mr Rodgers, Dr Hustad, Ms Ramsey, Ms Woll, and Dr Skobieranda).

Address for reprints: Franck Skobieranda, MD, Merck & Co, Inc, PO Box 4, HM-323, West Point, PA 19486.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC_0-2h than ODTs and that ODTc has a greater geometric mean AUC_0-1h than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t_max) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC_0-2h compared with ODTs (33.84 h·ng/mL vs 18.83 h·ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC_0-1h compared with rizatriptan tablet (17.07 h·ng/mL vs 13.32 h·ng/mL). The median t_max was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.

Key Words: Rizatriptan • pharmacokinetics • clinical trial • migraine medication

Using a statistical model, Fox demonstrated that the onset of effect of sumatriptan, also a selective 5-HT_1B/1D agonist approved for the acute treatment of migraine, is related to the rate of its absorption.⁵ He showed that the rate of absorption of sumatriptan was related to the formulation in which it was taken, with subcutaneous delivery having the fastest rate, followed by suppository, then the oral tablets. As described above, there is an 0.6- to 1.0-hour delay in t_max with rizatriptan ODT versus rizatriptan conventional tablet. This delay may be due to the less rapid delivery of rizatriptan ODT from the mouth to the gastrointestinal tract for systemic absorption. Rizatriptan ODT dissolves on the tongue, is dispersedinthe saliva, and must be swallowed to undergo absorption (relative to the rizatriptan tablet). Despite these differences, however, both formulations have comparable efficacy at the traditional 2-hour end point.^6-11 Thus, if Fox's⁵ observations for sumatriptan hold true for rizatriptan, then delivery of rizatriptan ODT to the gastrointestinal tract in a more rapid fashion (ie, with water, as a surrogate for a liquid formulation) may accelerate the absorption of drug and thus enhance efficacy.

The present study was conducted to compare the pharmacokinetic profiles of rizatriptan 10-mg tablet, rizatriptan 10-mg orally disintegrating tablet with water (ODTc), and rizatriptan 10-mg ODT without water (ODTs). It is recognized that the most relevant measure to evaluate relative rates of absorption is t_max, given that the drugs being compared have the same elimination characteristics. However, the blunt nature of t_max may prevent detection of small, but meaningful, differences in absorption. For the primary comparisons in this study, AUC up to a specific time point near t_max was used as a meaningful surrogate to evaluate relative rates of absorption. Based on existing data and anecdotal clinical reports, it was hypothesized that rizatriptan ODT taken with water has a faster rate of absorption compared with rizatriptan ODT without water. In addition, it was of interest to determine whether the rate of absorption of ODT taken with water was faster than that of rizatriptan tablet. A secondary objective was to compare the time of occurrence of the maximum plasma concentration (t_max) of rizatriptan tablet, rizatriptan ODTs, and rizatriptan ODTc.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subjects
Participants were healthy men and women between the ages of 18 and 45 years, with no more than 20% men (5 men). Subjects were nonsmokers for at least 6 months. Subjects agreed to avoid unusual, unaccustomed, or strenuous physical activity (ie, weight lifting, running, bicycling) throughout the study. Women of reproductive potential had a negative serum ß-hCG test and agreed to use double-barrier methods of contraception during the study. Women who were pregnant or breast-feeding were excluded. Subjects were not allowed to take concomitant prescription or nonprescription medicines, including herbal remedies or estrogen/progesterone-based contraceptives; all nonstudy medication was discontinued 2 weeks before the first dosing period. Subjects refrained from drinking any coffee, tea, or other caffeinated beverages for 24 hours before and after study drug administration on the day of each dosing period; at all other times, subjects were allowed to drink no more than 6 cups of coffee or the equivalent of caffeinated beverages per day. Subjects also were restricted to no more than 2 alcoholic beverages per day during the study and refrained from drinking any alcoholic beverages for 24 hours before and after study drug administration on the day of each dosing period. Subjects were excluded if they had donated a unit of blood or participated in another clinical trial with an investigational agent in the previous 4 weeks.

