CEPMAGH. Optimal routes of administration of ergotamine tartrate in-cluster headache patients. A pharmacokinetic study* Introduction

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1 Optimal routes of administration of ergotamine tartrate in-cluster headache patients. A pharmacokinetic study* K. Ekbom, A. E. Krabbe, G. Paalzow, L. Paalzow, P. Tfelt-Hansen and E. Waldenlind CEPMAGH Ekbom K., Krabbe, A. E., Paalzow, G., Paalzow, L., Tfelt-Hansen, P. & Waldenlind, E : Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study. Cephalalgia, Vol. 3, pp Oslo. ISSN Bioavailability and rate of absorption of ergotamine were studied in eight cluster headache patients outside attacks. In a cross-over design, approximately 2 mg ergotamine tartrate was administered as effervescent tablets, suppositories, and from an inhalation device, with 0.25 mg intravenously as the reference. Ergotamine in plasma was measured by high performance liquid chromatography with fluorescence detection from 5 to 420 min. For all three routes of administration, a similar low ( %) bioavailability of ergotamine was estimated. Only inhalation of ergotamine resulted in early (at 5 min) peak concentrations of ergotamine in plasma and is therefore most likely to relieve the short-lived attacks of cluster headache. The inhalation route for ergotamine poses problems, however, and we suggest ways of improving the inhalation device. 0 Cluster headache, ergotamine, pharmacokinetics. K. Ekbom, A. LE. Krabbe, G. Paalzow, L. Paalzow, P. Tfelt-Hansen and E. Waldenlind, Department of Neurology, Sodersjukhuset, Stockholm, Department of Pharmacology, Centrallaboratoriet, Apoteksbolaget AB, Solna, Sweden and Department of Neurology, Rigshospitalet, Copenhagen, Denmark. Correspondence and reprints requests to: P. Tfelt-Hansen, Department of Neurology, Rigshospitalet, D K-2100 Copenhagen 0, Denmark; Accepted 1982 I1 09. Introduction Ergotamine is generally regarded as the drug of choice for the treatment of cluster headache (1,2). Cluster headache attacks are of short duration ( min), so if a drug is to influence their natural course it has to be quickly available in the blood. In our experience ergotamine tablets are ineffective, whereas intravenous or intramuscular injections of ergotamine when effective give quick relief from attacks of cluster headache (within 2-15 mill, uncontrolled personal observation). Few patients can inject themselves, so an ergotarnine preparation which quickly reaches the blood would be valuable. Several ergotamine preparations-inhalator, effervescent tablets, sublingual tablets and fast dissolving tablets-have been developed to increase the rate of absorption. Because of the lack of suitable methods for determining the amount of ergotamine in * Presented in part at a Meeting of the Scandinavian Migraine Society, June 1981, Roros, Norway. the blood, neither the rate of absorption nor the amount of the drug absorbed have been documented. The aim of the present study was to investigate the rate and amount of ergotamine absorbed from an inhalation device, effervescent tablets, and suppositories. Intravenous ergotamine was also given to allow exact calculation of the bioavailability of ergotamine for these three forms of administration. Patients and methods Four male periodic cluster headache patients from each of our clinics were asked to join the study. Since they were to remain without any medication during the study period, they were selected as not being likely to have a cluster period within the following three months. Patients with hepatic, renal and cardiovascular diseases or with a history of dyspepsia were excluded. Thus, eight patients with a mean age of 35 years (range 23-61)

