Sagar Munjal

Predicting Inadequate Response to Acute Migraine Medication: Results From the American Migraine Prevalence and Prevention (AMPP) Study.

Pain freedom at 2 hours and sustained pain response at 24 hours are important outcomes of acute migraine therapy. Some studies have examined rates and predictors of successful treatment outcomes for single attacks in clinical trials. However, little is known about predictors of typical response to acute treatment over multiple attacks in the population.

Allodynia Is Associated With Initial and Sustained Response to Acute Migraine Treatment: Results from the American Migraine Prevalence and Prevention Study

In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2‐hour pain freedom (2hPF), 24‐hour pain response (24hPR), and 24‐hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine.

A Randomized Trial Comparing the Pharmacokinetics, Safety, and Tolerability of DFN‐02, an Intranasal Sumatriptan Spray Containing a Permeation Enhancer, With Intranasal and Subcutaneous Sumatriptan in Healthy Adults

Intranasal sumatriptan (Imitrex®) may be an alternative for patients who refuse injections and cannot tolerate oral agents, but due to low bioavailability and slow absorption, the clinical utility of the currently marketed formulation is limited, highlighting an unmet need for an effective non‐oral migraine medication with a rapid onset of action. To overcome the slow absorption profile associated with intranasal administration, we evaluated the impact of 1‐O‐n‐Dodecyl‐β‐D‐Maltopyranoside (DDM, Intravail A‐3™), a permeation enhancer, on sumatriptans pharmacokinetic profile by comparing the pharmacokinetic characteristics of two commercial sumatriptan products, 4 mg subcutaneous and 6 mg subcutaneous in healthy adults, with DFN‐02 – a novel intranasal agent comprised of sumatriptan 10 mg plus 0.20% DDM. We also determined the pharmacokinetic characteristics of DDM and evaluated its safety and tolerability.

Subcutaneous sumatriptan delivery devices: comparative ease of use and preference among migraineurs

Background Several sumatriptan subcutaneous autoinjector devices for acute treatment of migraine patients are available, each device differs with respect to design and features. Determining device preference and ease of use is important because patients experiencing a migraine attack are often functionally impaired. Objective The objective of this human factors study was to compare migraine patients’ device use performance and preferences for three sumatriptan subcutaneous autoinjectors: a disposable two-step device (Zembrace® SymTouch®), a disposable three-step device (Sumavel® DosePro®), and a multistep reloadable device (Imitrex® STATdose®), using simulated injections. Methods Each study subject performed two unaided simulated injections with each of three different drug delivery devices, which were presented in counterbalanced order. The participants were then asked to rate the three devices on various subjective measures. The primary end point was overall device preference using a visual analog scale. Results A total of 54 subjects participated and each subject performed two simulated injections with each of the three devices. Most subjects preferred the two-step device (88.9%) to the three-step (13.0%) and the reloadable (1.9%). The two-step device had higher mean overall preference ratings (F (2, 159)=56.6, P<0.01) and higher ratings for ease of use, intuitiveness, convenience, portability, and control. The two-step device had a first injection full-dose delivery success rate of 44.4%, higher than both the reloadable (24.1%) and the three-step (3.7%) devices. The number of errors with the two-step device (n=3) was ~90% lower than the three-step (n=49) and reloadable (n=44) devices. Conclusion In this human factors study, 54 migraineurs used simulated injections to compare three sumatriptan subcutaneous delivery devices. Zembrace SymTouch, a two-step device, was most preferred compared with Sumavel DosePro and Imitrex STATdose. It also ranked highest for ease of use and various other measures. In this study, migraine patients preferred the autoinjector that they rated as simpler and more intuitive.

DFN-02 (Sumatriptan 10 mg With a Permeation Enhancer) Nasal Spray vs Placebo in the Acute Treatment of Migraine: A Double-Blind, Placebo-Controlled Study: Headache

The objective of this study was to evaluate the efficacy, safety, and tolerability of DFN‐02 — a nasal spray comprising sumatriptan 10 mg and a permeation‐enhancing excipient (0.2% 1‐O‐n‐Dodecyl‐β‐D‐Maltopyranoside [DDM]) — for the acute treatment of migraine with or without aura in adults.

Human factors validation study of 3 mg sumatriptan autoinjector, for migraine patients.

Background Migraine pain relief is reported by more than 50% of patients who receive low dose (3 mg) of sumatriptan. Currently, there is no two-step autoinjector of low-dose sumatriptan available on the market for acute migraine treatment. To fulfill this need, a fully assembled, single-dose, subcutaneous autoinjector (sumatriptan 3 mg; product-code DFN-11) was developed. The device allows for injection with a simple two-step, push-to-inject process and provides feedback of the injection activation, progress, and completion. Objective To determine if DFN-11 autoinjector can be used correctly and safely by migraine patients. Methods and participants A human factors validation study was conducted with 45 migraine patients (30 oral-only medications users; 15 injectable sumatriptan users) who performed one unaided simulated injection. Two days prior, half the oral participants were briefly trained. All others were only given the device to inspect and written instructions to review. No injections were performed during the initial session. All participants received written instructions at the injection session. Results All participants (45/45; 100%) performed the injection without any errors. Objective measures included device removal from packaging, cap removal, expiration date check, inspection of fluid in window, identification of allowable injection site, proper device positioning, dose confirmation, and device disposal. All participants (45/45; 100%) reported no difficulty administering the injection and no concerns about using the autoinjector during a severe migraine onset. Conclusion The results showed that the DFN-11 autoinjector can be used with safe handling without patterns of confusion, failures, high-risk errors, wet injections, or patient safety risks. The DFN-11 autoinjector was validated to be used correctly and safely by migraine patients, whether they were injection experienced, unexperienced, trained, or self-trained.

