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Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration
European Journal of Pharmaceutical Sciences, 6 (1998) 99–104
Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration a, b c d C. Duquesnoy *, J.P. Mamet , D. Sumner , E. Fuseau a
Department of Clinical Pharmacology, Laboratoire Glaxo Wellcome, 20, rue Rouget de Lisle, 92442 Issy les Moulineaux Cedex, France b Department of Biostatistics, Laboratoire Glaxo Wellcome, 20, rue Rouget de Lisle, 92442 Issy les Moulineaux Cedex, France c Department of Clinical Pharmacology, Glaxo Wellcome Research and Development Ltd, UK d Department of Clinical Pharmacokinetics, Glaxo Wellcome Research and Development Ltd, UK Received 13 August 1996; accepted 13 June 1997
Abstract Sumatriptan, a 5-HT 1 receptor agonist active for the acute treatment of migraine, is currently available as subcutaneous injection and oral tablets. Rectal or intranasal formulations may offer advantages over those marketed. This study compared the pharmacokinetics of sumatriptan via all four routes. Usual absorption parameters were described and the rate of absorption was assessed using deconvolution technics. There were no statistical differences between the non-parenteral routes for t max or Cmax /AUC ` . However, Cmax and AUC t max were statistically greater with the suppository than with the tablet, but there was no difference between intranasal and oral routes. The highest rate of absorption occurred earlier with the intranasal than with the oral route. Relative to the subcutaneous route, the bioavailability for the suppository was greater than for intranasal spray and oral tablet. The amount of sumatriptan excreted in the urine unchanged was similar for all routes. Sumatriptan in this study was well tolerated. 1998 Elsevier Science B.V. Keywords: Sumatriptan; Cmax /AUC ` , AUC t max ; Deconvolution; Bioavailability; Absorption
1. Introduction Sumatriptan is a selective agonist at the vascular 5hydroxytryptamine-1 (5-HT 1D ) receptor which mediates vasoconstriction of cranial blood vessels. This action may form the basis of its efficacy in migraine (Humphrey and Feniuk, 1991). Sumatriptan is currently available as a 6-mg subcutaneous injection (administered via an autoinjector) and as 25-, 50- and 100-mg oral tablets. Gastrointestinal absorption of drugs may be impaired during the migraine attack, and furthermore migraine episodes are often associated with nausea and vomiting (Volans, 1978). Patients suffering from these symptoms may find difficult to use an oral formulation. The subcutaneous administration of sumatriptan is an alternative, but is not acceptable to all migraineurs as some may fear or dislike injections. This has prompted the development of alternative formulations through different routes of administration. Intranasal and rectal formulations may offer
*Corresponding author. Tel.: 133 1 47553684; fax: 133 1 47553687. 0928-0987 / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII S0928-0987( 97 )00073-0
advantages over those marketed; they have been developed and are currently under review by Regulatory Authorities. The pharmacokinetic profile of sumatriptan administered as a suppository or intranasal spray to healthy subjects have been investigated. Cmax was proportional to the dose over the range from 25 up to 100 mg with the sumatriptan suppository (Hussey et al., 1995). A study to investigate the pharmacokinetics and pharmacodynamics of intranasal sumatriptan 5–20 mg showed an increase in absorption with dose, however, dose proportionality was not demonstrated across the whole range (Moore et al., 1996). In order to provide comparative information on the pharmacokinetics and more precisely on both the absorption profile and the bioavailability of sumatriptan administered as subcutaneous, oral, suppository and intranasal formulations, a pharmacokinetic study across all four routes of administration was performed in healthy subjects. Bioavailability of subcutaneous sumatriptan is nearly 100% (Fowler et al., 1991) and, therefore, the current marketed dose of subcutaneous sumatriptan (6 mg) was used as a reference for the non-parenteral formulations. A 25-mg oral tablet was administered to offer comparison
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C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
with suppository (25 mg) and intranasal (20 mg) formulations at a similar plasma concentration level.
2. Experimental procedures
2.1. Ethics All subjects gave written informed consent prior to participation to the study. The study was conducted in compliance with the principles of the Declaration of Helsinki and revisions and was approved by a local Ethical Review Committee before the start of the study. The study was undertaken in accordance with Good Clinical Practice.
2.2. Safety Each subject had a routine medical examination within 3 weeks of the start of the study. A total volume of less than 300 ml of blood was taken from each subject during the study. All adverse events were recorded in detail.
2.3. Study design An open, randomised, four-way cross-over study was carried out.
2.6. Study procedures Subjects attended the Unit on four separate study days and were subject to food, alcohol, smoking and exercise restrictions as usually applies for such a study in healthy subjects. An indwelling cannula was inserted into a suitable forearm vein for blood sampling.
