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ABSTRACT Purpose To demonstrate drug/polymer nanoparticles can increase the rate and extent of oral absorption of a low-solubility, high-permeability drug. Methods Amorphous drug/polymer nanoparticles containing celecoxib were prepared using ethyl cellulose and either sodium caseinate or bile salt. Nanoparticles were characterized using dynamic light scattering, transmission and scanning electron microscopy, and differential scanning calorimetry. Drug release and resuspension studies were performed using high-performance liquid chromatography. Pharmacokinetic studies were performed in dogs and humans. Results A physical model is presented describing the nanoparticle state of matter and release performance. Nanoparticles dosed orally in aqueous suspensions provided higher systemic exposure and faster attainment of peak plasma concentrations than commercial capsules, with median time to maximum drug concentration (Tmax) of 0.75 h in humans for nanoparticles vs . 3 h for commercial capsules. Nanoparticles released celecoxib rapidly and provided higher dissolved-drug concentrations than micronized crystalline drug. Nanoparticle suspensions are stable for several days and can be spray-dried to form dry powders that resuspend in water. Conclusions Drug/polymer nanoparticles are well suited for providing rapid oral absorption and increased bioavailability of BCS Class II drugs.

Prostaglandin E (PGE ) synthesis is modulated by COX2. Changes in PGE could be used to quantify the COX2 inhibition after ibuprofen administration. This study investigated the pharmacokinetic and pharmacodynamic relationships for COX2 inhibition according to three formulations of ibuprofen in healthy male subjects. A randomized, open-label, single-dose, three-treatment, six-sequence crossover study was performed in 36 healthy South Korean male volunteers. Enrolled subjects received the following three 200 mg ibuprofen formulations: ibuprofen arginine, solubilized ibuprofen capsule, and standard ibuprofen. Pharmacokinetic and pharmacodynamic blood samples were collected for 16 hours following treatment. For pharmacodynamic evaluations, lipopolysaccharide (LPS)-induced PGE inhibition at each time point compared to predose was measured. Noncompartmental analysis was used for pharmacokinetic assessment, and time-weighted average inhibition (WAI) of PGE was applied to the pharmacodynamic evaluation. After a single oral dose of the ibuprofen formulations, the median times to maximum concentration were 0.42, 0.5, and 1.25 hours in ibuprofen arginine, solubilized ibuprofen capsule, and ibuprofen, respectively. The maximum observed plasma concentration was lower in ibuprofen, and the area under the plasma concentration-time curve was comparable among the three formulations. A significant difference was observed between fast-acting formulations and standard ibuprofen tablets for both maximum concentration and time taken to reach it. Individual formulations had an effect on PGE WAI during the 8 hours following treatment, resulting in significantly lower WAI in standard ibuprofen: ibuprofen arginine 18.4%, solubilized ibuprofen capsule 18.4%, and standard ibuprofen 11.6%. Rapid absorption and higher peak concentration were observed in ibuprofen arginine and the solubilized ibuprofen capsule. Additionally, fast-acting formulations had more predominant inhibitory activity on the COX2 enzyme.

ObjectiveRenal insufficiency may influence the pharmacokinetics of drugs. We have investigated the pharmacokinetic parameters of imrecoxib and its two main metabolites in individuals with osteoarthritis (OA) with normal renal function and renal insufficiency, respectively.MethodsThis was a prospective, parallel, open, matched-group study in which 24 subjects were enrolled (renal insufficiency group, n = 12; healthy control group, n = 12). Blood samples of subjects administered 100 mg imrecoxib were collected at different time points and analyzed. Plasma concentrations of imrecoxib and its two metabolites (M1 and M2) were determined by the liquid chromatography-tandem mass spectrometry method, and pharmacokinetic parameters (clearance [CL], apparent volume of distribution [Vd], maximum (or peak) serum concentration [Cmax], amount of time drug is present in serum at Cmax [Tmax], area under the curve [AUC; total drug exposure across time], mean residence time [MRT] and elimination half-life [t1/2]) were calculated.ResultsThe demographic characteristics of the two groups were not significantly different, with the exception of renal function. The mean Cmax and AUC0-t (AUC from time 0 to the last measurable concentration) of imrecoxib in the renal insufficiency group were 59 and 70%, respectively, of those of the healthy control volunteers with normal renal function, indicating a significant decline in the former group (P < 0. 05). The mean pharmacokinetic parameters of Ml in the renal insufficiency and healthy control groups did not significantly differ. In contrast, the mean Cmax and AUC0-t of M2 in the renal insufficiency group were 233 and 367%, respectively, of those of the normal renal function group, indicating a significant increase in the former group (P < 0.05). The mean CL/F (clearance/bioavailability) of M2 of the renal insufficiency group was 37% of that of the normal renal function group, indicating a notable reduction in the former group (P < 0.05).ConclusionThe exposure of imrecoxib in OA patients with renal insufficiency showed a decline compared to that in healthy subjects. However, in patients with renal insufficiency the exposure of M2 was markedly increased and the CL was noticeably reduced. These results indicate that the dosage of imrecoxib should be reduced appropriately in patients with renal insufficiency.