2 16 K. Ekborn et al. CEPHALALGIA 3 (1983) were studied. Routine blood chemistry including liver enzymes was normal in all patients. All gave their informed consent. Investigations of ergotamine administration were done at least at weekly intervals. The patients came to the clinic in the mornirg, having fasted since midnight. After a blood sample had been drawn they received 0.25 mg ergotamine tartrate* i.v. (Gynergen@, Sandoz), or 2 mg ergotamine tartrate plus 50 mg caffeine as an effervescent tablet (EffergotB, Wander) dissolved in 150 ml water, or 2mg ergotamine tartrate plus 100 mg caffeine as a suppository (Gynergen Caffeine@, Sandoz), or six puffs of 0.36mg each (a total of 2.16 mg) ergotamine tartrate within 2 min of an inhaler (Medihaler Ergotamine@, Riker). The inhalation technique was rehearsed several times with a dummy inhaler before the active drug was given. Blood samples were then drawn after 5, 10,20,30,60,120,180,240,300 and 420 min. Each time, 10ml blood was drawn and immediately centrifuged. Plasma was kept deep-frozen at -20 C until analysed. The analysis of ergotamine in plasma samples was performed with high performance liquid chromatography with fluorescence detection, using ergocristilie as the internal standard (3). The practical detection limit with a 3 ml sample was determined to be 0.1 ng/ml. Multiexponential equations were fitted to the obtained plasma concentration data after i.v. administration by the nonlinear least squares regression program NONLIN run on an IBM 370 computer. Pharmacokinetic parameters were calculated according to standard formulas (4). Area under the curve (AUC) for other routes of administration was calculated with the trapezoidal rule. Bioavailability was then calculated from the formula (e.g. for rectal AUCrectaI X D0sei.v. route) AUCi.v. X Doserectal In most cases the exact AUC could not be calculated (ergotamine undetectable) ~ so an * Ergotamine in solution is partly epimerised to a stereochemic isomer ergotaminine. Thus a solution of ergotamine tartrate contains 60% ergotamine and 40% ergotaminine. The dose used in the calculations of pharmacokinetic parameters and bioavailability has been corrected for this. estimate of the maximal possible AUC for 10 h was calculated with the use of 0.05 ng/ ml when ergotamine was undetectable. This estimate was then used for calculating the maximal possible bioavailability. The plasma concentration data were analysed statistically with two-sided analysis of variance for difference between administration forms. Results The pharmacokinetic parameters for i.v. ergotamine are shown in Table 1. The very low and variable concentrations of ergotamine in plasma after the other three routes of administration are shown in Tables 2-4. At 5 min the ergotamine concentrations obtained in plasma were significantly higher (p < 0.05, two-sided analysis of variance) after inhalation than they were after the other two routes of administration; later on, concentrations did not differ significantly. For inhalation the peak was observed at 5 min, the concentrations at this time always being higher than the later ones (p < 0.05, sign test). After inhalation the ergotamine concentrations declined in a seemingly biexponential manner as illustrated in Fig. 1. Calculation of bioavailability could be made in only three cases. For the rectal route the bioavailability of ergotamine was 2.8% in pt. no. 6 and for inhalation 3.3% (pt. no. 1) and 4.2% (pt. no. 3). In all other cases only the maximal possible bioavailability of ergotamine could be estimated. This estiaate of bioavailability had a mean value of x 0 C it Ergotarnine Pulmonal administration I min Fig. 1. Mean plasma concentration of ergotamine after inhalation of 2.16 mg ergotarnine tartrate in eight patients.

3 CEPHALALGIA 3 (1983) Ergotarnine for cluster headache 17 Table 1. Pharmacokinetic parameters for 0.25 mg ergotamine tartrate intravenously in eight cluster headache patients. Patient number Area under the plasma concentration curve ng X hr X ml+' Volume of distribution for the Pphase 1 x kg-' Plasma clearance 1 x kg-' x hr-' Half life for the Pphase hr Mean Range ~~ 3.91 ( ) ( ) ( ) ( ) Table 2. Ergotamine concentration (ndml) in plasma of eight patients after 2mg ergotamine tartrate as an effervescent tablet. Min after administration Pt. no ~ -~ Mean* Dashes: Concentration of ergotamine below the detection limit of 0.1 ng/ml. * In the calculation of the mean, levels below detection limit were given a value of 0.05 ng/ml Table 3. Ergotamine concentration (ndml) in plasma of eight patients after 2mg ergotamine tartrate as a suppository. Min after administration Pt. no ~ Mean* Notes: As for Table 2.

