Roger Yates

Preliminary Studies of the Pharmacokinetics and Tolerability of Zolmitriptan Nasal Spray in Healthy Volunteers

Two preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray were conducted, each involving 12 healthy volunteers. In study 1, an initial double‐blind, dose escalation phase (placebo or 2.5, 5.0, or 10 mg zolmitriptan intranasally) was followed by an open crossover phase in which all subjects received 10 mg zolmitriptan as a nasal spray, tablet, and oral solution. In study 2, subjects received, on three separate occasions, zolmitriptan 2.5 mg as an intranasal solution at pH7.4, at pH 5.0, and as an oral tablet. In study 1, plasma concentrations of zolmitriptan and its active metabolite, 183C91, were broadly dose proportional. Plasma concentrations of zolmitriptan were detected earlier following nasal spray administration than after either tablet or oral solution. Similarly, in study 2, zolmitriptan was absorbed more rapidly following nasal spray administration with detectable plasma concentrations 5 minutes after dosing. Plasma levels were maintained at a plateau between 1 and 6 hours postdose, then decreased with a half‐life of approximately 3 hours. There was no statistically significant difference for AUC or Cmax values between the two nasal spray solutions or between nasal spray and oral formulations. Other pharmacokinetic parameters for zolmitriptan were similar between the formulations. Plasma concentrations of 183C91 were higher for the first 2 hours after oral than after nasal spray administration. All formulations of zolmitriptan were well tolerated.

Pharmacokinetics, dose proportionality, and tolerability of single and repeat doses of a nasal spray formulation of zolmitriptan in healthy volunteers.

The objective of this study was to investigate the pharmacokinetics, dose proportionality, and tolerability of a range of single and multiple doses of a nasal spray formulation of zolmitriptan in a randomized, double‐blind, placebocontrolled, balanced, incomplete crossover study. Thirty healthy male or female volunteers received two of five dose levels of zolmitriptan nasal spray: 0 (placebo), 0.5,1,2.5, and 5 mg. At each level, treatment comprised a single dose on day 1 and two doses (separated by 2 h) on each of days 2, 3, and 4. Zolmitriptan was well tolerated, and symptoms were generally mild and of short duration. The most commonly reported adverse events were taste disturbance, paresthesia, hyperesthesia, headache, and nasal/throat discomfort. Volunteers generally reported fewer adverse events during the multiple‐dose phase than after the single‐dose phase. Zolmitriptan was detectable in plasma within 15 minutes, and tmax was similar for each dose and after single and multiple dosing. Dose proportionality was shown for the Cmax and AUC of both zolmitriptan and its active metabolite, 183C91. Mean t1/2 for zolmitriptan and 183C91 was approximately 3 hours. It was concluded that the pharmacokinetics (Cmax and AUC) for both zolmitriptan and 183C91 was proportional to dose after both single and multiple dosing. Nasal spray zolmitriptan was well tolerated; the frequency and nature of adverse events did not increase after multiple dosing.

Effects of the aromatase inhibitor anastrozole on serum oestrogens in Japanese and Caucasian women.

Purpose: Substantial differences in plasma oestrogen disposition have been reported between Japanese and Caucasian women, but there are currently few data available on the relative endocrinological effects of aromatase inhibitors in these two groups. Hence, the effects of the nonsteroidal aromatase inhibitor anastrozole on serum oestrogen concentrations were compared in 24 healthy postmenopausal Japanese women and 24 healthy postmenopausal Caucasian women. Methods: Anastrozole, 1 mg/day, was given once daily for 16 days. Serum oestradiol and oestrone sulphate levels were measured on three consecutive days beginning 2 days before the first dose, and on a further three consecutive days beginning on the penultimate day of dosing. Trough concentrations of anastrozole (measured 24 h after dosing) were also determined during the same periods. Results: There were no substantial differences in plasma oestrogen concentrations between the Japanese and Caucasian women at baseline. On average, anastrozole suppressed serum oestradiol and oestrone sulphate levels by approximately 87% and 93%, respectively, for both Japanese and Caucasian women, and minimum plasma anastrozole concentrations at steady-state (anastrozole Cmin) were also similar in both groups. Statistical analysis of serum oestradiol and serum oestrone sulphate levels, and plasma anastrozole Cmin showed that there were no statistically significant differences between the Japanese and Caucasian women. Conclusion: Neither the pharmacodynamic effects of anastrozole on serum oestrogens nor the pharmacokinetics of anastrozole differ between postmenopausal Japanese and Caucasian women. Hence, these findings suggest that the therapeutic benefits of anastrozole in Caucasians will be predictive of the drugs effect in Japanese women and support the use of anastrozole in postmenopausal Japanese women with breast cancer.

