Search

Objective Background Methods Results Conclusion The potential for drug–drug interaction of multiple‐dose intranasal zavegepant on the single‐dose oral contraceptive ethinyl estradiol and levonorgestrel (EE‐LNG) was evaluated.Zavegepant (as a nasal spray) is a calcitonin gene‐related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults.This single‐center, Phase 1, open‐label, fixed‐sequence study included healthy, nonsmoking females (18–45 years old). In treatment Period 1, a single oral dose of EE‐LNG 0.02–0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1–5; 1 oral dose of EE‐LNG 0.02–0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE‐LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (Cmax), area under the concentration‐time curve (AUC) from Time 0 to last non‐zero concentration (AUC0‐t), and AUC from Time 0 to infinity (AUC0‐inf). The safety and pharmacokinetic sample sizes were 26 and 23, respectively.Statistical comparisons of pharmacokinetic exposure parameters after co‐administration of zavegepant and EE‐LNG versus EE‐LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC0‐inf and 110.2% (104.6%, 116.1%) for Cmax. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC0‐inf and 108.8% (99.9%, 118.4%) for Cmax. Frequently reported treatment‐emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%).Co‐administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE‐LNG exposure. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusions Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the in vivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4‐related drug–drug interactions (DDIs).Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene‐related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs.Each study was an open‐label, single‐arm, single‐sequence, crossover study. Rimegepant was tested as a victim drug by separate co‐administration of itraconazole (a strong CYP3A4 inhibitor and P‐glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co‐administration with midazolam (a CYP3A4 substrate) in Study 4.Mean values of single‐dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0–inf) increased with itraconazole co‐administration (n = 22) by 1.42‐fold (90% confidence interval [CI] 1.25–1.61) and by 4.14‐fold (90% CI 3.87–4.44), respectively, and decreased with rifampin co‐administration (n = 21) to 36% (90% CI 31.2–41.4%) and to 19% (90% CI 16.3–21.4%), respectively. Co‐administration with fluconazole (n = 23) increased rimegepant mean AUC0–inf by 1.80‐fold (90% CI 1.68–1.93), with no impact on Cmax (1.04‐fold; 90% CI 0.94–1.15). Co‐administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38‐fold (90% CI 1.13–1.67) and 1.53‐fold (90% CI 1.32–1.78), respectively, and the AUC0–inf of midazolam by 1.86‐fold (90% CI 1.58–2.19) and 1.91‐fold (90% CI 1.63–2.25), respectively.Based on the magnitude of DDIs, these studies indicate the following: co‐administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co‐administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co‐administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults.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.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.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 AUC0‐inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. 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 AUC0–24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. 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.Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults. [ABSTRACT FROM AUTHOR]

Zavegepant, a high‐affinity, selective, small‐molecule calcitonin gene‐related peptide receptor antagonist, is approved as a nasal spray for acute treatment of migraine in adults. This phase I, open‐label, single‐center, single‐period, nonrandomized study in six healthy male subjects assessed mass balance recovery after a single 15‐min intravenous (IV) infusion dose of carbon‐14 ([14C])‐zavegepant. Blood, urine, and fecal samples were collected over 192 h for analysis of zavegepant in plasma and urine; total radioactivity (TR) in plasma, whole blood, urine, and feces; and zavegepant metabolite profiling and structural identification in plasma, urine, and feces. An average of 96.6% of radioactivity administered was recovered in excreta. Most TR (mean 84.9%) was recovered in the feces, indicating that biliary/fecal elimination was the main route. Volume of distribution of zavegepant based on the terminal phase (129 L) was higher than total body water (42 L), indicating substantial distribution into tissue. Total plasma clearance of zavegepant (220 mL/min) is identical to whole blood clearance given the blood/plasma partition ratio of 1, lower than typical hepatic blood flow (1450 mL/min). The observed plasma terminal half‐life of zavegepant was 6.8 h. Exposure to zavegepant accounted for ~90% of circulating plasma TR, suggesting that very low levels of uncharacterized circulating metabolites were present. Metabolite profiling did not identify any metabolites representing ≥10% of radioactivity in plasma, urine, or feces. A single IV infusion of 5 mg [14C]‐zavegepant was well tolerated in healthy male subjects. Disposition findings of IV [14C]‐zavegepant are applicable to the disposition of the approved zavegepant nasal spray. [ABSTRACT FROM AUTHOR]

