Assessment of pharmacokinetic and pharmacodynamic interactions between zavegepant and sumatriptan: A phase 1, randomized, placebo‐controlled study in healthy adults

Abstract

Objective

To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults.

Background

Zavegepant is a high‐affinity, selective, small‐molecule calcitonin gene–related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug–drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings.

Methods

This was a Phase 1, single‐center, partially blind, randomized, placebo‐controlled, single‐arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre‐specified time points.

Results

Forty‐two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty‐one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time‐weighted average (TWA) of mean arterial pressure (MAP [sumatriptan + zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: −0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: −0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: −0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC_0‐inf and 104.1% (90% CI: 98.0%, 110.6%) for C _max. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC_0–24 and 96.7% (90% CI: 88.9%, 105.2%) for C _max. Overall, 90% (38/42) of participants experienced ≥ 1 treatment‐emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated.

Conclusion

Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults.

Plain Language Summary

Because there can be concerns about unsafe interactions between medications that are often given together in clinical settings, we studied the effects of taking two medications that are used for acute migraine treatment (zavegepant and sumatriptan) at the same time. Healthy adults were given the medications alone or together, and we measured their blood pressure, blood levels of both medications, and their number of side effects. We found that taking zavegepant and sumatriptan together did not change patients’ blood pressure, blood levels of either drug, or number of side effects compared with sumatriptan alone, suggesting that co‐administering these medications is safe.

Abbreviations

5‐HT_1B/1D

5‐hydroxytryptamine serotonin receptor

AE

adverse event

ANOVA

analysis of variance

AUC

area under the concentration‐time curve

AUC_0–24

AUC from time zero to 24 h

AUC_0‐inf

AUC from time zero to infinity

AUC_0–t

AUC from time zero to the last non‐zero concentration

BMI

body mass index

BP

blood pressure

CGRP

calcitonin gene–related peptide

CI

confidence interval

C _max

maximum observed concentration

CV

coefficient of variation

CYP

cytochrome P450

DBP

diastolic blood pressure

ECG

electrocardiogram

EDTA

ethylenediaminetetraacetic acid

MAP

mean arterial pressure

PD

pharmacodynamic

PK

pharmacokinetic

SAE

serious adverse event

SBP

systolic blood pressure

SC

subcutaneous

SD

standard deviation

S‐STS

Sheehan Suicidality Tracking Scale

T _{½ el}

elimination half‐life

TEAE

treatment‐emergent adverse event

T _max

time of observed C _max

TWA

time‐weighted average

ULN

upper limit of normal

INTRODUCTION

Migraine is a chronic neurological disorder characterized by recurrent headaches of moderate to severe intensity, often with sensitivity to light and sound and nausea and/or vomiting. ¹ It affects more than 1 billion people each year globally. ² Standard migraine therapies include nonspecific agents such as analgesics, non‐steroidal anti‐inflammatory drugs, and specific treatments such as triptans. ³ While triptans are frequently used in the treatment of migraine, their vasoconstrictive properties ⁴ , ⁵ and associated risk for increased blood pressure (BP) significantly limit their use. Triptans, including sumatriptan (5‐hydroxytryptamine serotonin receptor [5‐HT_1B/1D] agonist), the most commonly prescribed triptan for acute migraine treatment, ⁶ , ⁷ are contraindicated in patients with a number of cardiovascular conditions, including ischemic coronary artery disease (e.g., angina pectoris, history of myocardial infarction), history of stroke or transient ischemic attack, and uncontrolled hypertension. ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² Also, poor tolerability and low adherence have been reported among sumatriptan and other triptan users, possibly due to side effects and lack of sustained efficacy. ¹³ , ¹⁴ , ¹⁵

Gepants, a newer class of small molecule antimigraine drugs, are calcitonin gene–related peptide (CGRP) receptor antagonists. CGRP is a neuropeptide that has an important role in migraine pathophysiology. ¹⁶ , ¹⁷ , ¹⁸ Zavegepant 10 mg nasal spray (Pfizer Inc., New York, NY, USA) is a high‐affinity, selective, small molecule CGRP receptor antagonist approved in the United States in 2023 for the acute treatment of migraine with or without aura in adults. It is the first and only CGRP receptor antagonist available as a nasal spray. The efficacy and safety of zavegepant 10 mg nasal spray for the acute treatment of migraine have been demonstrated in two pivotal, randomized, double‐blind, placebo‐controlled clinical trials. ¹⁹ , ²⁰ In both trials, zavegepant 10 mg nasal spray was more effective than placebo for the coprimary endpoints of freedom from pain (zavegepant 22.5% vs. placebo 15.5% ¹⁹ ; zavegepant 23.6% vs. placebo 14.9% ²⁰ ) and freedom from the most bothersome symptom at 2 h postdose (zavegepant 41.9% vs. placebo 33.7% ¹⁹ ; zavegepant 39.6% vs. placebo 31.1% ²⁰ ) and had a favorable safety and tolerability profile.