2.7. Sampling Blood samples (5 ml) for serum sumatriptan concentration were collected prior to dosing and 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 6 and 8 h post oral and suppository treatments, and prior to dosing and 2, 5, 10, 15, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 6 and 8 h post subcutaneous and intranasal treatments. All urine voided 0–24 h post treatment was collected as 0–2-, 2–4-, 4–6-, 6–12- and 12–24h samples for determination of sumatriptan concentrations and sumatriptan pharmacologically inactive metabolite (GR49336) levels. Serum samples for determination of sumatriptan concentrations were analysed using HPLC with electrochemical detection. This method has been validated over the range 1.0–30 ng / ml. Urine samples for determination of sumatriptan concentrations were analysed using a direct injection HPLC method with electrochemical detection. Urine samples for determination of sumatriptan metabolite (GR49336) levels were analysed by a direct injection HPLC method with UV detection.
2.4. Subjects
2.8. Pharmacokinetic method
Twenty-four healthy subjects aged 22–49 years (mean age 35.9 years) and weighing 70.8–97.3 kg (mean weight 82.1 kg) completed the study. Although male or female subjects were eligible to take part in the study, only male subjects were recruited. Subjects fulfilled the usual inclusion and exclusion criteria for a study in the healthy population. In addition, subjects were excluded if they suffered from a cold or rhinitis on a study day or if they had diarrhea within 2 weeks prior to the study. No protocol deviation has been observed. Based on an estimate of within-subject coefficient of variation of 25% for AUC ` , the study had an estimated power of over 80% that the 90% confidence interval for the relative AUC ` of any two treatments would be contained within 80–125% of the true value.
The pharmacokinetic parameters were calculated using PCNONLIN Program-version 4.2 (SCI Software, KY, USA). The relative bioavailability of subcutaneous (s.c.) sumatriptan is 96% (Lacey et al., 1995) and, therefore, this route was used as a reference for the determination of non-parenteral bioavailabilities. The relative bioavailability (F ) after non-parenteral (np) routes was calculated using the following equation:
2.5. Treatments Each subject received in random order at least 3 days apart and on four separate occasions: 6 mg subcutaneous sumatriptan, 25 mg sumatriptan oral tablet, 25 mg sumatriptan suppository and 20 mg sumatriptan intranasal spray. The night before treatment with sumatriptan suppository, subjects self-administered a 4-g glycerol suppository to empty their bowels.
F 5 (AUC ` )np ? (Dose)sc /(AUC ` )sc ? (Dose)np The area under the curve from time zero to t max , AUC t max was calculated using a linear trapezoidal method. Serum clearance was obtained following subcutaneous administration and the apparent clearances (Cl /F ) were obtained for the other routes using the following equation: Cl /F 5 Dose /AUC ` The renal clearances were calculated using 4-h post-dose data as follows: Cl r 5 A e4 /AUC ` where A e4 is the cumulative amount of drug or metabolite excreted into a volume of urine recovered from time zero to 4 h post-dose and AUC 4 is the area under the serum concentration curve from time zero to 4 h post-dose.
C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
In addition to usual derived pharmacokinetic parameters (Cmax , t max , AUC ` and t 1 / 2z ), Cmax /AUC ` ratio was calculated as well as the partial area AUC t max . AUC t max is the area under the concentration–time curve from time zero to t max and describes solely the absorption phase. The deconvolution of data obtained by intranasal, rectal and oral administration was carried out using MKMODEL (Nick Holford, Biosoft, Cambridge, UK) and an in-housewritten program based on the point-area method (Vaughan and Dennis, 1978). The reference route used for the deconvolution of non-parenteral routes was predicted by modelling subcutaneous data with a two-compartment model: from the disposition parameters obtained, the whole curve from time zero has been calculated to simulate an intravenous administration. Cmax , AUC t max and AUC ` were divided by dose and log-transformed prior analysis of variance. Cmax /AUC ` has also been analysed using a standard analysis of variance (Pabst and Jaeger, 1990) after log-transformation. T max was analysed using the Wilcoxon signed rank test. No statistic was applied to rate of absorption analysis.
3. Results / discussion Serum concentrations were available on 23 subjects. The objectives of the study were to compare the absorption profile and estimate the bioavailability of different sumatriptan formulations based on analysis of Cmax , Cmax /AUC ` , AUC t max , AUC ` and t max . Cmax , t max and AUC ` are currently used as indirect measures of the
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average rate and of the extent of absorption and Cmax / AUC ` has recently been proposed as a new indirect measure of rate (Lacey et al., 1994a). Cmax /AUC ` has been shown to be a superior measure of rate of drug absorption than Cmax for immediate release dosage forms: it is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent, and Cmax /AUC ` is more sensitive than Cmax to detect differences in rate of drug absorption when they do exist. Another metric, the partial area under the curve AUC t max has been calculated in order to gain further information during the absorption phase, while this parameter describes only the rising part of the curve. AUC t max has previously been investigated as an alternative approach for assessment of rate of absorption (Chen, 1992; Lacey et al., 1994b). The partial area method was found to be more discriminating than Cmax and / or t max in the evaluation of the absorption rate of drugs and thus to be useful in the assessment of rate of absorption in bioequivalence studies. The cut-off time point for partial area is an important issue (Macheras et al., 1994), and may vary with the type of drug under study, depending on its clinical use and onset of action. Semi-logarithmic plots of the median serum sumatriptan concentrations are given in Fig. 1. Summary of the main pharmacokinetic parameters is presented in Table 1. Pharmacokinetic profiles were consistent with those observed in previous studies using the same formulations. The pharmacokinetics of intranasal sumatriptan showed multiple peaking for most subjects. A double absorption peak occurred with only few subjects following tablet administration, and rarely after suppository. Accordingly,
Fig. 1. Semi-logarithmic plots of the median concentrations of sumatriptan in serum for each route of administration. From Duquesnoy et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration.
