Background
Methods
Extraction of pharmacokinetic and pharmacodynamic parameters
Extraction of clinical trial data
Calculation of drug concentration and serotonin 5-HT1B/1D receptor occupancy
Calculation of total amount of exposure to drug and serotonin 5-HT1B/1D receptor occupancy
Calculation of systemic drug transfer and serotonin 5-HT1B/1D receptor binding rates
Analysis of relationship between parameters for receptor occupancy and clinical effects of each drug following administration
Results
Extraction of pharmacokinetic and pharmacodynamic parameters
Drugs | Administration route (dosage form) | Standard dose in Japan (mg) | MW (g/mol) | Plasma unbound fraction; fu | Ki1B* (nM) | Ki1D* (nM) |
---|---|---|---|---|---|---|
SC | 3 | 295.41 | 0.66 | 12.6 | 12.6 | |
PO | 50 | |||||
NS | 20 | |||||
PO | 2.5 | [unchanged drug] | [unchanged drug] | [unchanged drug] | [unchanged drug] | |
ODT | 287.30 | 0.8 | 6.31 | 2.51 | ||
[active metabolite] | [active metabolite] | [active metabolite] | [active metabolite] | |||
273.36 | 0.75 | 1.58 | 0.5 | |||
Eletriptan[17] | PO | 20 | 382.52 | 0.13 | 10.0 | 1.2 |
PO | 10 | 269.35 | 0.86 | 138 | 13.1 | |
ODT | ||||||
Naratriptan[20] | PO | 2.5 | 335.47 | 0.71 | 2.2 | 2.3 |
Extraction of clinical trial data
t (Time after administration) (hr) | 0.17 | 0.25 | 0.5 | 0.75 | 1 | 1.5 | 2 | 3 | 4 |
---|---|---|---|---|---|---|---|---|---|
SC 3 mg※ | 30.3 | 37.0-63.3 | 62.0-81.8 | 73.7 | 78.9-93.9 | - | - | - | - |
SC 6 mg | - | 71.4 | 71.4 | - | 85.7 | - | - | - | - |
Sumatriptan[23] | |||||||||
PO 50 mg※ | - | - | 7 | - | 32 | - | 41 | 63 | 68 |
PO 100 mg | - | - | 10 | - | 29 | - | 55 | 65 | 68 |
Sumatriptan[24] | |||||||||
NS 10 mg | - | - | 19.3 | - | 33.3 | - | 58.9 | - | 62.5 |
NS 20 mg※ | - | - | 15.7-27.8 | - | 31.5-56.4 | 49.1 | 63.0-70.9 | - | 73.2 |
Zolmitriptan[16] | |||||||||
PO 2.5 mg※ | - | - | 9.8 | - | 28.3 | - | 55.6 | - | 76.5 |
Eletriptan[25] | |||||||||
PO 20 mg※ | - | - | 13 | - | 37 | - | 64 | - | 86 |
PO 40 mg | - | - | 12 | - | 33 | - | 67 | - | 88 |
Rizatriptan[26] | |||||||||
PO 10 mg※ | - | - | 10.1 | - | 26.1 | 50.7 | 59.4 | - | - |
Naratriptan[27] | |||||||||
PO 1 mg | - | - | - | - | 21.2 | - | 41.3 | 60.6 | 71.2 |
PO 2.5 mg※ | - | - | - | - | 15.6 | - | 50.5 | 71.6 | 77.1 |
Calculation of serotonin 5-HT1B/1D receptor occupancy at time of administration of each drug