In vitro studies have demonstrated that zavegepant is primarily metabolized by cytochrome P450 (CYP)3A4 and, to some extent, by CYP2D6. ²¹ Administration of a single 10 mg dose of zavegepant nasal spray produces peak plasma concentrations within 30 min and has an effective half‐life of 6.55 h. ²¹ The majority of the zavegepant dose is excreted unchanged via the biliary/fecal route. ²¹ In contrast, sumatriptan is primarily metabolized by monoamine oxidase type A and has a short half‐life of 2 h. It is excreted as an indole acetic acid mainly via urine. ²² Given their distinct routes of metabolism and excretion, drug–drug interactions between sumatriptan and zavegepant are unlikely. Previous studies that evaluated the safety of coadministration of sumatriptan with other antimigraine CGRP receptor antagonists, such as rimegepant, ²³ erenumab, ²⁴ ubrogepant, ²⁵ and atogepant, ²⁶ did not observe clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) interactions or safety concerns. As patients with migraine often require concomitant treatments or have comorbidities, it is important to ensure the safety of potential coadministration of zavegepant nasal spray with a commonly used triptan, such as sumatriptan, in clinical settings. Based on the different routes of metabolism, coadministration of zavegepant with sumatriptan was hypothesized not to induce drug–drug interaction and influence BP compared to sumatriptan alone. This study was conducted to evaluate the potential for PD or PK interactions between zavegepant and sumatriptan in healthy adults following the concomitant administration of these drugs.

METHODS

Institutional review board approval

An institutional review board and an independent ethics committee reviewed (Advarra IRB, Aurora, Ontario, Canada) and approved the study protocol and study‐associated procedures. The study was conducted in accordance with Good Clinical Practice, as defined by the International Conference on Harmonisation, and in accordance with the ethical principles underlying the United States Code of Federal Regulations, Title 21, Part 50. Written informed consent was signed by all participants before the start of any study‐related activities.

Study participants

This was a Phase 1, single‐center (Syneos Health, Quebec, Canada), partially blind, randomized, placebo‐controlled, single‐arm study. The primary objective of the study was to evaluate the effect of coadministration of zavegepant and sumatriptan on resting BP in healthy participants. The secondary objectives were (a) to assess the effects of zavegepant on resting BP compared to placebo, (b) to evaluate the PK of sumatriptan and zavegepant when administered alone or in combination, and (c) to assess the safety and tolerability of zavegepant coadministered with sumatriptan.

Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years with a body mass index (BMI) >18.5 and <30.0 kg/m². The participants had to be nonsmokers (i.e., no use of tobacco or nicotine products within 3 months prior to screening), and healthy (i.e., absence of any clinically significant illness) with a Sheehan Suicidality Tracking Scale (S‐STS) score of 0 at screening. Participants with liver disorders, gastrointestinal diseases that may interfere with drug absorption, seizures, cardiovascular and hypertensive disorders, migraine, and other clinically significant illnesses were excluded during screening. No concomitant medications were allowed throughout the study period, including prescription drugs, over‐the‐counter products, and natural health products.

Study design

On Day 1 of the study, the participants were administered sumatriptan 12 mg (Taro Pharmaceuticals Inc., Canada) as two subcutaneous (SC) injections of sumatriptan succinate (2 × 6 mg) 1 h apart to the outer thigh region. Subsequently, the participants were randomly assigned at a 6:1 ratio according to a computer‐generated scheme to receive zavegepant or placebo. On Days 2 and 3, zavegepant 20 mg nasal spray (2 × 10 mg; 1 spray in each nostril) or matching placebo was administered. On Day 4, zavegepant 20 mg nasal spray or placebo was coadministered with sumatriptan 12 mg immediately after the second sumatriptan injection. A schematic representation of the study design is provided in Figure 1.

FIGURE 1.

Schematic representation of the study design. On Day 1, the participants were administered sumatriptan 12 mg (2 × 6 mg) as 2 subcutaneous (SC) injections approximately 1 h apart. After randomization at a 6:1 ratio, the participants received zavegepant nasal spray 20 mg (2 × 10 mg; one spray in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant nasal spray 20 mg or placebo was administered immediately after the second sumatriptan injection. *1 participant in the zavegepant group received the first dose of sumatriptan on Day 1 and withdrew from the study. N, number of participants dosed. [Colour figure can be viewed at wileyonlinelibrary.com]

Zavegepant, 20 mg dose, a supratherapeutic dose twice the approved 10 mg dose, was selected based on safety and PK data from single and multiple ascending dose studies, and sumatriptan 12 mg was selected based on the maximum recommended dose that could be administered in 24 h. ⁸ After zavegepant or placebo nasal spray administration, the participants remained seated upright for the first 10 min to avoid drug leakage (except during BP measurements, when participants were placed in a supine position after the first 5 min). The participants were not allowed to blow their nose for 2 h after dosing and were requested to gently sniff up any nasal drip. Food intake was restricted before and after drug administration.