C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
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Table 1 Main pharmacokinetic parameters and associated statistics Parameter
Cmax (ng / ml) Cmax /AUC ` (1 / h) AUC t max (h?ng / ml) t max (h) F (s.c.) (%) t 1 / 2z (h) Cl r (l / min)
Route of administration
Geo. Mean 95% CI Geo. Mean 95% CI Geo. Mean 95% CI Median Range Geo. Mean 95% CI Geo. Mean 95% CI Geo. Mean 95% CI
S.c., 6 mg
Oral, 25 mg
Suppository, 25 mg
Intranasal, 20 mg
69.5 62.8–76.8 0.77 0.71–0.84 9.0 7.5–10.9 0.17 0.08–0.33 — — 1.9 1.7–2.0 0.22 0.19–0.25
16.5 13.5–20.1 0.31 0.27–0.35 8.7 6.1–12.5 1.50 0.50–2.00 14.3 11.4–17.9 1.7 1.4–1.9 0.17 0.14–0.21
22.9 18.4–28.6 0.32 0.26–0.39 14.6 11.3–18.8 1.00 0.75–3.00 19.2 15.3–24.1 1.8 1.6–2.2 0.17 0.14–0.21
12.9 10.5–15.9 0.27 0.24–0.30 7.4 5.0–10.8 1.50 0.25–3.00 15.8 12.6–19.8 1.8 1.7–2.0 0.21 0.18–0.25
t max was more variable (CV 62.8%) than other routes. The intranasal spray behaved very similar to the oral tablet in terms of absorption and excretion, perhaps due to a proportion of the dose being swallowed. Pharmacokinetic parameters (Cmax , t max , AUC ` and Cl r ) following 25 mg suppository in the current study are greater than in a previous study (Hussey et al., 1995). This may be explained by the demography: in the present study, the subjects were older and heavier than in the previous study, resulting in smaller values for the pharmacokinetic parameters. Statistical results of treatment comparisons are summarised in Table 2. No statistically significant differences between the intranasal or suppository and oral formulations were observed for the rate of absorption described by Cmax /AUC ` or time to maximum serum concentration, although Cmax tended to occur earlier with the suppository. The subcutaneous route was assumed to be 100% bioavailable and all values were calculated relative to this. The bioavailability relative to the subcutaneous route was
19.2% for the suppository, 15.8% for the intranasal spray and 14.3% for the oral tablet. The bioavailability of the suppository formulation was significantly greater than oral tablet; there was no significant difference between the oral and intranasal formulations. The maximum serum concentration normalised by the dose was 39% greater for the suppository than that achieved via the oral route, which did not differ from Cmax following intranasal administration. The partial area up to t max normalised by the dose was also much greater for the suppository than for other nonparenteral formulations due to higher values of Cmax . AUC t max demonstrated an important intersubject variability (CV up to 90% for the oral tablet). AUC t max was statistically greater with the suppository than with the oral tablet but no difference between the intranasal and the oral tablet was demonstrated. The average rate of absorption as determined by Cmax / AUC values was similar between the tablet, the suppository and the intranasal spray.
Table 2 Statistical results of treatment comparison for the main pharmacokinetic parameters Parameter AUC
b `
C bmax Cmax /AUC ` AUC t max b t max a
Treatment comparison
Estimate a (%)
90% CI
P value
Oral / s.c. Suppository / s.c. Intranasal / s.c. Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral
14.3 19.2 15.8 134.7 111.0 139.1 97.5 103.5 87.2 166.3 104.7 0.00 20.13
11.8–17.2 15.9–23.2 13.1–19.1 111.6–162.7 91.9–134.1 113.8–169.9 79.8–119.1 89.5–119.8 75.3- 100.8 120.7–229.2 76.0–144.3 20.25–0.38 20.42–0.13
,0.001 ,0.001 ,0.001 0.011 0.359 0.008 0.832 0.693 0.120 0.010 0.811 0.902 0.529
Estimate for t max is median difference. Values for AUC ` , Cmax and AUC t max are dose-normalised.