Calculation of total amount of exposure to drug and serotonin 5-HT1B/1D receptor occupancy
t (Time after administration) (hr) | 0.17 | 0.25 | 0.5 | 0.75 | 1 | 1.5 | 2 | 3 | 4 |
---|---|---|---|---|---|---|---|---|---|
(1) AUC
cp
(ng · hr/mL)
| |||||||||
Sumatriptan | |||||||||
SC 3 mg※ | 4.9 | 8.3 | 17.0 | 22.6 | 26.4 | - | - | - | - |
SC 6 mg | - | 17.0 | 34.8 | - | 51.9 | - | - | - | - |
Sumatriptan | |||||||||
PO 50 mg※ | - | - | 4.7 | - | 15.7 | - | 40.0 | 66.4 | 87.4 |
PO 100 mg | - | - | 9.7 | - | 32.6 | - | 83.3 | 138.6 | 181.6 |
Sumatriptan | |||||||||
NS 10 mg | - | - | 1.2 | - | 4.0 | - | 10.7 | - | 18.2 |
NS 20 mg※ | - | - | 3.5 | - | 7.2 | 12.8 | 19.4 | - | 38.0 |
Zolmitriptan | |||||||||
PO 2.5 mg※ | - | - | 0.51 | - | 1.87 | - | 5.4 | - | 11.3 |
Eletriptan | |||||||||
PO 20 mg※ | - | - | 7.7 | - | 25.2 | - | 56.9 | - | 99.2 |
PO 40 mg | - | - | 12.4 | - | 43.0 | - | 105.9 | - | 214.1 |
Rizatriptan | |||||||||
PO 10 mg※ | - | - | 3.6 | - | 11.8 | 20.6 | 28.5 | - | - |
Naratriptan | |||||||||
PO 1 mg | - | - | - | - | 0.8 | - | 2.7 | 4.6 | 6.4 |
PO 2.5 mg※ | - | - | - | - | 2.1 | - | 6.6 | 11.2 | 15.6 |
(2) AUC
Φ
1B
(% · hr)
| |||||||||
Sumatriptan | |||||||||
SC 3 mg※ | 11.3 | 18.3 | 39.7 | 59.6 | 77.7 | - | - | - | - |
SC 6 mg | - | 19.6 | 42.7 | - | 85.0 | - | - | - | - |
Sumatriptan | |||||||||
PO 50 mg※ | - | - | 19.3 | - | 58.9 | - | 140.0 | 222.5 | 300.4 |
PO 100 mg | - | - | 21.8 | - | 66.3 | - | 156.2 | 247.0 | 334.9 |
Sumatriptan | |||||||||
NS 10 mg | - | - | 14.5 | - | 38.9 | - | 93.2 | - | 169.2 |
NS 20 mg※ | - | - | 26.3 | - | 54.6 | 87.5 | 122.6 | - | 243.2 |
Zolmitriptan | |||||||||
PO 2.5 mg※ | - | - | 17.1 | - | 55.2 | - | 140.7 | - | 314.9 |
Eletriptan | |||||||||
PO 20 mg※ | - | - | 12.5 | - | 38.6 | - | 87.3 | - | 163.2 |
PO 40 mg | - | - | 15.3 | - | 47.9 | - | 113.3 | - | 237.2 |
Rizatriptan | |||||||||
PO 10 mg※ | - | - | 6.2 | - | 19.9 | 34.4 | 47.8 | - | - |
Naratriptan | |||||||||
PO 1 mg | - | - | - | - | 36.9 | - | 101.2 | 165.7 | 229.1 |
PO 2.5 mg※ | - | - | - | - | 53.9 | - | 135.1 | 216.7 | 297.6 |
(3) AUC
Φ
1D
(% · hr)
| |||||||||
Sumatriptan | |||||||||
SC 3 mg※ | 11.3 | 18.3 | 39.7 | 59.6 | 77.7 | - | - | - | - |
SC 6 mg | - | 19.6 | 42.7 | - | 85.0 | - | - | - | - |
Sumatriptan | |||||||||
PO 50 mg※ | - | - | 19.3 | - | 58.9 | - | 140.0 | 222.5 | 300.4 |