Blinding and randomization

The study was partially blinded. Because sumatriptan was administered as an SC injection, the participants and the clinical personnel involved in the study were blinded only to zavegepant and placebo administration. Participants and clinical personnel with responsibility for collection of samples, monitoring, revision, or evaluation of adverse events (AEs) were blinded to zavegepant or placebo treatment. The study medication was prepared and dispensed by pharmacy personnel not directly involved in clinical aspects of the study. The blinding was maintained until the study was completed. Participants were randomized using sequentially numbered blind envelopes.

Blood pressure assessments

BP was recorded using an ambulatory BP monitoring system at pre‐specified time points on the same arm throughout the study. The participants rested supine for at least 5 min before each BP recording. On Days 1 and 4, BP was measured manually before the first sumatriptan injection and recorded automatically at the following time intervals after the first sumatriptan injection for a total 13‐h period: every 10 min for the first 6 h, every 30 min for the next 2 h, and every 60 min for the last 5 h, for a total of 13 h. On Day 3, BP was measured following zavegepant or placebo administration at the same time points as mentioned above. The BP parameters measured included mean arterial pressure (MAP), diastolic BP (DBP), and systolic BP (SBP).

Blood sample collection for PK analyses

On Day 1, blood was collected from the participants before the first and second sumatriptan injections, and 1.083, 1.167, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 5, 7, and 13 h after the first sumatriptan injection. On Day 3, blood was drawn before zavegepant or placebo administration, followed by 0.083, 0.167, 0.333, 0.5, 0.667, 0.833, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 h post‐zavegepant or placebo dose. On Day 4, blood was drawn before each sumatriptan injection, zavegepant or placebo nasal spray administration, and 1.083, 1.167, 1.25, 1.33, 1.5, 1.67, 1.83, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 13, and 25 h after the first sumatriptan injection. Blood that was collected 24 h post‐zavegepant or placebo administration on Day 3 corresponded to the pre‐zavegepant or placebo blood sampling on Day 4. Therefore, only one blood sample was collected at that time point.

Bioanalytical method

Liquid chromatography with tandem mass spectrometry

High‐performance liquid chromatography with tandem mass spectrometry was used to analyze plasma zavegepant or sumatriptan. Using automated solid phase extraction, zavegepant and its internal standard, BHV3500‐d₈, were extracted from 0.075 mL of human ethylenediaminetetraacetic acid (EDTA) K₂ plasma. Extracted samples were transferred to a liquid chromatograph with an ACE EXCEL 2 C18‐PFP, 50 × 3.0 mm, 2 μm column with Milli‐Q type water/acetonitrile (75/25) with ammonium acetate 5 mM and formic acid 0.1% for mobile phase A and Milli‐Q type water/acetonitrile (5/95) with ammonium formate 2 mM and formic acid 0.2% for mobile phase B. The lower limit of quantification for zavegepant was 20 pg/mL with a validation calibration range from 20 to 50,000 pg/mL. The between‐run accuracy bias of the assay was 0.85% to 3.47% (precision coefficient of variation [CV]: 1.61% to 6.44%), and the within‐run accuracy bias was −2.20% to 6.39% (precision CV: 0.98% to 7.80%). The data were captured by Analyst version 1.6.3 or higher (AB Sciex, Toronto, ON, Canada) and then imported into Watson LIMS version 7.4.1 or higher (Thermo Fisher Scientific Corporation, Philadelphia, PA, USA).

For plasma sumatriptan analyses, sumatriptan and its internal standard, sumatriptan‐d₆, were extracted from 0.100 mL of human EDTA K₃ plasma using the same technique mentioned above. Extracted samples were transferred to a Zorbax SB‐C18, 50 × 4.6 mm, 5 μm column with Milli‐Q type water/methanol with ammonium acetate and acetic acid for mobile phase A and methanol for mobile phase B. The validation calibration range was between 100 to 150,000 pg/mL. The between‐run accuracy bias of the assay was −6.15% to 9.12% (precision CV: 2.92% to 9.74%), and the within‐run accuracy bias was −13.20% to 19.90% (precision CV: 0.74% to 11.69%).