b
C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
Time to peak concentration was similar for all nonparenteral routes (1–1.5 h) and in accordance with values found in the literature. The maximum serum concentration occurred earlier with the suppository than with the tablet and the intranasal spray, but with no statistical significance. All formulations demonstrated a similar elimination phase, and the profiles were consistent with those observed in previous studies using the same formulation. For most subjects, t 1 / 2z could be precisely estimated and was close to 2 h, which is consistent with values found in the literature. However, results of the non-compartmental pharmacokinetic analysis described above do not explain the observed rates of migraine relief at early time points after treatment by intranasal or rectal sumatriptan as compared ¨ to oral route (Becker, 1995; Gobel, 1995), in a number of placebo-controlled studies of sumatriptan. The deconvolution method produced estimates of timepoints rate of absorption. The median rate of absorption time profiles for intranasal, rectal and oral routes are given in Fig. 2. Although curves are similar, the rate of absorption–time curve is clearly shifted to the left for the intranasal route compared to the oral route: the highest rate occurred around 5 min post intranasal dose when it occurred 30 min post oral dose. These results may explain why, 15 min after dosing with intranasal sumatriptan, headache relief, defined by a change in headache severity score from 3 / 2 to 1 / 0, is observed in 38% of patients compared to only 2% after oral treatment (Fig. 3). A relatively high rate of absorption following sumatriptan suppository administration is reached earlier (0.25 h) than
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following oral administration (0.5 h). The rate of absorption for the suppository described then a plateau up to 1 h post dose and, from this time point, the three profiles looked very similar. Again, this may explain the difference observed in headache relief at early time points between the suppository and the oral tablet: 1 h post dose, 46% of patients experienced headache relief with the suppository versus 23% following oral tablet. Non-compartmental pharmacokinetic parameters used for bioequivalence studies may be not appropriate enough to investigate the local relationship between pharmacokinetics and drug effect. They only represent surrogate markers of rate of drug absorption which can be used to assess bioequivalence when formulations are compared but not to accurately describe the rate of absorption. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism as the pharmacologically inactive indoleacetic acid analogue (GR49336). The amounts of sumatriptan excreted unchanged in urine in 24 h represented 1.8, 2.8 and 2.2% of the dose after the oral, suppository or intranasal routes, respectively. The amounts of GR49336 excreted in the urine in 24 h represent approximately 52.5, 27.2 and 39.2% of the dose by oral, suppository and intranasal routes, after correcting for molecular weight (31.03). The urinary recoveries of the main metabolite GR49336 after intranasal and rectal administration were lower compared to recovery after oral administration (respectively P50.02 and P,0.01), consistent with a partial escape from firstpass metabolism. In this study, adverse events characteristic of sumatriptan were mainly reported following the subcutaneous
Fig. 2. Median rate of absorption within the first 2 h post-dose for the intranasal, oral and suppository sumatriptan formulations. From Duquesnoy et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration.
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C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
Fig. 3. Percentage of patients with headache relief (defined by a change in headache severity score from 3 / 2 to 1 / 0) winthin the first 2 h post-dose for the ] intranasal, oral and suppository sumatriptan formulations. From Duquesnoy et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration.
injection (stinging at the injection site, sensations of tingling, etc.). The intranasal spray produced sensations involving the nose or throat and an unpleasant taste. Only a few adverse events, characteristic of sumatriptan, were experienced following the oral tablet and suppository. In general, adverse events were mild to moderate in severity, with all routes of administration being well tolerated. No serious adverse events occurred during the study.
References Becker, W.J., 1995. A placebo-controlled, dose-defining study of sumatriptan nasal spray in the acute treatment of migraine. Cephalgia 15 (S14), 239t. Chen, M.L., 1992. An alternative approach for assessment of rate of absorption in bioequivalence studies. Pharm. Res. 9 (11), 1380–1385. Fowler, P.A., Lacey, L.F., Thomas, M., Keene, O.N., Tanner, R.J., Baber, N.S., 1991. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. Eur. Neurol. 31 (5), 291–294. ¨ Gobel, H., 1995. A placebo-controlled, dose-defining study of sumatriptan suppositories in the acute treatment of migraine. Cephalgia 15 (S14), 232. Humphrey, P.P.A., Feniuk, W., 1991. Mode of action of the anti-migraine drug sumatriptan. Trends. Pharmacol. Sci. 12, 444–446.