PO 100 mg | - | - | 21.8 | - | 66.3 | - | 156.2 | 247.0 | 334.9 |
Sumatriptan | |||||||||
NS 10 mg | - | - | 14.5 | - | 38.9 | - | 93.2 | - | 169.2 |
NS 20 mg※ | - | - | 26.3 | - | 54.6 | 87.5 | 122.6 | - | 243.2 |
Zolmitriptan | |||||||||
PO 2.5 mg※ | - | - | 21.6 | - | 66.6 | - | 161.2 | - | 351.8 |
Eletriptan | |||||||||
PO 20 mg※ | - | - | 22.3 | - | 67.4 | - | 156.0 | - | 322.9 |
PO 40 mg | - | - | 23.2 | - | 70.2 | - | 164.2 | - | 350.5 |
Rizatriptan | |||||||||
PO 10 mg※ | - | - | 19.4 | - | 59.3 | 99.8 | 139.5 | - | - |
Naratriptan | |||||||||
PO 1 mg | - | - | - | - | 36.9 | - | 101.2 | 165.7 | 229.1 |
PO 2.5 mg※ | - | - | - | - | 53.9 | - | 135.1 | 216.7 | 297.6 |
Calculation of systemic drug-transfer rate and rate of serotonin 5-HT1B/1D receptor binding
Tmax(hr) | Cmax(ng/mL) | A
cp
* (Cmax/Tmax) | Φmax1B* (%) | Φmax1D* (%) | A
Φ
1B
* (Φmax1B/Tmax) | A
Φ
1D
* (Φmax1D/Tmax) | |
---|---|---|---|---|---|---|---|
Sumatriptan[11] | |||||||
SC 3 mg※ | 0.21 | 44 | 209.52 | 88.6 | 88.6 | 422.09 | 422.09 |
SC 6 mg | 0.2 | 95.5 | 477.50 | 94.4 | 94.4 | 472.12 | 472.12 |
Sumatriptan[23] | |||||||
PO 50 mg※ | 1.8 | 32.6 | 18.11 | 85.3 | 85.3 | 47.36 | 47.36 |
PO 100 mg | 2 | 58.2 | 29.10 | 91.2 | 91.2 | 45.58 | 45.58 |
Sumatriptan[24] | |||||||
NS 10 mg | 1.1 | 6.4 | 5.82 | 53.2 | 53.2 | 48.33 | 48.33 |
NS 20 mg※ | 1.3 | 12.2 | 9.38 | 68.4 | 68.4 | 52.61 | 52.61 |
Zolmitriptan[16] | |||||||
PO 2.5 mg※ | [unchanged drug] | [unchanged drug] | [unchanged drug] | 89.4 | 96.2 | 26.79 | 32.1 |
3 | 5.23 | 1.74 | |||||
[active metabolite] | [active metabolite] | [active metabolite] | |||||
3 | 3.5 | 1.17 | |||||
Eletriptan[25] | |||||||
PO 20 mg※ | 1 | 38.9 | 38.90 | 56.9 | 91.7 | 56.93 | 91.7 |
PO 40 mg | 1.2 | 69.7 | 58.08 | 70.3 | 95.2 | 58.6 | 79.3 |
Rizatriptan[26] | |||||||
PO 10 mg※ | 1 | 20.3 | 20.30 | 32.0 | 83.2 | 32.0 | 83.2 |
Naratriptan[27] | |||||||
PO 1 mg | 2.17 | 2.12 | 0.98 | 67.1 | 66.1 | 30.9 | 30.5 |
PO 2.5 mg※ | 2.68 | 5.62 | 2.10 | 84.4 | 83.8 | 31.5 | 31.3 |
Analyses of relationships between parameters for receptor occupancy and clinical effects at the time of administration of each drug
Parameter | Estimated value ± S.E. | |
---|---|---|
A
Φ
1B
· AUCΦ1B | A
Φ
1D
· AUCΦ1D | |
Emax | 92.5 ± 9.9 | 92.5 ± 8.5 |
EC50 | 3529.7 ± 985.6 | 4740.0 ± 995.7 |
γ | 0.97 ± 0.18 | 1.11 ± 0.18 |