Zavegepant, a high‐affinity, selective, small‐molecule calcitonin gene‐related peptide (CGRP) receptor antagonist, is approved in the United States for acute treatment of migraine in adults. The effects of moderate hepatic impairment (8 participants with Child‐Pugh score 7–9 points) on the pharmacokinetics of a single 10‐mg intranasal dose of zavegepant versus eight matched participants with normal hepatic function were evaluated in a phase I study. Pharmacokinetic sampling determined total and unbound plasma zavegepant concentrations. Moderate hepatic impairment increased the exposure of total zavegepant (~2‐fold increase in AUC0–inf and 16% increase in Cmax) versus normal hepatic function, which is not considered clinically meaningful. The geometric least squares mean ratios (moderate impairment/normal) of plasma zavegepant AUC0−inf and Cmax were 193% (90% confidence interval [CI]: 112, 333; p = 0.051) and 116% (90% CI: 69, 195; p = 0.630), respectively. The geometric mean fraction unbound of zavegepant was similar for participants with moderate hepatic impairment (0.13; coefficient of variation [CV] 13.71%) versus those with normal hepatic function (0.11; CV 21.43%). Similar exposure findings were observed with unbound zavegepant versus normal hepatic function (~2.3‐fold increase in AUC0−inf and 39% increase in Cmax). One treatment‐emergent adverse event (mild, treatment‐related headache) was reported in a participant with normal hepatic function. No dosage adjustment of intranasal zavegepant is required in adults with mild or moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1–40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5–40 mg zavegepant or placebo for 1–14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia‐corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T‐wave morphology, and U‐wave presence) were analyzed pre‐ and post‐zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time‐matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed‐effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration‐dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration‐QTcF model was −0.053 ms per ng/mL with a 90% confidence interval of −0.0955 to −0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent. [ABSTRACT FROM AUTHOR]

Rimegepant is a small‐molecule calcitonin gene‐related peptide receptor antagonist approved for the acute treatment of migraine ± aura and preventive treatment of migraine in adults. The pharmacokinetics of rimegepant in elderly and nonelderly subjects were evaluated. In an open‐label Phase 1 study, 14 elderly (aged 65 years or older) and 14 nonelderly (aged 18 to less than 45 years) subjects each received a single oral dose of rimegepant 75 mg. Blood samples were collected before dosing and through 96 hours after dosing. The pharmacokinetic parameters of rimegepant after a single dose were similar in both age groups. Geometric least‐squares mean ratios (elderly/nonelderly) of the natural log‐transformed maximum observed plasma concentration and natural log‐transformed area under the plasma concentration–time curve from time 0 extrapolated to infinity were 96.6 and 104.6, respectively. Eight (28.6%) subjects (4 elderly, 4 nonelderly) experienced 1 or more adverse events (AEs); all AEs were mild in intensity, and no serious AEs or AEs leading to discontinuation were reported. Following a single 75‐mg dose of oral rimegepant, pharmacokinetic parameters were similar in elderly and nonelderly adults; no dose adjustment is warranted in elderly subjects. [ABSTRACT FROM AUTHOR]

Aims: To optimise the dosing regimen of oseltamivir for immunocompromised (IC) paediatric patients (<18 years) with influenza, we used an extrapolation approach alongside clinical data. Methods: Efficacy was extrapolated from adult IC patients to paediatric IC patients by leveraging existing efficacy, safety, pharmacokinetic (PK)/pharmacodynamic (PD), and disease‐progression models of oseltamivir and oseltamivir carboxylate (OC). Data of IC paediatric patients from two studies (NV25719 and NV20234) were included in the population PK (n = 30), PK/PD analysis (n = 22) and disease modelling approach (n = 36). Simulations were performed to identify the optimal dosing regimen. Results: Clearance of oseltamivir (CL) and OC (CLM) were similar in IC and otherwise‐healthy (OwH) patients <10 years, but decreased by 44.4% (95% CI: 26.8–62.0) and 49.1% (95% CI: 34.5–63.8), respectively, in IC patients aged 10–17 years versus OwH patients. There were no notable exposure–response relationships for any of the virologic PD analyses. Thus, no additional benefit was seen with oseltamivir carboxylate exposures higher than achieved with the conventional dose (75 mg twice daily, age‐ and weight‐adjusted for children <13 years). The disease model illustrated that doses above the conventional oseltamivir dose had limited impact on viral kinetics in IC paediatric patients and a prolonged treatment duration of 10 days was favoured to limit potential viral rebound. Conclusion: An oseltamivir dosage recommendation (conventional dose, twice daily for 10 days) was established in IC paediatric patients with influenza, based on extrapolation of efficacy from IC adults, leveraging population PK, PK/PD, and disease modelling, whilst taking resistance and safety data into account. [ABSTRACT FROM AUTHOR]