Hussey, E.K., Aubert, B., Richard, I., Kunka, R.L., Fowler, P., 1995. The clinical pharmacology of sumatriptan suppositories. Cephalgia 15 (S14), 233. Lacey, L.F., Keene, O.N., Duquesnoy, C., Bye, A., 1994. Evaluation of different indirect measures of rate of drug absorption in comparative pharmacokinetic studies. J. Pharm. Sci. 83 (2), 212–215. Lacey, L.F., Keene, O.N., Duquesnoy, C., Bye, A., 1994. Evaluation of different partial AUCs as indirect measures of rate of drug absorption in comparative pharmacokinetic studies. Pharm. Res. 11 (10), S–415. Lacey, L.F., Hussey, E.K., Fowler, P.A., 1995. Single dose pharmacokinetics of sumatriptan in healthy volunteers. Eur. J. Clin. Pharmacol. 47, 543–548. Macheras, P., Symillides, M., Reppas, C., 1994. The cut-off time point of the partial area method for assessment of rate of absorption in bioequivalence studies. Pharm. Res. 11 (6), 831–834. Moore, K.H.P., Hussey, E.K., Shaw, S., Fuseau, E., Duquesnoy, C., Pakes, G., 1996. Safety, tolerability and pharmacokinetics of sumatriptan in healthy volunteers following ascending single intranasal doses and multiple doses. Submitted to Cephalgia (June). Pabst, G., Jaeger, H., 1990. Review of methods and criteria for the evaluation of bioequivalence studies. Eur. J. Clin. Pharmacol. 38, 5–10. Vaughan, D.P., Dennis, M., 1978. Mathematical basis of point-area deconvolution method for determining in vivo input functions. J. Pharm. Sci. 67, 663–665. Volans, G.N., 1978. Migraine and drug absorption. Clin. Pharmacokinet. 3, 313–318.
Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration a, b c d C. Duquesnoy *, J.P. Mamet , D. Sumner , E. Fuseau a
Department of Clinical Pharmacology, Laboratoire Glaxo Wellcome, 20, rue Rouget de Lisle, 92442 Issy les Moulineaux Cedex, France b Department of Biostatistics, Laboratoire Glaxo Wellcome, 20, rue Rouget de Lisle, 92442 Issy les Moulineaux Cedex, France c Department of Clinical Pharmacology, Glaxo Wellcome Research and Development Ltd, UK d Department of Clinical Pharmacokinetics, Glaxo Wellcome Research and Development Ltd, UK Received 13 August 1996; accepted 13 June 1997
Abstract Sumatriptan, a 5-HT 1 receptor agonist active for the acute treatment of migraine, is currently available as subcutaneous injection and oral tablets. Rectal or intranasal formulations may offer advantages over those marketed. This study compared the pharmacokinetics of sumatriptan via all four routes. Usual absorption parameters were described and the rate of absorption was assessed using deconvolution technics. There were no statistical differences between the non-parenteral routes for t max or Cmax /AUC ` . However, Cmax and AUC t max were statistically greater with the suppository than with the tablet, but there was no difference between intranasal and oral routes. The highest rate of absorption occurred earlier with the intranasal than with the oral route. Relative to the subcutaneous route, the bioavailability for the suppository was greater than for intranasal spray and oral tablet. The amount of sumatriptan excreted in the urine unchanged was similar for all routes. Sumatriptan in this study was well tolerated. 1998 Elsevier Science B.V. Keywords: Sumatriptan; Cmax /AUC ` , AUC t max ; Deconvolution; Bioavailability; Absorption
1. Introduction Sumatriptan is a selective agonist at the vascular 5hydroxytryptamine-1 (5-HT 1D ) receptor which mediates vasoconstriction of cranial blood vessels. This action may form the basis of its efficacy in migraine (Humphrey and Feniuk, 1991). Sumatriptan is currently available as a 6-mg subcutaneous injection (administered via an autoinjector) and as 25-, 50- and 100-mg oral tablets. Gastrointestinal absorption of drugs may be impaired during the migraine attack, and furthermore migraine episodes are often associated with nausea and vomiting (Volans, 1978). Patients suffering from these symptoms may find difficult to use an oral formulation. The subcutaneous administration of sumatriptan is an alternative, but is not acceptable to all migraineurs as some may fear or dislike injections. This has prompted the development of alternative formulations through different routes of administration. Intranasal and rectal formulations may offer
*Corresponding author. Tel.: 133 1 47553684; fax: 133 1 47553687. 0928-0987 / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII S0928-0987( 97 )00073-0
advantages over those marketed; they have been developed and are currently under review by Regulatory Authorities. The pharmacokinetic profile of sumatriptan administered as a suppository or intranasal spray to healthy subjects have been investigated. Cmax was proportional to the dose over the range from 25 up to 100 mg with the sumatriptan suppository (Hussey et al., 1995). A study to investigate the pharmacokinetics and pharmacodynamics of intranasal sumatriptan 5–20 mg showed an increase in absorption with dose, however, dose proportionality was not demonstrated across the whole range (Moore et al., 1996). In order to provide comparative information on the pharmacokinetics and more precisely on both the absorption profile and the bioavailability of sumatriptan administered as subcutaneous, oral, suppository and intranasal formulations, a pharmacokinetic study across all four routes of administration was performed in healthy subjects. Bioavailability of subcutaneous sumatriptan is nearly 100% (Fowler et al., 1991) and, therefore, the current marketed dose of subcutaneous sumatriptan (6 mg) was used as a reference for the non-parenteral formulations. A 25-mg oral tablet was administered to offer comparison
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C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
with suppository (25 mg) and intranasal (20 mg) formulations at a similar plasma concentration level.