Pharmacokinetic assessments

The PK parameters were calculated for sumatriptan on Days 1 and 4 by standard noncompartmental methods using validated Phoenix WinNonlin version 8.0. The parameters included area under the concentration‐time curve (AUC) from time zero to infinity (AUC_0‐inf), AUC from time zero to the last non‐zero concentration (AUC_0–t ), maximum observed concentration (C _max), time of observed C _max (T _max), and elimination half‐life (T _{½ el}). On Days 3 and 4, the zavegepant PK parameters analyzed by standard noncompartmental methods included AUC from time zero to 24 h (AUC_0–24), AUC_0–t , C _max, T _max, and T _{½ el}.

Safety and tolerability

The safety and tolerability of zavegepant and sumatriptan were evaluated through the assessment of AEs (e.g., serious AEs [SAEs], treatment‐emergent AEs [TEAEs]), clinical laboratory parameters (biochemistry, hematology, coagulation, serology, and urinalysis), 12‐lead electrocardiogram (ECG), vital signs, physical and nasal cavity examination, and S‐STS.

Statistical analyses

Forty‐two healthy adults were planned to be included in this study. Based on a previous study that analyzed the effects of erenumab and sumatriptan coadministration on BP, ²⁴ the baseline standard deviation (SD) in BP parameters in this study was estimated to be approximately 7 mmHg. Assuming a within‐subject correlation of 0, the SD for a within‐subject difference would be 10 mmHg. With no shift in the true value of BP, 36 participants would provide a 90% probability that the upper bound of a two‐sided 90% confidence interval (CI) for the within‐subject difference in BP would be less than 5 mmHg. An additional 6 participants could receive placebo to serve as a control for the safety data.

Demographic parameters (mean [SD] for age, height, and weight; frequency counts and percentages n [%] for age group, sex, ethnicity, and race), time‐weighted average (TWA) of MAP, DBP, and SBP (arithmetic mean [SD]); PK parameters for sumatriptan and zavegepant (arithmetic mean [SD] for plasma concentrations; geometric means, %CV for AUC_0–t , AUC_0‐inf, AUC_0–24, C _max, and T _{1/2 el}; and median [minimum, maximum] for T _max); and safety assessments (n [%]) were summarized using descriptive statistics. From the BP recordings, the TWA of MAP, DBP, and SBP were calculated as the measurement‐time curve area from predose to 4 h divided by the time over which the measurements were made on Days 1, 3, and 4. For the statistical comparison of BP parameters between sumatriptan + zavegepant on Day 4 versus sumatriptan on Day 1, the random effects repeated measures analysis of variance (ANOVA) was fit on untransformed TWA of MAP, SBP, and DBP at p < 0.0500. The variables in the ANOVA model were participants within the batch (random effect), treatment (sumatriptan on Day 1; sumatriptan + zavegepant on Day 4), and participant dosing batch. The intra‐ and inter‐participant CV was estimated. The difference in means of sumatriptan + zavegepant on Day 4 and sumatriptan on Day 1 and the corresponding 90% CI based on least‐squares means from the ANOVA were calculated.

For sumatriptan PK, random effects repeated measures ANOVA was performed on untransformed T _max and T _{½ el} and on ln‐transformed AUC_0–t , AUC_0‐inf, and C _max at p < 0.05 to estimate the within‐subject effect of sumatriptan + zavegepant on Day 4 versus sumatriptan on Day 1. The ratio of geometric means (sumatriptan + zavegepant on Day 4/sumatriptan on Day 1) and the corresponding 90% CI, based on least square means from the ANOVA of ln‐transformed data was calculated for AUC_0–t , AUC_0‐inf, and C _max.

For zavegepant PK, the same calculations as above were used (an exception is the use of ln‐transformed AUC_0–24 for zavegepant, whereas AUC_0‐inf was used for sumatriptan) to estimate the within‐subject effect of sumatriptan + zavegepant on Day 4 versus zavegepant on Day 3, the ratio of geometric means (sumatriptan + zavegepant on Day 4/zavegepant on Day 3), and the corresponding 90% CI. Statistical analyses were performed using SAS version 9.4.

RESULTS

Participant demographics

Forty‐one participants completed the study, had adequately characterized BP and PK profiles for sumatriptan and zavegepant, and were included in the BP and PK analyses. The first participant was enrolled in the study on November 19, 2020, and the last participant completed the last visit on March 13, 2021. Forty‐two participants received at least one dose of any treatment and were included in the safety analyses. One participant in the zavegepant group received the first dose of sumatriptan on Day 1 and withdrew from the study. Apart from this, no data were missing from any of the analyses. The mean (SD) age of the BP and PK population was 32.4 (7.5) years. Most participants were male (58%), and White (88%). The overall mean (SD) weight of the population was 74.3 (11.5) kg, and the mean (SD) BMI was 25.1 (2.3) kg/m² (Table 1).