The effect of weight, body mass index, age, sex , and race on plasma concentrations of subcutaneous sumatriptan: a pooled analysis

Objective/background Factors such as body size (weight and body mass index [BMI]), age, sex, and race might influence the clinical response to sumatriptan. We evaluated the impact of these covariates on the plasma concentration (Cp) profile of sumatriptan administered subcutaneously. Methods We conducted three pharmacokinetic studies of subcutaneous sumatriptan in 98 healthy adults. Sumatriptan was administered subcutaneously (236 administrations) as either DFN-11 3 mg, a novel 0.5 mL autoinjector being developed by Dr. Reddy’s Laboratories; Imitrex® (Sumatriptan) injection 3 mg or 6 mg (6 mg/0.5 mL); or Imitrex STATdose 4 mg or 6 mg (0.5 mL). Blood was sampled for 12 hours to determine sumatriptan Cp. Maximum Cp (Cmax), area under the curve during the first 2 hours (AUC0–2), and total area under the curve (AUC0–∞) were determined using noncompartmental methods. Post hoc analyses were conducted to determine the relationship between these exposure metrics and each of body weight, BMI, age, sex, and race (categorized as white, black, or others). Results Both weight and BMI correlated negatively with each exposure metric for each treatment group. Across all treatment groups, AUC0–2 for subjects with BMI less than or equal to median value was 1.03–1.12 times the value for subjects with BMI more than median value. For subjects with BMI less than or equal to median value receiving DFN-11, median AUC0–2 was slightly less than that for subjects with BMI more than median value receiving Imitrex 4 mg and larger than that for subjects with BMI more than median value receiving Imitrex 3 mg. Results were similar for the other exposure metrics and for weight. Exposure was higher in women than in men, which can be attributed in part to differences in weight. There was no relationship between exposure and age. For DFN-11, AUC0–2 and AUC0–∞ were lower in nonwhites compared with whites; the ratio of median values was 0.84 and 0.89, respectively. A similar, nonstatistically significant, trend was observed in the other products (ratio of median values ranging from 0.84 to 0.89). Conclusion Weight and BMI appear to be important covariates for sumatriptan exposure: subjects with lower values for either metric of body size have higher systemic exposure compared with subjects with higher values. Additional studies are required to determine if doses of subcutaneous sumatriptan may be adjusted based on BMI for comparable efficacy and a potentially improved tolerability profile.

Migraine in America Symptoms and Treatment (MAST) Study: Baseline Study Methods, Treatment Patterns, and Gender Differences

To summarize the baseline methods for the Migraine in America Symptoms and Treatment (MAST) Study and evaluate gender differences in sociodemographics and headache features; consultation and diagnosis patterns; and patterns of acute and preventive treatment use for migraine among study participants.

Pharmacokinetic Characterization and Dose Selection of a Novel Sumatriptan Nasal Spray Formulation, DFN‐02

This 3‐way, single‐dose, randomized crossover study evaluated the pharmacokinetics (PK) and dose proportionality of 5‐, 10‐, and 15‐mg doses of intranasal sumatriptan (DFN‐02) coformulated with a permeation enhancer (DDM) in 18 healthy adults. The objective was to determine which DFN‐02 dose approximates the PK of a 6‐mg dose of sumatriptan delivered via subcutaneous injection in the deltoid muscle of the arm. Sumatriptan plasma concentrations peaked with DFN‐02 between 10 and 15 minutes postdose, declining thereafter, with a t1/2 of about 2.5 hours; mean Cmax and AUC0–∞ values increased linearly across doses. After DFN‐02 doses of 5, 10, and 15 mg, mean Cmax was 40.7 ± 14.2, 71.2  ±  22.1, and 101.0  ±  49.5 ng/mL, and mean AUC0–∞ was 49.9  ±  20.6, 87.1  ± 31.2, and 120.5  ± 53.3 ng·h/mL, respectively. The increase in sumatriptan bioavailability was less than dose‐proportional among the DFN‐02 doses studied. Based on the established PK of a 6‐mg subcutaneous sumatriptan injection (mean Tmax,  12 minutes; mean Cmax,  74  ± 15 ng/mL in the deltoid area of the arm) and the peak and time to peak sumatriptan concentrations of the DFN‐02 doses tested, a 10‐mg dose of DFN‐02 was found to be the closest match. Overall, DFN‐02 was well tolerated at doses of 5 to 15 mg, and no new safety concerns were identified.

Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects

In a randomized, parallel‐group, single‐center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP‐08) following single‐ and multiple‐dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0–inf values for a 50‐mg oral tablet and an 18.75‐mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP‐08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP‐08 18.75‐mg groups and 2 subjects in the DFP‐08 37.5‐mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP‐08 18.75‐mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75‐ and 37.5‐mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.