2. Experimental procedures
2.1. Ethics All subjects gave written informed consent prior to participation to the study. The study was conducted in compliance with the principles of the Declaration of Helsinki and revisions and was approved by a local Ethical Review Committee before the start of the study. The study was undertaken in accordance with Good Clinical Practice.
2.2. Safety Each subject had a routine medical examination within 3 weeks of the start of the study. A total volume of less than 300 ml of blood was taken from each subject during the study. All adverse events were recorded in detail.
2.3. Study design An open, randomised, four-way cross-over study was carried out.
2.6. Study procedures Subjects attended the Unit on four separate study days and were subject to food, alcohol, smoking and exercise restrictions as usually applies for such a study in healthy subjects. An indwelling cannula was inserted into a suitable forearm vein for blood sampling.
2.7. Sampling Blood samples (5 ml) for serum sumatriptan concentration were collected prior to dosing and 10, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 6 and 8 h post oral and suppository treatments, and prior to dosing and 2, 5, 10, 15, 20, 30, 45 min, 1, 1.5, 2, 3, 4, 6 and 8 h post subcutaneous and intranasal treatments. All urine voided 0–24 h post treatment was collected as 0–2-, 2–4-, 4–6-, 6–12- and 12–24h samples for determination of sumatriptan concentrations and sumatriptan pharmacologically inactive metabolite (GR49336) levels. Serum samples for determination of sumatriptan concentrations were analysed using HPLC with electrochemical detection. This method has been validated over the range 1.0–30 ng / ml. Urine samples for determination of sumatriptan concentrations were analysed using a direct injection HPLC method with electrochemical detection. Urine samples for determination of sumatriptan metabolite (GR49336) levels were analysed by a direct injection HPLC method with UV detection.
2.4. Subjects
2.8. Pharmacokinetic method
Twenty-four healthy subjects aged 22–49 years (mean age 35.9 years) and weighing 70.8–97.3 kg (mean weight 82.1 kg) completed the study. Although male or female subjects were eligible to take part in the study, only male subjects were recruited. Subjects fulfilled the usual inclusion and exclusion criteria for a study in the healthy population. In addition, subjects were excluded if they suffered from a cold or rhinitis on a study day or if they had diarrhea within 2 weeks prior to the study. No protocol deviation has been observed. Based on an estimate of within-subject coefficient of variation of 25% for AUC ` , the study had an estimated power of over 80% that the 90% confidence interval for the relative AUC ` of any two treatments would be contained within 80–125% of the true value.
The pharmacokinetic parameters were calculated using PCNONLIN Program-version 4.2 (SCI Software, KY, USA). The relative bioavailability of subcutaneous (s.c.) sumatriptan is 96% (Lacey et al., 1995) and, therefore, this route was used as a reference for the determination of non-parenteral bioavailabilities. The relative bioavailability (F ) after non-parenteral (np) routes was calculated using the following equation:
2.5. Treatments Each subject received in random order at least 3 days apart and on four separate occasions: 6 mg subcutaneous sumatriptan, 25 mg sumatriptan oral tablet, 25 mg sumatriptan suppository and 20 mg sumatriptan intranasal spray. The night before treatment with sumatriptan suppository, subjects self-administered a 4-g glycerol suppository to empty their bowels.
F 5 (AUC ` )np ? (Dose)sc /(AUC ` )sc ? (Dose)np The area under the curve from time zero to t max , AUC t max was calculated using a linear trapezoidal method. Serum clearance was obtained following subcutaneous administration and the apparent clearances (Cl /F ) were obtained for the other routes using the following equation: Cl /F 5 Dose /AUC ` The renal clearances were calculated using 4-h post-dose data as follows: Cl r 5 A e4 /AUC ` where A e4 is the cumulative amount of drug or metabolite excreted into a volume of urine recovered from time zero to 4 h post-dose and AUC 4 is the area under the serum concentration curve from time zero to 4 h post-dose.
C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
In addition to usual derived pharmacokinetic parameters (Cmax , t max , AUC ` and t 1 / 2z ), Cmax /AUC ` ratio was calculated as well as the partial area AUC t max . AUC t max is the area under the concentration–time curve from time zero to t max and describes solely the absorption phase. The deconvolution of data obtained by intranasal, rectal and oral administration was carried out using MKMODEL (Nick Holford, Biosoft, Cambridge, UK) and an in-housewritten program based on the point-area method (Vaughan and Dennis, 1978). The reference route used for the deconvolution of non-parenteral routes was predicted by modelling subcutaneous data with a two-compartment model: from the disposition parameters obtained, the whole curve from time zero has been calculated to simulate an intravenous administration. Cmax , AUC t max and AUC ` were divided by dose and log-transformed prior analysis of variance. Cmax /AUC ` has also been analysed using a standard analysis of variance (Pabst and Jaeger, 1990) after log-transformation. T max was analysed using the Wilcoxon signed rank test. No statistic was applied to rate of absorption analysis.