TABLE 1.

Demographic characteristics of BP and PK population.

Parameter	Sumatriptan on Day 1 (N = 41)	Zavegepant on Days 2 & 3 or Zavegepant + Sumatriptan on Day 4 (N = 35)	Placebo on Days 2 & 3 or Placebo + Sumatriptan on Day 4 (N = 6)
Age (years), mean (SD)	32.4 (7.5)	32.9 (6.9)	30.0 (10.7)
Age groups, n (%)
18–40	35 (85)	31 (89)	4 (67)
>40	6 (15)	4 (11)	2 (33)
Sex, n (%)
Female	17 (42)	13 (37)	4 (67)
Male	24 (58)	22 (63)	2 (33)
Ethnicity, n (%)
Not Hispanic or Latino	11 (27)	10 (29)	1 (17)
Hispanic or Latino	30 (73)	25 (71)	5 (83)
Race, n (%)
White	36 (88)	31 (89)	5 (83)
Black	4 (10)	3 (9)	1 (17)
Asian	1 (2)	1 (3)	0
Height (cm), mean (SD)	171.8 (9.7)	172.4 (9.9)	167.8 (8.4)
Weight (kg), mean (SD)	74.3 (11.5)	75.1 (11.2)	69.8 (13.4)
BMI (kg/m2), mean (SD)	25.1 (2.3)	25.1 (2.1)	24.7 (3.3)

Abbreviations: BMI, body mass index; BP, blood pressure; n (%), number and percent of participants; N, number of participants dosed; PK, pharmacokinetic; SD, standard deviation.

Blood pressure assessments

The mean (SD) of MAP over time showed no difference following sumatriptan and zavegepant coadministration on Day 4 compared to sumatriptan alone on Day 1 (Figure 2A). Similar tendencies for MAP over time for DBP and SBP were observed when sumatriptan and zavegepant treatments were compared (Figure 2B,C).

FIGURE 2.

Mean (SD) of mean arterial pressure (A), diastolic blood pressure (B), and systolic blood pressure (C) over time following sumatriptan and zavegepant coadministration on Day 4 compared to sumatriptan alone on Day 1. The vertical line at 4 h denotes the time at which window analysis was applied to the nominal time point. h, hours; SD, standard deviation. [Colour figure can be viewed at wileyonlinelibrary.com]

The mean TWA for MAP after sumatriptan and zavegepant coadministration on Day 4 (87.2) did not change compared to sumatriptan alone on Day 1 (86.9). Likewise, the mean TWA for MAP after zavegepant, placebo, or sumatriptan + placebo treatments was similar and ranged between 81.0 and 85.1. The TWA for DBP and SBP were also similar among the various treatments (Table 2).

TABLE 2.

Summary of BP parameters.

Treatment	Day	TWA, mmHg, mean (SD)
		MAP	DBP	SBP
Sumatriptan (N = 41)	1	87 (6.0)	72 (6.2)	116 (8.6)
Zavegepant (N = 35)	3	84 (6.7)	69 (6.8)	114 (9.1)
Placebo (N = 6)	3	81 (6.9)	67 (5.6)	109 (9.3)
Sumatriptan + zavegepant (N = 35)	4	87 (6.8)	72 (6.8)	117 (10.2)
Sumatriptan + placebo (N = 6)	4	85 (6.7)	70 (6.7)	113 (8.3)

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; N, number of participants dosed; SBP, systolic blood pressure; SD, standard deviation; TWA, time‐weighted average.

Statistical comparisons did not show any significant differences in BP between sumatriptan and zavegepant coadministration on Day 4 and sumatriptan alone on Day 1. The TWA for MAP between sumatriptan and zavegepant coadministration on Day 4 and sumatriptan on Day 1 was similar (<5 mmHg); the difference observed was 0.04 mmHg, and the upper bound of the 90% CI (−0.69, 0.77 mmHg). The difference in TWA between sumatriptan + zavegepant versus sumatriptan alone was 0.00 mmHg (90% CI: −0.76, 0.76 mmHg) for DBP and 0.33 mmHg (90% CI: −0.97, 1.63 mmHg) for SBP (Table 3).

TABLE 3.

Statistical comparison of BP parameters.

