Opioid-sparing Effects of SoluMatrix Indomethacin in a Phase 3 Study in Patients With Acute Postoperative Pain.

OBJECTIVES: To report the opioid-sparing effects of SoluMatrix indomethacin, developed using SoluMatrix Fine Particle Technology, in a phase 3 study in patients with acute pain following bunionectomy. METHODS: This phase 3, placebo-controlled study randomized 462 patients with moderate-to-severe pain following bunionectomy surgery to receive SoluMatrix indomethacin 40 mg 3 times daily, SoluMatrix indomethacin 40 mg twice daily, SoluMatrix indomethacin 20 mg 3 times daily, celecoxib 400-mg loading dose followed by 200 mg twice daily, or placebo. Patients were permitted to receive opioid-containing rescue medication throughout the study. The proportion of patients who used rescue medication and the amount of rescue medication used on the first (0 to 24 h) and second (>24 to 48 h) days following initial dose of study medication, as well as time to first rescue medication use, were assessed. RESULTS: Significantly fewer patients who received SoluMatrix indomethacin 40 or 20 mg 3 times daily used opioid-containing rescue medication on day 1 compared with those receiving placebo (P≤0.034), and fewer patients in all active treatment groups used rescue medication during the second day compared with those in the placebo group (P<0.001). All active treatment groups used significantly fewer rescue medication tablets on days 1 and 2 following randomization compared with placebo (P<0.001). The most common adverse events were nausea, postprocedural edema, and headache. DISCUSSION: SoluMatrix indomethacin was associated with opioid-sparing effects in patients with acute postoperative pain.

Pharmacokinetic properties of low-dose SoluMatrix meloxicam in healthy adults.

SoluMatrix® meloxicam has been developed using SoluMatrix Fine Particle Technology™ to produce a meloxicam drug product with enhanced absorption properties to enable treatment at lower doses than available oral meloxicam drug products. This follows recognition of serious dose-dependent adverse events (AEs) associated with nonsteroidal anti-inflammatory drugs, including meloxicam. This study investigated the pharmacokinetic (PK) properties of SoluMatrix meloxicam 5-mg (fasting conditions) and 10-mg capsules (fasting and fed conditions) and compared SoluMatrix meloxicam 10-mg capsules with meloxicam 15-mg tablets under fasting conditions. This four-period crossover study randomized 28 healthy adult participants to receive single doses of SoluMatrix meloxicam 5-mg capsules (fasting) and 10-mg capsules (fasting or fed) and meloxicam tablets 15 mg (fasting). Meloxicam plasma concentrations were assessed through 96 h postdose. Safety was assessed. Twenty-five participants (89.3 %) completed the study. Under fasting conditions, SoluMatrix meloxicam 10 mg [1252.8 (254.22) ng/mL] produced similar meloxicam mean (standard deviation (SD)) maximum plasma concentrations vs meloxicam 15-mg tablets [1288.8 (424.40) ng/mL]. The overall mean (SD) systemic meloxicam exposure was 33 % lower for SoluMatrix meloxicam 10 mg [29,173.01 (11,042.09) ng*h/mL] vs meloxicam 15-mg tablets [40,875.6 (11,733.47) ng*h/mL]. The median time to maximum plasma meloxicam levels occurred earlier following SoluMatrix meloxicam 5 mg (2.0 h) and 10 mg (2.0 h) administration vs meloxicam 15-mg tablets (4.0 h). Few study-medication-related AEs were reported. SoluMatrix meloxicam 10 mg was more rapidly absorbed and associated with a lower overall exposure compared with meloxicam 15-mg tablets in this study in healthy adults under fasting conditions.

Pharmacokinetics and safety of low-dose submicron indomethacin 20 and 40 mg compared with indomethacin 50 mg.