Study Design
Protocol 070 was an open-label, 3-period crossover study conducted at a single study center, DaVita Clinical Research (Minneapolis, Minn). The protocol was approved by the site institutional review board, and all participants gave written informed consent before any protocol-required procedures were performed. At each of the 3 dosing periods, subjects received a single dose of either rizatriptan 10-mg tablet, rizatriptan 10-mg ODTc, or rizatriptan 10-mg ODTs. The order of dosing was determined by a computer-generated randomized allocation schedule. Each dosing period was separated by at least 7 days.

Subjects fasted from all food and drink from midnight the night before each dosing period but were allowed water up to 1 hour before each dosing period. Between 8 AM and 10 AM on each dosing day, subjects received 1 of the 3 dosing regimens. The rizatriptan tablet was administered with 240 mL of water. Rizatriptan ODTc was dissolved on the tongue and was immediately followed with 240 mL of water. Rizatriptan ODTs was dissolved on the tongue without additional water or liquids for at least 2 hours postdose. Except as described here, subjects were not allowed to drink any additional water or liquids until 2 hours postdose. Subjects refrained from eating until 4 hours postdose. A standard lunch, light snack, and standard dinner were provided at 4, 6, and 8 hours postdose. On all other study days, subjects followed their regular diet.

Pharmacokinetic Sampling and Drug Analysis
Whole-blood samples were collected to measure plasma rizatriptan concentrations before and after treatment on each dosing day. Samples were collected at predose (up to 15 minutes before each dosing); 5, 10, 15, 20, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 95, 100, 105, 110, and 115 minutes postdose; and 2, 3, 4, 6, 8, and 12 hours postdose. Five milliliters of blood (to yield 2 mL of plasma) was collected into a glass sodium heparin Vacutainer at the appropriate time points for measurement of rizatriptan levels. The blood was placed in an ice bath after collection for 5 to 20 minutes. The Vacutainer then was centrifuged for 10 minutes, and the resulting plasma sample was stored frozen at –70°C.

Frozen plasma samples were shipped on dry ice to PPD Development (Richmond, Va) for analysis. A 400 µL aliquot of plasma was extracted using a 96-well polypropylenes plate. The sample was applied to an Empore Ethyl C2 SD High Performance Extraction Plate (3M Bioanalytical Technologies, St. Paul, Minn) conditioned with methanol and reagent water. The extraction plate was washed with reagent water followed by 30:70 methanol:reagent water. The sample was then eluted with 60:40 methanol:ammonium acetate pH 5.0. The eluant was dried and reconstituted with 35:65 (0.1% trifluoroacetic acid in 10:90 methanol:water):(0.1% trifluoroacetic acid in 90:10 acetonitrile:water). The reconstituted sample was injected on the liquid chromatography tandem mass spectrometry system. Chromatography was on a BetaBasic CN Drop In Guard Cartridge 3 µm x 10 mm x 4 mm guard column (Therno Electron Corporation, Waltham, Mass) and a Spherisorb S3 CN column 4.6 mm x 100 mm analytical column (Waters Corporation, Milford, Mass). Mobile phase A consisted of 0.1% trifluoroacetic acid in 10:90 methanol:water and mobile phase B consisted of 0.1% trifluoroacetic acid in 90:10 acetonitrile:water. Mass spectrometry detection was on a Sciex API 3000 (MDS Sciex, South San Francisco, Calif) using atmospheric pressure chemical ionization positive ion tandem mass spectrometry. The mass transitions monitored were m/z 270.2 to 201.0 and 275.2 to 201.0 for rizatriptan and its internal standard, respectively. The assay was validated over a range of 0.5 to 100 ng/mL. During validation, quality controls prepared at concentrations of 0.500, 1.50, 8.00, and 80.0 ng/mL ranged in accuracy from 99.9% to 109%, with a precision (expressed as percentage coefficient of variation) ranging from 5.18% to 11.0%.

Pharmacokinetic Measurements
Individual plasma concentrations of rizatriptan after dosing were used to estimate the following pharmacokinetic parameters: area under the plasma concentration-time curve from time 0 to 2 hours (AUC_0-2h) for the comparison between ODTc and ODTs, area under the plasma concentration-time curve from time 0 to 1 hour (AUC_0-1h) for the comparison between ODTc and tablet, and time of occurrence of t_max for all 3 dosing regimens.