Parameter	LSM (mmHg)		Comparison (Sumatriptan + Zavegepant vs. Sumatriptan)
	Sumatriptan + Zavegepant	Sumatriptan	Difference (mmHg)	90% CI	p‐value (treatment)	p‐value (group)
TWA of MAP (mmHg)	86.79	86.75	0.04	−0.69, 0.77	0.924	0.015
TWA of DBP (mmHg)	71.97	71.97	0.00	−0.76, 0.76	0.996	0.0210
TWA of SBP (mmHg)	116.39	116.06	0.33	−0.97, 1.63	0.670	0.104

Abbreviations: BP, blood pressure; CI, confidence interval; DBP, diastolic blood pressure; LSM, least square mean; MAP, mean arterial pressure; SBP, systolic blood pressure; TWA, time‐weighted average.

Pharmacokinetics

The mean plasma concentration‐time profiles of sumatriptan (Figure 3A) and zavegepant (Figure 3B) following the coadministration of these drugs were comparable with respect to single‐drug treatment profiles. The PK parameters of sumatriptan and zavegepant following single administration or coadministration are given in Table 4. The geometric means of C _max, AUC_0‐inf (for sumatriptan), or AUC_0–24 (for zavegepant) were comparable among treatments.

FIGURE 3.

Plasma sumatriptan and zavegepant concentration‐time profiles. (A) Mean (SD) plasma sumatriptan concentration‐time profile following sumatriptan and zavegepant coadministration on Day 4 and sumatriptan alone on Day 1. (B) Mean (SD) plasma zavegepant concentration‐time profile following sumatriptan and zavegepant coadministration on Day 4 and zavegepant alone on Day 3. The inset graphs are in a semi‐log scale. h, hours; SD, standard deviation. [Colour figure can be viewed at wileyonlinelibrary.com]

TABLE 4.

Pharmacokinetic parameters of sumatriptan and zavegepant.

	Day	Sumatriptan PK Parameters a
		AUC0–t (h∙ng/mL)	AUC0‐inf (h∙ng/mL)	C max (ng/mL)	T max (h)	T 1/2 el (h)
Sumatriptan (N = 41)	1	165.1 (15.4%)	166.9 (15.4%)	92.6 (25.5%)	1.2 (1.2, 1.3)	2.0 (16.5%)
Sumatriptan + zavegepant (N = 35)	4	168.6 (15.9%)	170.8 (15.8%)	96.7 (19.6%)	1.2 (0.9, 1.4)	2.1 (14.6%)
Placebo + sumatriptan (N = 6)	4	165.3 (14.4%)	167.2 (14.5%)	91.4 (12.8%)	1.2 (1.2, 1.3)	2.1 (18.6%)

	Day	Zavegepant PK Parameters a
		AUC0–t (h∙ng/mL)	AUC0–24 (h∙ng/mL)	C max (ng/mL)	T max (h)	T 1/2 el (h)
Zavegepant (N = 35)	3	58.3 (49.4%)	58.3 (49.4%)	22.2 (47.2%)	0.5 (0.2, 0.7)	7.0 (22.7%)
Sumatriptan + zavegepant (N = 35)	4	65.4 (55.7%)	65.5 (55.6%)	21.4 (56.4%)	0.5 (0.3, 0.9)	6.7 (25.7%) b

Abbreviations: AUC, area under the concentration‐time curve; AUC_0–t , AUC from time zero to the last non‐zero concentration; AUC_0‐inf, AUC from time zero to infinity; AUC_0–24, AUC from time zero to 24 h postdose; C _max, maximum observed concentration; geomean, geometric mean; N, number of participants dosed; PK, pharmacokinetic; T _max, time of observed C _max; T _{1/2 el}, elimination half‐life; %CV, percent coefficient of variation.

^a All PK parameters are presented as geometric mean (%CV), except for T _max that is presented as median (minimum, maximum).

^b n = 33.

Sumatriptan PK exposure, as assessed by AUC_0‐inf and C _max, was similar after sumatriptan and zavegepant coadministration versus sumatriptan alone; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC_0‐inf and 104.1% (90% CI: 98.0%, 110.6%) for C _max (Table 5). Similarly, the difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone were 112.4% (90% CI: 103.4%, 122.3%) for AUC_0–24 and 96.7% (90% CI: 88.9%, 105.2%) for C _max (Table 5). None of the PK parameter ratios exceeded the bioequivalence criteria of 80% to 125%.

TABLE 5.

Statistical comparison of plasma sumatriptan and zavegepant parameters.