INTRODUCTION: Indomethacin is a potent analgesic that, similar to other nonsteroidal anti-inflammatory drugs, is associated with serious dose-related adverse events. There is a need for newer nonsteroidal anti-inflammatory drug products with improved tolerability. Low-dose submicron indomethacin was developed using SoluMatrix Fine Particle Technology™ to enable treatment at lower doses than commercially available indomethacin drug products. This study evaluated the pharmacokinetics and safety of submicron indomethacin 20 and 40 mg compared with indomethacin 50-mg capsules. METHODS: This was a phase 1, randomized, open-label, 4-period, 4-sequence, single-dose crossover study. Forty healthy volunteers received low-dose submicron indomethacin 20- or 40-mg capsules, or indomethacin 50-mg capsules under fasting or fed conditions. Pharmacokinetic parameters and safety were assessed. RESULTS: Comparable fasting peak plasma levels (mean ± standard deviation) were demonstrated for submicron indomethacin 40 mg (2368.79 ± 631.38 ng/ml) and indomethacin 50 mg (2369.40 ± 969.06 ng/ml). The overall systemic exposure (geometric least squares mean; 95% CI) was > 21% lower for submicron indomethacin 40 mg (6007.71 ng·h/mL; 5585.73-6461.58) compared with indomethacin 50 mg (7646.23 ng·h/ml; 7110.44-8222.40) under fasting conditions. Food delayed the rate but did not affect the extent of indomethacin absorption from submicron indomethacin 40 mg. Submicron indomethacin 40 mg administration resulted in earlier time to peak plasma levels (median 1.67; min-max 0.5-3.5 hours) under fasting conditions compared with indomethacin 50 mg (2.02; 0.5-5.0 hours). Submicron indomethacin 20 and 40 mg were dose proportional and generally well tolerated. CONCLUSION: Compared with indomethacin 50 mg, submicron indomethacin 40 mg achieved similar peak plasma concentrations, lower systemic exposure, and a faster time to peak plasma concentration, indicating rapid absorption. The current formulation of low-dose submicron indomethacin has recently demonstrated efficacy in 2 phase 3 studies in patients with acute pain following bunionectomy and represents a new, low-dose treatment option for patients with acute pain.

Pharmacokinetic properties and tolerability of low-dose SoluMatrix diclofenac.

PURPOSE: This study compared the pharmacokinetic properties and safety profile of low-dose (18- and 35-mg) diclofenac capsules manufactured using SoluMatrix Fine Particle Technology (Trademark of iCeutica Inc. (Philadelphia, Pennsylvania), and the technology is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania) for exclusive use in NSAIDs), which produces submicron-sized drug particles with enhanced dissolution properties, to those of diclofenac potassium immediate-release (IR) 50-mg tablets. METHODS: This Phase 1, single-center, randomized, open-label, single-dose crossover study was conducted in 40 healthy volunteers. Subjects received, in randomized order, SoluMatrix diclofenac 18- or 35-mg capsules in the fasting condition, SoluMatrix diclofenac 35-mg capsules under fed conditions, and diclofenac potassium IR 50-mg tablets under fasting and fed conditions. Pharmacokinetic parameters (T(max), C(max), AUC(0-t), AUC(0-∞)) were calculated from the concentrations of diclofenac in the plasma. Absorption, food effect, and dose proportionality were determined using a mixed-model ANOVA for C(max), AUC(0-t), AUC(0-∞). Tolerability was assessed by recording adverse events, physical examination findings, vital sign measurements: clinical laboratory test results. FINDINGS: Overall, 35 healthy volunteers aged 18 to 52 years completed the study. The mean age of the subjects was 33.4 years, and approximately half were men (47.5%). Median T(max) values were similar between the low-dose SoluMatrix diclofenac 35-mg capsules and the diclofenac potassium IR 50-mg tablets (both, ~1.0 hour). The mean maximum plasma concentration (C(max)) after the administration of low-dose SoluMatrix diclofenac 35-mg capsules was 26% lower than that with diclofenac potassium IR 50-mg tablets under fasting conditions (868.72 vs 1194.21 ng/mL). The administration of low-dose SoluMatrix diclofenac 35-mg capsules was associated with a 23% lower overall systemic exposure compared with that of diclofenac potassium IR 50-mg tablets under fasting conditions. Food decreased the rate but not the overall extent of absorption of SoluMatrix diclofenac. No serious AEs and no clinically significant abnormalities in physical examination findings, including vital sign measurements, or clinical laboratory test results, were noted during this study. IMPLICATIONS: The pharmacokinetic properties of low-dose SoluMatrix diclofenac capsules in the healthy volunteers in this study suggest rapid diclofenac absorption as measured by T(max). Low-dose SoluMatrix diclofenac capsules represent a potential option for the management of acute and osteoarthritis-related pain.

Angiotensinogen genotype affects renal and adrenal responses to angiotensin II in essential hypertension.

BACKGROUND: Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen (AGT) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies. METHODS AND RESULTS: Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng x kg(-1) x min(-1)) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular (P=0.0002) and adrenal (P=0.002) responses to infused exogenous Ang II were associated with the AGT -6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT -6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT -6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT -6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the -6AA genotype was present in only 17.8% (P=0.001). CONCLUSIONS: A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT -6A genotype results in increased tissue expression of angiotensinogen and Ang II.