Background: Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation. Methods: A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and l-rhamnose. Pharmacokinetic profiles were assessed at steady state. Results: On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p<0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:l-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p<0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87–101%) of that after naproxen administration. Conclusions: This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.

Objective: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. Methods: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 μg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. Results: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (∼77% inhibition within 2 hours), and return to baseline values occurred within 72–96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6–8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (k out ) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h −1 and 0.152 (mg/L) −1 · h −1 , with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. Conclusions: A mechanism-based pharmacodynamic model has been developed that characterizes the anti-platelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.

Background COX-2 inhibitors can be effective for acute migraine, but none is supplied in a rapidly absorbed, ready-to-use oral liquid formulation. DFN-15, a novel oral liquid formulation of celecoxib, is being developed for the acute treatment of migraine with or without aura. Clinical studies with this formulation are ongoing. Objectives The objectives of the present study were to compare the bioavailability of DFN-15 with that of the commercial formulation of celecoxib 400-mg oral capsules (Celebrex ® ) and to determine the dose proportionality of DFN-15 in healthy fasted volunteers. Methods This single-dose randomized crossover study in 16 healthy fasted volunteers evaluated the pharmacokinetics and relative bioavailability of DFN-15 at doses of 120, 180, and 240 mg against the commercial formulation of celecoxib 400-mg oral capsules and determined the dose proportionality of DFN-15. Results The maximum observed plasma concentrations ( C max ) of celecoxib after the administration of DFN-15 120, 180, and 240 mg (1062–1933 ng/ml) were higher than for the 400-mg oral capsules (611 ng/ml). The median time to peak concentration ( T max ) was within 1 h for DFN-15 and 2.5 h for the oral capsules. The pharmacokinetics of DFN-15 were dose proportional from 120 to 240 mg. Partial area under the plasma concentration–time curves (AUCs) from 15 min to 2 h for DFN-15 120 mg were at least threefold higher than for the oral capsules, and the relative bioavailability of DFN-15 was approximately 140% that of the oral capsules. DFN-15 was well tolerated, with no new or unexpected adverse events. Conclusions Based on a faster rate of absorption and increased bioavailability, DFN-15 is being evaluated as an abortive medication for acute treatment in patients with migraine.

Background and Objective Co-Crystal of Tramadol–Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac-tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions. Methods Healthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O -desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed. Results Thirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O -desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration ( C max ) and extrapolated area under the plasma concentration–time curve to infinity (AUC ∞ ) were within the pre-defined range for comparative bioavailability (80–125%). For celecoxib, C max and AUC ∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98–146.49) and 129.34% (121.78–137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions. Conclusions As reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O -desmethyltramadol bioavailability. Clinical trial registration number 152052 (registered with the Therapeutic Products Directorate of Health Canada)

Purpose The effect of topical miconazole oral gel and systemic oral voriconazole on the pharmacokinetics of oral etoricoxib was studied in 12 healthy volunteers. Methods Plasma concentrations of etoricoxib, miconazole, voriconazole, and thromboxane B₂ generation were followed after ingestion of 60 mg etoricoxib without pretreatment, after topical administration of miconazole oral gel (85 mg x 3, 3 days), or after oral voriconazole (400 mg x 2, 1st day, 200 mg x 2, 2nd day). Results Etoricoxib area under the plasma concentration-time curve [graphic removed] and maximum plasma concentration (Cmax) geometric mean ratios (GMR) with/without miconazole were 1.69 {90% confidence interval (CI); 1.46-1.92} and 1.12 (90% CI; 0.99-1.25), respectively, and corresponding GMRs with/without voriconazole were 1.49 (90% CI; 1.37-1.61) and 1.19 (90% CI; 1.08-1.31), respectively. Conclusions Miconazole oral gel and oral voriconazole produced comparable increase in the exposure to etoricoxib, presumably via CYP3A inhibition.