4 18 K. Ekbom et al. CEPHALALGIA 3 (1983) Table 4. Ergotamine concentration (ng/ml) in plasma of eight patients after 2.16 mg (six puffs) ergotamine tartrate by inhalation. Mn after administration Pt. no Mean* Notes: As for Table % (range 052.2%: n = 6) for inhalation, 1.8% (range %, n = 7) for suppositories, and 1.5% (range %, n = 8) for effervescent tablets. No side-effects were observed. Discussion Evidence from the literature of the rate of absorption from different ergotamine preparations was available and determined our choice of preparations for investigation. Effervescent ergotamine tablets containing caffeine were found suitable, since ergotamine in solution is absorbed in man with an invasion half life of 30 min (5), and caffeine should enhance the rate of absorption (6). Observations of the effect of ergotamine on temporal artery pulsations during migraine attacks indicated a quicker absorption of the drug from suppositories than from tablets (7). Inhalation of ergotamine was introduced in order to deliver the drug rapidly to the blood by transpulmonary absorption (8). Relief of migraine and cluster headache attacks has been reported to occur within 15min (8,9) with this route of administration. In our eight cluster headache patients the kinetic parameters of ergotamine after intravenous administration of 0.25 mg ergotamine tartrate are similar to our previous results with 0.5 mg intravenously in 10 mig- raine patients (10). The mean plasma clearance of X kg-' X h-', which varied four-fold in our patients, is similar to the mean value of X kg-' X h-*, which varied three-fold in migraine patients (10). There is thus no indication of a difference in metabolism and therefore pharmacokinetic studies on ergotamine should be comparable in these two groups of patients. Because of the very low concentrations of ergotamine in plasma, in most cases bioavailability of ergotamine could only be calculated as the maximal possible. In the three cases in which the bioavailability could be calculated it was 34%. This figure probably represents the real maximal values for ergotamine. In a previous study of ergotamine tablets no ergotamine was detectable in plasma with the present HPLC method and a maximal possible bioavailability of 1% was estimated (11). Studies on oral and rectal ergotamine administration, where radio immunoassay was used for ergotamine detection, showed somewhat higher plasma concentrations of the drug in plasma, but the bioavailability could not be calculated (12,13). The very low oral bioavailability of ergotamine is probably due to the extensive first-pass extraction by the liver, since 62% of orally administered ergotamine is absorbed (5). In a recent study on dihydroergotamine, a 9699% extraction by the liver of the drug absorbed resulted in an oral

5 CEPHALALGIA 3 (1983) bioavailability of 0.5% (14). In rectal administration the concentrations of ergotamine in plasma are marginally higher than after oral administration. This indicates that some of the rectally administered drug is absorbed to the systemic circulation, thereby escaping the first-pass extraction by the liver. The low bioavailability of ergotamine inhaled through using an aerosol is not surprising since the major part of a drug administered with the use of an aerosol is swallowed (15). The main purpose of the present study was to investigate the rate of absorptionthe time to peak concentration of ergotamine-of the three routes of administration. Estimating time to peak is difficult because of the very low concentrations of ergotamine obtained in plasma. For effervescent tablets the results give no indication of the time to peak. For suppositories the results indicate a time to peak of 60 min. A similar time to peak for ergotamine suppositories was found with a radio immunoassay for ergotamine (12). By contrast, inhalation of ergotamine resulted in a peak at 5min. This early peak and a similar mean plasma concentration curve seen after intravenous administration indicate an almost instantaneous delivery of ergotamine to the blood by the inhalation route. Buccal absorption of measurable amounts of ergotamine from aerosol particles deposited in the mouth is unlikely. Previously, we were unable to detect ergotamine in