Sumatriptan Parameters	Geometric LSM		Comparison (Sumatriptan + Zavegepant vs. Sumatriptan)
	Sumatriptan + Zavegepant	Sumatriptan	Ratio (%)	90% CI	p‐value (treatment)	p‐value (group)
AUC0–t (h∙ng/mL)	169.8	166.0	102.3%	100.6%, 104.0%	0.0321	0.321
AUC0‐inf (h∙ng/mL)	171.9	167.8	102.5%	100.7%, 104.2%	0.0212	0.311
C max (ng/mL)	98.1	94.2	104.1%	98.0%, 110.6%	0.264	0.324

Zavegepant Parameters	Geometric LSM		Comparison (Sumatriptan + Zavegepant vs. Zavegepant)
	Sumatriptan + Zavegepant	Zavegepant	Ratio (%)	90% CI	p‐value (treatment)	p‐value (group)
AUC0–t (h∙ng/mL)	65.4	58.2	112.3%	103.2%, 122.2%	0.0257	0.758
AUC0–24 (h∙ng/mL)	65.5	58.3	112.4%	103.4%, 122.3%	0.0244	0.764
C max (ng/mL)	20.9	21.6	96.7%	88.9%, 105.2%	0.510	0.413

Abbreviations: AUC, area under the concentration‐time curve; AUC_0–t , AUC from time zero to the last non‐zero concentration; AUC_0‐inf, AUC from time zero to infinity; AUC_0–24, AUC from time zero to 24 h postdose; CI, confidence interval; C _max, maximum observed concentration; LSM, least squares mean.

Safety

All the treatments (sumatriptan alone, zavegepant or placebo alone, sumatriptan + zavegepant, and sumatriptan + placebo) were generally safe and well tolerated by healthy participants. None of the participants discontinued the study due to SAEs or TEAEs, and no deaths were reported. Thirty‐eight of 42 (90%) participants experienced ≥ 1 TEAE (sumatriptan: n = 25 [60%]; zavegepant: n = 31 [89%]; sumatriptan + zavegepant: n = 28 [80%]; placebo: n = 5 [83%]; and placebo + sumatriptan: n = 4 [67%]).

In the sumatriptan alone treatment group, all the TEAEs were reported by ≤ 5 participants each. The most frequently reported TEAEs (≥ 5 participants) following zavegepant alone administration were dysgeusia (n = 31 [89%]), throat irritation (n = 10 [29%]), and pharyngeal paresthesia (n = 6 [17%]). The most frequently reported TEAEs (≥ 5 participants) following sumatriptan and zavegepant coadministration were dysgeusia (n = 18 [51%]), head discomfort (n = 8 [23%]), and paresthesia (n = 6 [17%]). All the reported TEAEs were mild or moderate in severity. No participant had alanine aminotransferase or aspartate aminotransferase > 3× upper limit of normal (ULN), total bilirubin > 2× ULN, or alkaline phosphatase > 1.5× ULN. No clinically meaningful abnormal changes from baseline in laboratory parameters, hematology parameters, vital signs, ECGs, DBP, SBP, or S‐STS were observed.

DISCUSSION

This Phase 1, single‐center, partially blind, placebo‐controlled study assessed the effect of zavegepant on resting BP when administered concomitantly with sumatriptan in healthy adults. No significant changes in TWA of MAP, DBP, and SBP were observed following the coadministration of zavegepant + sumatriptan on Day 4 compared to sumatriptan alone on Day 1. As the upper bound of the 90% CIs for the difference between zavegepant + sumatriptan on Day 4 and sumatriptan alone on Day 1 was < 5 mmHg, the MAP between the two treatments was concluded to be similar.

The observation in this study indicating no significant change in resting BP after coadministration of sumatriptan 12 mg SC injection and the supratherapeutic zavegepant 20 mg nasal spray compared to sumatriptan alone is in line with previous studies that found no PD interactions between sumatriptan and other CGRP antagonists (rimegepant, ²³ erenumab, ²⁴ ubrogepant, ²⁵ and atogepant ²⁶ ). The route of administration influences the exposure and efficacy of sumatriptan. ²⁷ , ²⁸ , ²⁹ Sumatriptan 6 mg SC injection is reported to be quickly absorbed, reaching maximum plasma concentrations within 10 min, with a bioavailability of 96%. ²⁸ , ²⁹ Other routes of exposure, including oral, intranasal, and rectal, have an approximate maximum plasma concentration time of 1.5 h and a bioavailability of 14% to 19%. ²⁸ , ²⁹ In this study, administration of the maximum recommended 24 h dose of sumatriptan as a SC injection (2 × 6 mg) ⁸ represented the maximum sumatriptan exposure to enable evaluation of any possible drug–drug interaction with zavegepant nasal spray. Because zavegepant produced no clinically meaningful changes in sumatriptan's effects on BP at peak systemic concentrations of both drugs, it was concluded that the coadministration of these drugs is unlikely to cause a risk for increased BP due to a PD interaction.

This study also evaluated the PK of zavegepant and sumatriptan following single administration or coadministration of the drugs. Previous studies have demonstrated that the AUC and C _max of sumatriptan increase linearly and dose proportionally after oral (100 to 400 mg) and SC (1 to 16 mg) administration in healthy volunteers. ²² PK parameters following the coadministration of sumatriptan + zavegepant with sumatriptan alone showed similar exposure for sumatriptan. The T _{1/2 el} of 2 h for sumatriptan observed in this study corresponded to the literature‐reported T _{1/2 el} for sumatriptan. ²² Also, sumatriptan and zavegepant coadministration did not have a clinically meaningful impact on zavegepant exposure. Because all triptans share the core indole structure, exert their action via serotonin receptors (5‐HT_1B/1D), and share the same metabolic fate, ³⁰ the findings of this study likely apply to other triptan drug classes.

Overall, all treatments evaluated in this study (sumatriptan 12 mg SC, zavegepant 20 mg nasal spray, or sumatriptan and zavegepant coadministration) were well tolerated by healthy participants and exhibited a favorable safety profile. No deaths, SAEs, or TEAEs were reported that led to the discontinuation of zavegepant or sumatriptan. Dysgeusia, the most frequently reported TEAE following sumatriptan and zavegepant coadministration, was considered related to zavegepant, not sumatriptan. All the reported TEAEs were mild or moderate in severity.

A limitation of the study is that it involves a healthy population without cardiovascular disease, hypertensive disorders, or migraine. Migraine is a complex neurological disorder, and the effects of triptans and CGRP antagonists during migraine attacks may differ from those reported in this study.

CONCLUSIONS

In conclusion, zavegepant 20 mg nasal spray coadministered with sumatriptan 12 mg SC injection showed no significant PD or PK interactions in healthy participants compared to sumatriptan alone. No significant changes in the TWA of MAP, SBP, or DBP were observed after sumatriptan–zavegepant coadministration compared to sumatriptan. Also, the coadministration of sumatriptan 12 mg SC injection and zavegepant 20 mg nasal spray did not have any clinically meaningful effect on the PK of either sumatriptan or zavegepant. Concomitant administration of zavegepant and sumatriptan was well tolerated by healthy adult participants and exhibited a favorable safety profile.

AUTHOR CONTRIBUTIONS

Rajinder Bhardwaj: Conceptualization; methodology; writing – original draft; writing – review and editing. Mary K. Donohue: Conceptualization; investigation; project administration; writing – original draft; writing – review and editing. Jennifer Madonia: Conceptualization; writing – original draft; writing – review and editing. Kyle Matschke: Software; validation; writing – original draft; writing – review and editing. Matt S. Anderson: Conceptualization; methodology; writing – original draft; writing – review and editing. Beth Morris: Conceptualization; writing – original draft; writing – review and editing. Richard Bertz: Conceptualization; methodology; writing – original draft; writing – review and editing. Robert Croop: Conceptualization; funding acquisition; investigation; project administration; supervision; writing – original draft; writing – review and editing. Jing Liu: Software; validation; visualization; writing – original draft; writing – review and editing.

CLINICAL TRIALS REGISTRATION NUMBER

This was a Phase I trial and not required to be registered.

FUNDING INFORMATION

This study was supported by Biohaven Pharmaceuticals Inc., which was acquired by Pfizer in October 2022.

CONFLICT OF INTEREST STATEMENT

Rajinder Bhardwaj is an employee of Certara Strategic Consulting and serves in a consultant/advisory role for Biohaven Pharmaceuticals Inc., which was acquired by Pfizer in October 2022. Mary K. Donohue, Jennifer Madonia, Beth Morris, and Richard Bertz were employees of Biohaven Pharmaceuticals Inc. and owned Biohaven stock and/or stock options at the time of the study. Robert Croop was an employee of Biohaven Pharmaceuticals, owns stock in Biohaven Ltd., was an employee of Pfizer, has received research payments from Pfizer, and provides services to Collima LLC, which has had consulting agreements with Pfizer, Actio Biosciences, Inc., Aptose Biosciences Inc., Biohaven Pharmaceuticals, Inc., Manistee Therapeutics, NVP Associates, LLC, and Vida Ventures Management Co., LLC. Matt S. Anderson is an employee of Certara Strategic Consulting and served in a consultant/advisory role for Biohaven Pharmaceuticals Inc. at the time of the study. Kyle Matschke and Jing Liu are employees of Pfizer and hold Pfizer stock and/or stock options.

Bhardwaj R, Donohue MK, Madonia J, et al. Assessment of pharmacokinetic and pharmacodynamic interactions between zavegepant and sumatriptan: A phase 1, randomized, placebo‐controlled study in healthy adults. Headache. 2025;65:315‐325. doi: 10.1111/head.14853

DATA AVAILABILITY STATEMENT

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.