3. Results / discussion Serum concentrations were available on 23 subjects. The objectives of the study were to compare the absorption profile and estimate the bioavailability of different sumatriptan formulations based on analysis of Cmax , Cmax /AUC ` , AUC t max , AUC ` and t max . Cmax , t max and AUC ` are currently used as indirect measures of the
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average rate and of the extent of absorption and Cmax / AUC ` has recently been proposed as a new indirect measure of rate (Lacey et al., 1994a). Cmax /AUC ` has been shown to be a superior measure of rate of drug absorption than Cmax for immediate release dosage forms: it is a more powerful metric than Cmax in establishing bioequivalence when the formulations are truly bioequivalent, and Cmax /AUC ` is more sensitive than Cmax to detect differences in rate of drug absorption when they do exist. Another metric, the partial area under the curve AUC t max has been calculated in order to gain further information during the absorption phase, while this parameter describes only the rising part of the curve. AUC t max has previously been investigated as an alternative approach for assessment of rate of absorption (Chen, 1992; Lacey et al., 1994b). The partial area method was found to be more discriminating than Cmax and / or t max in the evaluation of the absorption rate of drugs and thus to be useful in the assessment of rate of absorption in bioequivalence studies. The cut-off time point for partial area is an important issue (Macheras et al., 1994), and may vary with the type of drug under study, depending on its clinical use and onset of action. Semi-logarithmic plots of the median serum sumatriptan concentrations are given in Fig. 1. Summary of the main pharmacokinetic parameters is presented in Table 1. Pharmacokinetic profiles were consistent with those observed in previous studies using the same formulations. The pharmacokinetics of intranasal sumatriptan showed multiple peaking for most subjects. A double absorption peak occurred with only few subjects following tablet administration, and rarely after suppository. Accordingly,
Fig. 1. Semi-logarithmic plots of the median concentrations of sumatriptan in serum for each route of administration. From Duquesnoy et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration.
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Table 1 Main pharmacokinetic parameters and associated statistics Parameter
Cmax (ng / ml) Cmax /AUC ` (1 / h) AUC t max (h?ng / ml) t max (h) F (s.c.) (%) t 1 / 2z (h) Cl r (l / min)
Route of administration
Geo. Mean 95% CI Geo. Mean 95% CI Geo. Mean 95% CI Median Range Geo. Mean 95% CI Geo. Mean 95% CI Geo. Mean 95% CI
S.c., 6 mg
Oral, 25 mg
Suppository, 25 mg
Intranasal, 20 mg
69.5 62.8–76.8 0.77 0.71–0.84 9.0 7.5–10.9 0.17 0.08–0.33 — — 1.9 1.7–2.0 0.22 0.19–0.25
16.5 13.5–20.1 0.31 0.27–0.35 8.7 6.1–12.5 1.50 0.50–2.00 14.3 11.4–17.9 1.7 1.4–1.9 0.17 0.14–0.21
22.9 18.4–28.6 0.32 0.26–0.39 14.6 11.3–18.8 1.00 0.75–3.00 19.2 15.3–24.1 1.8 1.6–2.2 0.17 0.14–0.21
12.9 10.5–15.9 0.27 0.24–0.30 7.4 5.0–10.8 1.50 0.25–3.00 15.8 12.6–19.8 1.8 1.7–2.0 0.21 0.18–0.25
t max was more variable (CV 62.8%) than other routes. The intranasal spray behaved very similar to the oral tablet in terms of absorption and excretion, perhaps due to a proportion of the dose being swallowed. Pharmacokinetic parameters (Cmax , t max , AUC ` and Cl r ) following 25 mg suppository in the current study are greater than in a previous study (Hussey et al., 1995). This may be explained by the demography: in the present study, the subjects were older and heavier than in the previous study, resulting in smaller values for the pharmacokinetic parameters. Statistical results of treatment comparisons are summarised in Table 2. No statistically significant differences between the intranasal or suppository and oral formulations were observed for the rate of absorption described by Cmax /AUC ` or time to maximum serum concentration, although Cmax tended to occur earlier with the suppository. The subcutaneous route was assumed to be 100% bioavailable and all values were calculated relative to this. The bioavailability relative to the subcutaneous route was
19.2% for the suppository, 15.8% for the intranasal spray and 14.3% for the oral tablet. The bioavailability of the suppository formulation was significantly greater than oral tablet; there was no significant difference between the oral and intranasal formulations. The maximum serum concentration normalised by the dose was 39% greater for the suppository than that achieved via the oral route, which did not differ from Cmax following intranasal administration. The partial area up to t max normalised by the dose was also much greater for the suppository than for other nonparenteral formulations due to higher values of Cmax . AUC t max demonstrated an important intersubject variability (CV up to 90% for the oral tablet). AUC t max was statistically greater with the suppository than with the oral tablet but no difference between the intranasal and the oral tablet was demonstrated. The average rate of absorption as determined by Cmax / AUC values was similar between the tablet, the suppository and the intranasal spray.