Aim: Pharmacologic effects were analysed to determine a dose recommendation for oseltamivir in immunocompromised (IC) adults with influenza. Methods: Quantitative clinical pharmacology methods were applied to data from 160 adult IC patients (aged 18‐78 years) from two studies (NV20234, 150 patients; NV25118, 10 patients) who received oseltamivir 75‐200 mg twice daily for up to 10 days. An established population‐pharmacokinetic (PK) model with additional effects on oseltamivir and oseltamivir carboxylate (OC) clearance described the PK characteristics of oseltamivir in IC patients versus otherwise healthy (OwH) patients from previous clinical trials. Estimated PK parameters were used to evaluate exposure‐response relationships for virologic endpoints (time to cessation of viral shedding, viral load measures and treatment‐emergent resistance). A drug‐disease model characterized the viral kinetics of influenza accounting for the effect of OC on viral production. Results: Oseltamivir clearance was 32.5% lower (95% confidence interval [CI], 26.1‐38.8) and OC clearance was 33.7% lower (95% CI, 23.2‐44.1) in IC versus OwH patients. No notable exposure‐response relationships were identified for exposures higher than those achieved after conventional dose oseltamivir 75 mg, which appeared to be close to the maximum effect of oseltamivir. Simulations of the drug‐disease model predicted that initiating treatment within 48 hours of symptom onset had maximum impact, and a treatment duration of 10 days was favourable over 3‐5 days to limit viral rebound. Conclusions: Our findings support the use of conventional‐dose oseltamivir 75 mg twice daily for 10 days in the treatment of IC adult patients with influenza. [ABSTRACT FROM AUTHOR]

A total of 109 lactating does were screened for mastitis, both clinical and subclinical. The goats with swelling, pain, increased temperature or abnormal milk secretion were considered to have clinical mastitis while California mastitis test was used for detection of sub-clinical mastitis. Milk samples from does detected to be positive for mastitis were collected aseptically for bacterial isolation. The bacteria were identified based on standard microbiological techniques; however, confirmation of the bacterial species was done by PCR using universal primers specific for 16S rDNA followed by sequencing. Out of 109 lactating does screened, 45 (41.28%) were found positive for mastitis. Among these only seven (6.42%) exhibited clinical manifestations of mastitis while 38 does (34.86%) had subclinical mastitis. Staphylococci and Proteus mirabilis were found to be the predominant bacteria associated with mastitis. Bacillus spp. (including Bacillus cereus), E. coli, Pseudomonas aeruginosa, Citrobacter freundii and Streptococcus were also isolated from mastitic milk. Since, enteric pathogens were isolated from 40% of mastitic milk samples, it can be concluded that poor hygienic conditions could be a major factor responsible for mastitis in lactating goats. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non‐migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response.Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine.This was a Phase 1, multicenter, open‐label, randomized, single‐dose, two‐period, fixed‐sequence, comparative bioavailability study. Participants with a history of 2–8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non‐migraine period (Period 2). Blood samples were collected pre‐dose and at pre‐specified intervals up to 24 h post‐dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (Cmax), area under plasma concentration–time curve from time zero to infinity (AUC0–inf), and time of Cmax (Tmax).A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5–113.2) for Cmax and 90.1% (90% CI 70.2–115.5) for AUC0–inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9–90.8) for Cmax and 73.4% (90% CI 58.8–91.7) for AUC0–inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6–171.4) for Cmax and 157.0% (90% CI 133.6–184.5) for AUC0–inf. Median Tmax was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post‐dose and efficacy outcomes.Zavegepant exposure was comparable during a migraine attack and a non‐migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non‐migraine periods, there was a less‐than‐dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median Tmax was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non‐migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes. [ABSTRACT FROM AUTHOR]

Zavegepant (ZAVZPRET™) is a high‐affinity, selective, small‐molecule calcitonin gene‐related peptide receptor antagonist available for acute treatment of migraine in adults. A population pharmacokinetic analysis was performed to describe zavegepant plasma concentration–time course, characterize bioavailability, and identify covariates affecting zavegepant exposure. The model was developed and validated using data from 10 phase I clinical studies, wherein zavegepant was administered intravenously, intranasally, or orally to healthy adults and patients with migraine. Plasma concentration–time data were analyzed using nonlinear mixed‐effects modeling. A three‐compartment model with first‐order elimination from the central compartment, and sequential zero‐ and first‐order absorption best described the observed plasma concentration–time course of zavegepant. Bioavailability was 5.1% and 0.65% for intranasal and oral treatment, respectively; absorption rate constants were 5.8 and 0.8 h−1, respectively. Body weight‐based empirical allometric scaling was applied using standard exponents (0.75 for clearance and 1 for volume of distribution). Age (range 18–71 years), race, ethnicity, sex, renal function, and co‐administration of oral contraceptives or sumatriptan did not significantly change zavegepant pharmacokinetics. Moderate hepatic impairment (Child‐Pugh score 7–9) or co‐administration of rifampin decreased elimination clearance of oral zavegepant by ~40%. The zavegepant population pharmacokinetic model adequately characterized zavegepant concentration–time profiles, the bioavailability of intranasal and oral zavegepant, as well as the effect of intrinsic and extrinsic factors on zavegepant pharmacokinetics. [ABSTRACT FROM AUTHOR]