Distribution of Intranasal 11C-Zolmitriptan assessed by Positron Emission Tomography

Nine healthy volunteers aged 18-28 years were recruited into this open, single-centre, two-phase trial. In phase 1, two volunteers received a single dose of 11C-zolmitriptan 2.5 mg administered as a nasal spray and then underwent positron emission tomography (PET) scanning to determine the most appropriate times for scanning in phase 2. In phase 2, six volunteers received two doses and an additional volunteer one dose of 11C-zolmitriptan 2.5 mg intranasally. Volunteers underwent PET scanning over sectors covering one of the nasopharynx, lungs or abdomen, for up to 1.5 h postdose. The brain was also scanned and plasma zolmitriptan levels were measured. Almost 100% of the administered dose was detected in the nasopharynx immediately after dosing. This declined thereafter to about 50% at 20 min and to 35% at 80 min after dosing. Radioactivity appeared slowly in the upper abdomen, with 25% of given radioactivity detected at 20 min and persisting until 80 min after dosing. Minimal radioactivity was detected in the lungs. Radioactivity was detectable within brain tissue suggesting central penetration of zolmitriptan. Zolmitriptan in plasma had approached its maximum concentration by 15 min postdose. The data indicate initial absorption across the nasal mucosa contributing to an early systemic availability. 11C-Zolmitriptan administered intranasally was well tolerated.

Distribution of Zolmitriptan into the CNS in Healthy Volunteers

AbstractObjective: Triptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration. Subjects and methods: Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information.The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data. Results: PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors. Conclusion: This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.

True nasopharyngeal absorption of zolmitriptan after administration via nasal spray in healthy male volunteers

ObjectiveThe aim of this study was to quantify the fraction of zolmitriptan that is absorbed directly through the nasal mucosa after administration of zolmitriptan nasal spray.MethodsFollowing confirmation that activated charcoal blocks gastrointestinal absorption of zolmitriptan, healthy male volunteers were given zolmitriptan nasal spray 5mg (with and without charcoal) and zolmitriptan 5mg oral tablets (with and without charcoal) in a randomized, crossover design. Blood samples for pharmacokinetic analysis were collected up to 9 hours post-dose. Twelve subjects completed all treatments.ResultsThe fraction of bioavailable dose absorbed through the nasal mucosa was calculated to be 29% (95% CI 19, 43). Intranasal absorption contributed 71% of zolmitriptan exposure during the first hour post-dose and 49% during the first 2 hours.ConclusionsThis study confirms true nasopharyngeal absorption of zolmitriptan after nasal spray administration. This route of absorption contributed approximately 30% of total zolmitriptan exposure, with much higher proportions of exposure seen during the first 2 hours post-dose when patients would expect to benefit from treatment. These results suggest that intranasal absorption plays an important role in the early onset of efficacy of zolmitriptan nasal spray seen in clinical trials.

Effects of the antimigraine compound zolmitriptan (‘Zomig’) on psychomotor performance alone and in combination with diazepam in healthy volunteers

Zolmitriptan (ZomigTM) is a 5HT1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following “treatments” as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg + diazepam 10 mg, zolmitriptan 5 mg + diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination.