Method of rapidly achieving therapeutic concentrations of triptans for treatment of migraines and cluster headaches
Compositions, devices and methods employing therapeutic concentrations of a triptan for treatment of migraine are described. Also described are methods for treating migraine by administering zolmitriptan using an adhesive dermally-applied microarray (ADAM) resulting in rapid and durable pain relief, pain freedom and reduction in most bothersome migraine-associated symptoms (MBS), or a combination thereof.
1. A method for treating migraine in a patient in need thereof, comprising intracutaneously administering about 3.8 mg zolmitriptan using an adhesive dermally-applied microarray (ADAM) comprising a plurality of microprojections coated with the zolmitriptan, the microprojections adapted to penetrate or pierce the stratum corneum of the patient, wherein the method provides rapid and durable pain relief and pain freedom and wherein zolmitriptan has a pharmacodynamic effect that arises from combined activities of zolmitriptan and its primary metabolite N-desmethyl zolmitriptan (NDZ).
2. The method of claim 1 , wherein the patient is pain-free at 2 hours post-dose and does not have migraine recurrence within 24 hours post-dose.
3. The method of claim 1 , wherein on-rate constant (k on ) is 6 to 10 times faster for zolmitriptan and NDZ than for sumatriptan on both the 5-HT 1B and 5-HT 1D receptors based on in vitro binding data.
4. The method of claim 3 , wherein the on-rate constant (k on ) for zolmitriptan on 5-HT 1B receptors is about 0.053 nM −1 min −1 and the on-rate constant (k on ) for zolmitriptan on 5-HT 1D receptors is about 0.174 nM −1 min −1 based on in vitro binding data.
5. The method of claim 3 , wherein equilibrium dissociation constant (K D ) of zolmitriptan on 5-HT 1B receptors is about 1.47 nM and equilibrium dissociation constant (K D ) of zolmitriptan on 5-HT 1D receptors is about 0.34 nM based on in vitro binding data.
6. The method of claim 3 , wherein on-rate constant (k on ) of NDZ on 5-HT 1B receptors is about 0.054 nM −1 min −1 and on-rate constant (k on ) of NDZ on 5-HT 1D receptors is about 0.126 nM −1 min −1 based on in vitro binding data.
7. The method of claim 3 , wherein equilibrium dissociation constant (K D ) of NDZ on 5-HT 1B receptors is about 0.92 nM and equilibrium dissociation constant (K D ) of NDZ on 5-HT 1D receptors is about 0.43 nM based on in vitro binding data.
8. The method of claim 1 , wherein zolmitriptan and NDZ have higher affinity than sumatriptan for 5-HT 1B and 5-HT 1D receptors based on in vitro binding data.
9. The method of claim 8 , wherein the affinities of zolmitriptan and NDZ for both 5-HT 1B and 5-HT 1D receptors are similar based on in vitro binding data.
10. The method of claim 1 , wherein zolmitriptan rapidly approaches about 98% occupancy at 5-HT 1B receptors and rapidly approaches an asymptotic level of receptor occupancy of greater than about 98% at 5-HT 1D receptors based on in vitro binding data.
11. The method of claim 10 , wherein occupancy by sumatriptan diminishes quicker than occupancy by zolmitriptan/NDZ at 5-HT 1B and at 5-HT 1D receptors based on in vitro binding data.
12. The method of claim 11 , wherein zolmitriptan/NDZ maintain a higher and more sustained level of receptor occupancy than sumatriptan at 5-HT 1B receptors based on in vitro binding data.
13. The method of claim 10 , wherein at 5-HT 1B and 5-HT 1D receptors, zolmitriptan/NDZ display higher receptor occupancy than sumatriptan at all time points beyond 30 minutes post-dose based on in vitro binding data.
14. The method of claim 1 , wherein fractional occupancy peaks at about 35xKD for zolmitriptan/NDZ at C max at 5-HT 1B receptors and fractional occupancy peaks about 145xKD for zolmitriptan+NDM-zolmitriptan at C max at 5-HT D receptors based on in vitro binding data.
15. The method of claim 1 , wherein observed in vitro residence times for zolmitriptan, NDZ, and sumatriptan on both 5-HT 1B and 5-HT 1D receptors are considerably less than elimination half life (t 1/2 ).
16. The method of claim 1 , wherein time-course of physiological responses to zolmitriptan is affected by ligand-receptor interactions for zolmitriptan/NDZ, target receptor density, agonist intrinsic efficacy, and drug partitioning into receptor biophase, or any combination thereof.
17. A method for treating migraine in a patient in need thereof, comprising intracutaneously administering about 3.8 mg zolmitriptan using an adhesive dermally-applied microarray (ADAM) comprising a plurality of microprojections coated with the zolmitriptan, the microprojections adapted to penetrate or pierce the stratum corneum of the patient, wherein the method provides rapid absorption of zolmitriptan with higher 2-hour exposure than orally delivered zolmitriptan.
18. The method of claim 17 , wherein zolmitriptan is associated with a high rate of pain relief and a low incidence of moderate or severe pain recurrence for migraine treatment.
19. The method of claim 1 , wherein the about 3.8 mg zolmitriptan is administered by two microarrays each comprising about 1.9 mg zolmitriptan.
20. A method for treating migraine in a patient in need thereof, comprising the steps of:
(a) providing a composition comprising 3.8 mg zolmitriptan, and
(b) intracutaneously administering the composition comprising the zolmitriptan using an adhesive dermally-applied microarray (ADAM) comprising a plurality of microprojections coated with the zolmitriptan, the microprojections adapted to penetrate or pierce the stratum corneum of the patient,
wherein the method results in pain relief, pain freedom, reduction in most bothersome migraine-associated symptoms (MBS), or a combination thereof.
21. The method of claim 20 , wherein when the treatment is administered to a population of patients, the treatment results in at least one of the following outcomes:
(a) about 23.2% of the patients achieve pain relief at 0.25 hour post-dose,
(b) about 46.3% of the patients achieve pain relief at 0.5 hour post-dose,
(c) about 56.1% of the patients achieve pain relief at 0.75 hour post-dose,
(d) about 68.3% of the patients achieve pain relief at 1 hour post-dose,
(e) about 80.5% of the patients achieve pain relief at 2 hours post-dose,
(f) about 81.7% of the patients achieve pain relief at 3 hours post-dose,
(g) about 82.9% of the patients achieve pain relief at 4 hours post-dose,
(h) about 41.5% of the patients achieve pain freedom at 2 hours post-dose,
(i) about 68.3% of the patients achieve freedom from MBS at 2 hours post-dose,
(j) about 15.2% of the patients have pain recurrence 24 hours after achieving pain relief,
(k) about 21.2% of the patients have pain recurrence 48 hours after achieving pain relief, and
(l) fast onset of pain relief that is not associated with a high rate of recurrence.