plasma for 2h after administration of 2 mg ergotamine tartrate as a sublingual tablet (16). The quick appearance of ergotamine in plasma after inhalation is therefore most likely due to transpulmonary absorption of ergotamine. Our present results indicate that, apart from injections of ergotamine, inhalation is the route of administration most likely to relieve the short-lived cluster headache attacks. But there are several problems with the inhalation of ergotamine. The technique is difficult even for such regular users of an aerosol as asthmatic patients (17). Even after practising the technique several times we found very variable plasma concentrations of ergotamine. Furthermore, a dose of 2.16 mg ergotamine tartrate requires as many as six puffs. Finally, the presently Ergotamine for cluster headache 19 available inhalation device is constructed to deliver an aerosol with the same particle size (median 3.5 pm) as used for bronchodilatator treatment. Ergotarnine in aerosol form is used to obtain a systemic effect and not a local effect in the bronchial tree. The particle size in the ergotamine aerosol might not therefore be optimal for this purpose. There is little knowledge about inhaled ergotamine in the treatment of cluster headache. Ergotamine inhalation was used in an open trial in 12 patients (9). Relief from pain was obtained within half an hour in 71% out of 114 attacks. Kudrow (1) mentions that of 100 patients treated, 79 had obtained significant relief from sublingual or inhalant ergotamine preparations. Since inhaled ergotamine was better than placebo in the treatment of migraine attacks (18), it is tempting to try to demonstrate its effect on cluster headache attacks in a controlled clinical trial. Before embarking on a comprehensive clinical trial we suggest that attempts should be made to optimize the dose of the single puff and also the particle size of the ergotamine aerosol. References 1. Kudrow L. Cluster headache. Mechanism and management. Oxford/New Yorfloronto: Oxford University Press, Ekbom K. Therapy of cluster headache. Migraine News 1974:27 3. Edlund P 0. Determination of ergot alkaloids in plasma by high performance liquid chromatography and fluorescence detection. J Chromatogr 1981 ;226: Wagner J G. Fundamentals of clinical pharmacokinetics. Drug intelligence publications. Illinois: Hamilton, Aellig W H, Niiesch E. Comparative pharmacokinetic investigations with tritium-labeled ergot alkaloids after oral and intravenous administration in man. Int J Clin Pharmacol Biopharm 1977;15: Schmidt R, Fanchamps A. Effect of caffeine on intestinal absorption of ergotamine in man. Eur J Clin Pharmacol 1974;7: Brazil P, Friedman A P. Further observations in craniovascular studies. Neurology 1957;7: Blumenthaler L S, Fuchs M. Transpulmonary absorption of ergotamine tartrate for vascular headaches. Med Ann D C 1961;30:1&13

6 20 K. Ekbom et al. CEPHALALGIA 3 (1983) 9. Graham J R, Malvea B P, Gramm H F. Aerosol ergotamine tartrate for migraine and Horton s syndrome. New Eng J Med 1960;263: Ibraheem J J, Paalzow, L, Tfelt-Hansen P. Kinetics of ergotamine after intravenous and intramuscular administration in migraine sufferers. Eur J Clin Pharmacol 1982;23: Ekbom K, Paalzow L, Waldenlind E. Low biological availability of ergotamine tartrate after oral dosing in cluster headache. Cephalalgia 1981;1: Ala-Hurula V, Myllyla V V, Arvela P, Heikkila J, Karki N, Hokkanen E. Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration. Eur J Clin Pharmacol 1979; 15: Ala-Hurula V, Myllyla V V, Arvela P, Karki N, Hokkanen E. Systemic availability of ergotamine tartrate after three successive doses and during continuous medication. Eur J Clin Pharmacol 1979 ; 16 : Little P J, Jennings G L, Skews H, Bobik A. Bioavailability of dihydroergotamine in man. Br J Clin Pharmacol 1982;13: Newman S P, Pavia D, Clarke S W. How should a pressurized Padrenergic bronchodilator be inhaled? Eur J Respir Dis 1981;62: Tfelt-Hansen P, Paalzow, L, Ibraheem J J. Bioavailability of sublingual ergotamine. Br J Clin Pharmacol 1982;13: Shim C, Williams Jr, M H. The adequacy of aerosol from cannister nebulizers. Am J Med 1980 ;69: Crooks J, Stephen S A, Brass W. Clinical trial of inhaled ergotamine tartrate. Br Med J 1964;1:221-4