Statistical Methods
The primary hypothesis compared the AUC_0-2h of rizatriptan ODTc to rizatriptan ODTs and the AUC_0-1h of rizatriptan ODTc to rizatriptan tablet. The different AUCtimepointswerechosentobenearthet_max of the reference formulation to which ODT with water was being compared: AUC_0-2h for comparison to ODT without water, which has a t_max of 1.6 to 2.5 hours, and AUC_0-1h for comparison to tablet, which has a t_max of 1 to 1.5 hours. The difference in mean natural log-transformed pharmacokinetic values was used as the basis for 90% confidence intervals (CIs). The hypotheses were satisfied if the lower bound of the 90% CIs (1-sided, = .05) around the observed differences of the mean natural log-transformed AUCs (rizatriptan ODTc—rizatriptan ODTs and rizatriptan ODTc—rizatriptan tablet) were greater than 0 (back-transformed to the scale of measurement, the lower bounds must be >1). The natural log-transformed data were analyzed using an analysis of variance (ANOVA) model with factors for subject (as a random effect), dosing regimen, and period. For the primary hypothesis, a within-subject mean square error for AUC_0-2h (based on t_max for ODTs) and AUC_0-1h (based on t_max for tablet) of 0.0441 and 0.0676, respectively, was calculated based on the rizatriptan pharmacokinetic data from a previous study (Merck protocol 042, data on file). Given a 3-period crossover study with 24 subjects (4 per sequence), a 1-sided type I error of 0.05, and similar variability in rizatriptan AUC data, there was >99% probability that the lower bound of the 90% CI for the observed geometric mean AUC ratio of rizatriptan ODTc/rizatriptan ODTs would be >1 if the true geometric mean ratio were 2 (amount of increase in the AUC to reach that seen with tablet formulation), and there was 91% probability that the lower bound of the 90% CI for the observed geometric mean AUC ratio of rizatriptan ODTc/rizatriptan tablet would be >1 if the true geometric mean ratio were 1.25. Overall, there was 90% probability to satisfy both of the above.

A test for first-order carryover was performed. Appropriate testing was used to ensure that the data conformed to the statistical assumptions of common variance and normality for log-transformed data. Other transformations (eg, rank, inverse) were applied to the pharmacokinetic parameters, as appropriate. The least-square means and the mean squared error from the ANOVA model were used to calculate the CIs.

Time of occurrence of maximum plasma concentration (t_max) was compared between dosing regimens using the signed rank test. A distribution-free 90% CI for the median difference (estimated by the Hodges-Lehmann estimator¹²) between dosing regimens was provided based on the signed rank test.

The exploratory objective of geometric mean AUC at each time point was summarized with descriptive statistics (number, least square mean, and standard error) and plotted over time by dosing regimen. AUC_0- and C_max were summarized with 90% CIs in a similar fashion as AUC_0-2h. Any 2 geometric mean AUC_0- values were considered bioequivalent if the 90% CI of the ratio lies within the interval of 0.8 to 1.25. Note that given the half-life of 2 to 3 hours, plasma concentration values measured out to 12 hours postdose is sufficient to approximate AUC_0-.

Tolerability
All patients were monitored for adverse experiences (AEs) throughout the study. Summary statistics for vital sign measurements and change from baseline were calculated, with baseline for each subject defined as the measurement taken immediately before dose administration on each dosing day.

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Subject Accounting
Of the 44 subjects screened for this study, 27 were randomized. Two subjects were randomized and discontinued before receiving any drug (withdrawal of consent, failed intravenous access). One subject was randomized and treated but discontinued the study after vomiting within 30 minutes of the initial dosing in the first period; data from this subject was excluded from the analysis and summary of pharmacokinetic data. The remaining 24 subjects were randomized and treated for all 3 treatment periods and were included in the analysis and summary of pharmacokinetic data.

View larger version (18K): [in this window] [in a new window]   Figure 1. Mean plasma concentrations of rizatriptan following administration of 10-mg single oral doses to healthy subjects (n = 24). ODTc = rizatriptan ODT with water (closed circles); ODTs = rizatriptan ODT without water (open circles); tablet = rizatriptan tablet (triangles). Inset: Same plot on the log scale.

Pharmacokinetics
The mean plasma concentration-time profiles for rizatriptan tablet and ODTc showed a comparable time to peak plasma concentration, but the concentration at peak was slightly higher for ODTc (Figure 1). The mean plasma concentration-time profile for rizatriptan ODTs showed a slower absorption rate and a lower concentration at peak than those seen for tablet and ODTc.

Geometric Mean AUC_0-2h of Orally Disintegrating Tablet With Water Versus Without Water
Rizatriptan ODTc had a statistically significantly greater AUC_0-2h geometric mean plasma concentration (33.84 h·ng/mL) compared with rizatriptan ODTs (18.83 h·ng/mL), P < .001. The geometric mean AUC_0-2h ratio (90% CI) of rizatriptan ODTc/rizatriptan ODTs was 1.80 (1.53, 2.12). There was no evidence of a first-order carryover effect.

Geometric Mean AUC_0-1h of Orally Disintegrating Tablet With Water Versus Tablet
Rizatriptan ODTc had a slightly, but not significantly, greater geometric mean AUC_0-1h plasma concentration (17.07 h·ng/mL) compared with rizatriptan tablet (13.32 h·ng/mL). The AUC_0-1h geometric mean ratio (90% CI) of rizatriptan ODTc/rizatriptan ODTs was 1.28 (0.79, 2.09). There was no evidence of a first-order carryover effect.

Secondary and Exploratory End Points
Time of occurrence of maximum plasma concentration (t_max). The median t_max values are shown in Table I. The Hodges-Lehmann estimates of the median differences in t_max and associated 90% CIs were –0.83 hours (–1.29, –0.50) for rizatriptan ODTc–rizatriptan ODTs and –0.08 (–0.29, 0.07) for rizatriptan ODTc–rizatriptan tablet. The earlier t_max of ODTc (approximately 50 minutes faster) compared with ODTs was statistically significant (Wilcoxon signed-rank test, P < .001), supporting the results of the primary analysis. The slightly earlier t_max of ODTc (approximately 5 minutes faster) compared to tablet was not statistically significant.

Cumulative plasma concentration AUC profile over 12 hours. The profiles of the cumulative plasma concentration AUC over 12 hours of rizatriptan ODTc and rizatriptan tablet were similar with the exception of a slightly higher AUC for ODTc within the first 4 hours (Figure 2). The cumulative plasma concentration AUC over 12 hours of rizatriptan ODTs was consistently lower than that for either ODTc or tablet.

View larger version (14K): [in this window] [in a new window]   Figure 2. Geometric mean plasma concentration area under the curve (AUC) over time. ODTc = rizatriptan ODT with water; ODTs = rizatriptan ODT without water.

Bioequivalence: geometric mean AUC_0- ratio. The geometric mean AUC_(0-) ratio (90% CI) of rizatriptan ODTc/rizatriptan ODTs was 1.06 (1.01, 1.10). Although this value falls within the bioequivalence bounds of 0.8 to 1.25, it excludes 1, suggesting that the geometric mean AUC_0- of rizatriptan ODTc is greater than ODTs (P = .031). The geometric mean AUC_0- ratio (90% CI) of rizatriptan ODTc/rizatriptan tablet was 1.00 (0.96, 1.04), which falls within the bioequivalence bounds of 0.8 to 1.25. There was no evidence of a first-order carryover effect.

Tolerability
Reports of headache (2 subjects), paraesthesia (3 subjects), dizziness (1 subject), lethargy (1 subject), nausea (1 subject), vomiting (1 subject), and fatigue (2 subjects) were reported as possibly, probably, or definitely related to test drug. All AEs were of moderate or less intensity, and there were no serious AEs.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
There are currently 2 formulations of rizatriptan available for the acute treatment of migraine: a conventional tablet and an ODT that rapidly dissolves in the mouth and can be administered without water. Pharmacokinetic studies of both formulations have shown that the rate of absorption of rizatriptan ODT is somewhat slower than that of rizatriptan tablet, which was confirmed in the current study, and that the bioavailabilities and C_max were similar.² Despite these differences in pharmacokinetic profiles, both formulations have similar efficacy, as measured by traditional 2-hour end points.^6-11