Background: A large number of patients experience ischemic stroke despite treatment with aspirin (acetylsalicylic acid, ASA). It is not clear whether all of these patients with ischemic stroke respond normally to ASA or are hyporesponsive as assessed by inhibition of aggregation and thromboxane (TX) synthesis. Methods: We studied the effect of ASA given orally and ASA in vitro on collagen- and arachidonic-acid-induced TX formation and aggregation in platelet-rich plasma of 90 patients with ischemic stroke and 25 healthy control subjects. Results: Thirty-seven patients were being treated with ASA at the time of stroke. Arachidonic-acid-induced TX formation was not depressed below a predefined threshold of 25 ng/ml in 9 patients. Eight of these however exhibited a normal platelet sensitivity to ASA in vitro, suggesting poor compliance or a pharmacokinetic mechanism of nonresponse. The addition of ASA in vitro did not inhibit arachidonic-acid-induced TX formation below the above threshold in 6 patients (11%) in the group of 53 stroke patients not receiving oral ASA, indicating an impaired response to ASA at the platelet level. Moreover, platelets from stroke patients showed an increased collagen-induced, TX-independent aggregation as compared with those of healthy individuals. Conclusion: Different categories of ASA nonresponders can be distinguished in patients with ischemic stroke. These include patients with poor bioavailability or noncompliance, an impaired platelet response to ASA in vitro and an increased, TX-independent hyperreactivity to collagen.

CG100649 is a novel anti-inflammatory drug that is currently under development. CG100649 demonstrates a dual mechanism of action on cyclooxygenase-2 and carbonic anhydrase that may result in favorable treatment effects and few adverse gastrointestinal and cardiovascular events. The objective of this study was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of administering multiple oral doses of CG100649 to healthy Korean volunteers. This was a randomized, double-blind, placebo-controlled, multiple ascending oral dose study that was performed on 8 male and 8 female subjects per dose cohort. Each subject was randomly selected to receive either a single loading dose followed by 6 days of once-daily placebo (n = 4; 2 male and 2 female subjects) or CG100649 (n = 12; 6 male and 6 female subjects). Each subject was administered 1 of 3 sequential dose levels (8-mg loading dose + 2 mg/d, 10-mg loading dose + 4 mg/d, or 12-mg loading dose + 8 mg/d). Blood samples for pharmacokinetic analysis were obtained ≤480 hours after the last dose. Blood samples for measuring serum thromboxane B2 (TXB2) and ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2) (markers of cyclooxygenase-1 and cyclooxygenase-2 activity, respectively) and urine samples for measuring prostanoid metabolites were collected ≤21 days after the last dose. During steady state, the median Tmax in blood and plasma after the last dose ranged from 3 to 10 hours and 3.5 to 7.3 hours, respectively. Mean terminal t½ values in blood and plasma ranged from 121 to 203 hours and 100 to 167 hours, respectively. Whole blood concentrations were 50 to 70 times higher than plasma concentrations in all 3 dose cohorts in both male and female subjects. Compared with baseline, serum TXB2 diminished by 68% to 91% at 8 hours after the administration of the last dose in all 3 cohorts (P < 0.001). Ex vivo lipopolysaccharide-stimulated PGE2 was maximally inhibited (89%–96%; P < 0.001) by all 3 dose levels on day 7. Urinary prostacyclin metabolite was inhibited by 64% (P < 0.001) on day 7 (12–24 hours) but only by the highest CG100649 dose. There were no clinically significant drug-related changes in blood pressure between treatment groups. The most frequently encountered adverse events were aphthous stomatitis and dyspepsia. CG100649 was well tolerated and demonstrated a whole blood concentration that is ~50 to 70 times higher than in plasma in these healthy subjects. CG100649 suppressed TXB2 and PGE2 at all 3 doses, and only the highest dose suppressed the urinary excretion of the urinary prostacyclin metabolite.