Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine

Figures & data

Table 1 Study treatments and assessments

	Treatment A	Treatment B	Treatment C
First dose	Inhaler placebo IV DHE 1.0 mg	MAP0004 1.0 mg nominal dose IV placebo	Inhaler placebo IV placebo
	2 hours of study assessments: PK sampling, echo, 12-lead ECG, vital signs
Second dose (2 hours after first dose)	Inhaler placebo	MAP0004 1.0 mg nominal dose	Inhaler placebo
	2 hours of study assessments: PK sampling, echo, 12-lead ECG, vital signs

Abbreviations: DHE, dihydroergotamine; IV, intravenous; PK, pharmacokinetics; ECG, electrocardiography.

Table 2 Baseline demographic characteristics of all randomized subjects

Characteristic	N = 24
Mean (SD) age, years	26.6 (6.6)
Range	19.9–40.1
Male:female	8:16
Mean (SD) weight, kg	81.8 (17.0)
Mean (SD) BMI, kg/m^2	28.2 (4.8)
Ethnicity and race, n (%)
Hispanic or Latino	1 (4.2)
Black or African American	1 (4.2)
American Indian or Alaska Native	10 (41.6)
White or Caucasian	12 (50.0)

Abbreviations: SD, standard deviation; BMI, body mass index.

Table 3 Summary of changes in PASP following treatment with IV DHE, MAP0004, and placebo

Parameter	Mean (standard deviation) PASP
	IV DHE 1.0 mg (n = 20)	MAP0004 1.0 mg (n = 20)	Placebo (n = 20)
AUC0–2h (mmHg*min)	2856.9 (510.78)	2624.0 (392.10)	2453.0 (404.76)
P-valuea	0.001 versus placebo	0.194 versus placebo	0.025 versus MAP0004
AUC0–4h (mmHg*min)	5700.1 (1016.86)	5336.4 (823.51)	4907.0 (773.11)
P-valuea	0.001 versus placebo	0.069 versus placebo	0.056 versus MAP0004
AUC2–4h (mmHg*min)	2843.2 (529.15)	2712.4 (455.26)	2454.0 (389.41)
P-valuea	0.002 versus placebo	0.040 versus placebo	0.201 versus MAP0004
	IV DHE 1.0 mg (n = 24)	MAP0004 1.0 mg (n = 24)	Placebo (n = 24)
Maximum change in PASP (mmHg) 0–2 hours	7.8 (2.4)	6.1 (2.8)	4.0 (1.7)
P-valuea	0.001 versus placebo	0.031 versus placebo	0.108 versus MAP0004

Note:

a Calculated using the ANOVA model for a 3-period crossover.

Abbreviations: AUC, area under the curve; ANOVA, analysis of variance; DHE, dihydroergotamine; IV, intravenous; PASP, pulmonary arterial systolic pressure.

Table 4 Pharmacokinetic parameters for DHE and 8′ OH-DHE

Treatment	Mean (standard deviation)
	Cmax (pg/mL)	Tmax (minutes)	AUC0–2h (pg*hour/mL)	AUC0–4h (pg*hour/mL)
DHE
IV DHE 1.0 mg, n = 18	58321.0 (9157.41)	3.1 (0.24)	8018.5 (1503.52)	9020.1 (1708.87)
MAP0004 1.0 mg (first dose), n = 19	2474.7 (755.52)	10.7 (3.00)	1318.9 (492.51)	–
MAP0004 1.0 mg (second dose), n = 19	3063.0 (1351.30)	9.2 (2.55)		3041.6a,b (1237.48)
8′ OH-DHE
IV DHE 1.0 mg, n = 17	328.6 (145.95)	8.5 (4.33)	214.2 (80.41)	311.8 (129.54)
MAP0004 1.0 mg (first dose), n = 16	97.9 (37.78)	19.4 (6.55)	104.9 (40.68)	–
MAP0004 1.0 mg (second dose), n = 18	117.9 (51.40)	15.1 (6.39)	154.9 (81.90)	277.9a,c (116.99)

Notes:

a AUC_0–4h is the sum of AUC_0–2h for the first and second doses;

b n = 18;

c n = 15; Subjects with values below the limit of quantitation were excluded.

Abbreviations: AUC, area under the curve; DHE, dihydroergotamine; IV, intravenous; OH-DHE, hydroxy-dihydroergotamine; C_max, mean peak plasma concentration; T_max, median time to peak plasma concentration.

Table 5 Summary of treatment emergent adverse events (TEAE)

	Number (%) of subjects
	IV DHE 1.0 mg (n = 24)	MAP0004 1.0 mg (n = 24)	Placebo (n = 24)
Reporting at least one
TEAE	19 (79.2)	10 (41.7)	6 (25.0)
Study drug related	19 (79.2)	6 (25.0)	4 (16.7)
TEAE
TEAE leading to discontinuation	1 (4.2)	0	0
Serious TEAE	0	0	0
TEAE by severity
Mild	12 (63.2)	9 (90.0)	6 (100.0)
Moderate	7 (36.8)	1 (10.0)	0
Severe	0	0	0
	IV DHE 1.0 mg (n = 20)	MAP0004 1.0 mg (n = 20)	Placebo (n = 20)
TEAE occurring at least twice
Headache	6 (30.0)	5 (25.0)	1 (5.0)
Nausea	10 (50.0)	1 (5.0)	0
Feeling hot	8 (40.0)	0	0
Pharmaceutical product complaint (taste)	4 (20.0)	2 (10.0)	1 (5.0)
Dizziness	3 (15.0)	2 (10.0)	1 (5.0)
Burning sensation	4 (20.0)	0	0
Paresthesia	3 (15.0)	0	0
Flushing	2 (10.0)	0	1 (5.0)
Chest discomfort	2 (10.0)	0	0
Head discomfort	2 (10.0)	0	0
Vomiting	2 (10.0)	0	0

Abbreviations: TEAE, treatment emergent adverse events; DHE, dihydroergotamine; IV, intravenous.

Figure 1 Mean plasma DHE concentrations over time with IV DHE 1.0 mg and MAP0004 1.0 mg.

Abbreviations: DHE, dihydroergotamine; IV, intravenous.