The current study was performed to address anecdotal reports of improved efficacy of the rizatriptan ODT formulation when administered with water; ODT with water was used as a surrogate for a liquid formulation. Fox⁵ has stated that rate of absorption of sumatriptan is predictive of the speed of onset of efficacy: that is, formulations with an accelerated pharmacokinetic profile are associated with a more rapid onset of efficacy. Because rizatriptan ODT is absorbed in the gastrointestinal tract and not in the mouth, administration with water would be expected to decrease the transit time from the mouth to the gastrointestinal tract and thus increase the rate of absorption.

Results of the current study confirm this concept: ODTc is absorbed faster than ODTs, as measured by geometric mean AUC_0-2h. In addition, administration of ODT with water decreased the t_max by nearly an hour. When compared with rizatriptan conventional tablet as a reference standard, the geometric mean AUC_0-1h of ODTc was slightly faster, but not significantly faster, than conventional tablet. The t_max of ODTc and conventional tablet were similar.

The results of this study are consistent with anecdotal reports of improved efficacy of the rizatriptan ODT formulation when administered with water. Using these pharmacokinetic parameters, rizatriptan ODT administered with water represents the "best" currently available delivery method. If Fox's⁵ analysis of sumatriptan is generalizable to rizatriptan, then ODTc would have a faster onset of efficacy than ODTs. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
This study was funded by Merck & Co, Inc, West Point, Pennsylvania. The authors thank Nancy Agrawal, Rita Chiou, Constance Billig, and Kay Schabold for their contributions toward the execution of the study and Mike Edwards of PPD for his assistance with the writing of the analytical methods section.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Vyas KP, Halpin RA, Geer LA, et al. Disposition and pharmacokinetics of the antimigraine drug, rizatriptan, in humans. Drug Metab Dispos. 2000;28: 89-95.[Abstract/Free Full Text]

2. MAXALT [prescribing information]. Whitehouse Station, NJ: Merck Research Laboratories.

3. Lee Y, Conroy JA, Stepanavage ME, et al. Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers. Br J Clin Pharmacol. 1999;47: 373-378.[CrossRef][Medline] [Order article via Infotrieve]

4. Cheng H, Polvino WJ, Sciberras D, et al. Pharmacokinetics and food interaction of MK-462 in healthy males. Biopharm Drug Dispos. 1996;17: 17-24.[Medline] [Order article via Infotrieve]

5. Fox AW. Onset of effect of 5-HT1B/1D agonists: a model with pharmacokinetic validation. Headache. 2004;44: 142-147.[Medline] [Order article via Infotrieve]

6. Goldstein J, Ryan R, Jiang K, et al. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Rizatriptan Protocol 046 Study Group. Headache. 1998;38: 737-747.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Kramer MS, Matzura-Wolfe D, Polis A, et al. A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Rizatriptan Multiple Attack Study Group. Neurology. 1998; 51: 773-781.[Abstract/Free Full Text]

8. Teall J, Tuchman M, Cutler N, et al. Rizatriptan (MAXALT) for the acute treatment of migraine and migraine recurrence: a placebo-controlled, outpatient study. Rizatriptan 022 Study Group. Headache. 1998;38: 281-287.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Tfelt-Hansen P, Teall J, Rodriguez F, et al. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group. Headache. 1998;38: 748-755.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

10. Ahrens SP, Farmer MV, Williams DL, et al. Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Rizatriptan Wafer Protocol 049 Study Group. Cephalalgia. 1999;19: 525-530.[Medline] [Order article via Infotrieve]

11. Cady R, Crawford G, Ahrens S, et al. Long-term efficacy and tolerability of rizatriptan wafers in migraine. MedGenMed. 2001;3: 1.[Medline] [Order article via Infotrieve]

12. Hodges JL, Lehmann EL. Estimates of location based on rank test. Ann Mathemat Stat. 1963;34: 598-611.
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Swan, S. K. Articles by Skobieranda, F. Search for Related Content PubMed PubMed Citation Articles by Swan, S. K. Articles by Skobieranda, F. Social Bookmarking                   What's this?