Table 2 Statistical results of treatment comparison for the main pharmacokinetic parameters Parameter AUC
b `
C bmax Cmax /AUC ` AUC t max b t max a
Treatment comparison
Estimate a (%)
90% CI
P value
Oral / s.c. Suppository / s.c. Intranasal / s.c. Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral Suppository / oral Intranasal / oral
14.3 19.2 15.8 134.7 111.0 139.1 97.5 103.5 87.2 166.3 104.7 0.00 20.13
11.8–17.2 15.9–23.2 13.1–19.1 111.6–162.7 91.9–134.1 113.8–169.9 79.8–119.1 89.5–119.8 75.3- 100.8 120.7–229.2 76.0–144.3 20.25–0.38 20.42–0.13
,0.001 ,0.001 ,0.001 0.011 0.359 0.008 0.832 0.693 0.120 0.010 0.811 0.902 0.529
Estimate for t max is median difference. Values for AUC ` , Cmax and AUC t max are dose-normalised.
b
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Time to peak concentration was similar for all nonparenteral routes (1–1.5 h) and in accordance with values found in the literature. The maximum serum concentration occurred earlier with the suppository than with the tablet and the intranasal spray, but with no statistical significance. All formulations demonstrated a similar elimination phase, and the profiles were consistent with those observed in previous studies using the same formulation. For most subjects, t 1 / 2z could be precisely estimated and was close to 2 h, which is consistent with values found in the literature. However, results of the non-compartmental pharmacokinetic analysis described above do not explain the observed rates of migraine relief at early time points after treatment by intranasal or rectal sumatriptan as compared ¨ to oral route (Becker, 1995; Gobel, 1995), in a number of placebo-controlled studies of sumatriptan. The deconvolution method produced estimates of timepoints rate of absorption. The median rate of absorption time profiles for intranasal, rectal and oral routes are given in Fig. 2. Although curves are similar, the rate of absorption–time curve is clearly shifted to the left for the intranasal route compared to the oral route: the highest rate occurred around 5 min post intranasal dose when it occurred 30 min post oral dose. These results may explain why, 15 min after dosing with intranasal sumatriptan, headache relief, defined by a change in headache severity score from 3 / 2 to 1 / 0, is observed in 38% of patients compared to only 2% after oral treatment (Fig. 3). A relatively high rate of absorption following sumatriptan suppository administration is reached earlier (0.25 h) than
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following oral administration (0.5 h). The rate of absorption for the suppository described then a plateau up to 1 h post dose and, from this time point, the three profiles looked very similar. Again, this may explain the difference observed in headache relief at early time points between the suppository and the oral tablet: 1 h post dose, 46% of patients experienced headache relief with the suppository versus 23% following oral tablet. Non-compartmental pharmacokinetic parameters used for bioequivalence studies may be not appropriate enough to investigate the local relationship between pharmacokinetics and drug effect. They only represent surrogate markers of rate of drug absorption which can be used to assess bioequivalence when formulations are compared but not to accurately describe the rate of absorption. Sumatriptan is a highly cleared compound that is eliminated from the body primarily by metabolism as the pharmacologically inactive indoleacetic acid analogue (GR49336). The amounts of sumatriptan excreted unchanged in urine in 24 h represented 1.8, 2.8 and 2.2% of the dose after the oral, suppository or intranasal routes, respectively. The amounts of GR49336 excreted in the urine in 24 h represent approximately 52.5, 27.2 and 39.2% of the dose by oral, suppository and intranasal routes, after correcting for molecular weight (31.03). The urinary recoveries of the main metabolite GR49336 after intranasal and rectal administration were lower compared to recovery after oral administration (respectively P50.02 and P,0.01), consistent with a partial escape from firstpass metabolism. In this study, adverse events characteristic of sumatriptan were mainly reported following the subcutaneous
Fig. 2. Median rate of absorption within the first 2 h post-dose for the intranasal, oral and suppository sumatriptan formulations. From Duquesnoy et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration.
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C. Duquesnoy et al. / European Journal of Pharmaceutical Sciences 6 (1998) 99 – 104
Fig. 3. Percentage of patients with headache relief (defined by a change in headache severity score from 3 / 2 to 1 / 0) winthin the first 2 h post-dose for the ] intranasal, oral and suppository sumatriptan formulations. From Duquesnoy et al. Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration.
injection (stinging at the injection site, sensations of tingling, etc.). The intranasal spray produced sensations involving the nose or throat and an unpleasant taste. Only a few adverse events, characteristic of sumatriptan, were experienced following the oral tablet and suppository. In general, adverse events were mild to moderate in severity, with all routes of administration being well tolerated. No serious adverse events occurred during the study.
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