Pharmacokinetic Comparison Between a Fixed-Dose Combination of Atorvastatin/Omega-3-Acid Ethyl Esters and the Corresponding Loose Combination in Healthy Korean Male Subjects.

Purpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects. Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters. Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054-1.1883) and 0.9885 (0.9588-1.0192) for atorvastatin, 0.9607 (0.9068-1.0178) and 0.9770 (0.9239-1.0331) for EPA, and 0.9961 (0.9127-1.0871) and 0.9634 (0.8830-1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated. Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia.

Potential role of the cell-penetrating peptide-conjugated soluble N-ethylmaleimide-sensitive factor attachment protein receptor motif of vesicle-associated membrane protein 2-patterned peptide in novel cosmeceutical skin product development.

AIM: This study aimed to investigate and verify the effect of cell-penetrating peptide (CPP)-conjugated soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) motif of vesicle-associated membrane protein 2 (VAMP2)-patterned peptide (INCI name: Acetyl sh-Oligopeptide-26 sh-Oligopeptide-27 SP, trade name: M.Biome-BT) on improving skin function in vitro. METHODS: The cytotoxicity of CPP-conjugated SNARE motif of VAMP2-patterned peptide (CVP) was investigated using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against B16-F10 cells and human dermal fibroblasts (HDFs) and a reconstructed skin irritation test. The anti-wrinkle activity of M.Biome-BT was determined by assessing the release of norepinephrine and dopamine in PC-12 cells via ELISA. The skin-whitening effects of CVP were assessed in B16-F10 cells by measuring the intra- and extracellular melanin contents and expression levels of melanin production-related genes, such as microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), and TRP-2. RESULTS: CVP is not cytotoxic to B16-F10 cells and HDFs, and no skin irritation was observed. CVP treatment considerably diminished K+ -induced norepinephrine and dopamine secretion compared with the non-treated control group (62% and 40%, respectively). Additionally, the inhibition ability of CVP on norepinephrine and dopamine release was comparable to that of botulinum neurotoxin type A (BoNT/A). CVP also increased intracellular melanin content in a dose-dependent manner, whereas extracellular melanin content decreased (76%-85%). However, CVP treatment did not affect the mRNA expression of MITF, TYR, TRP-1, and TRP-2. These results suggest that CVP does not inhibit melanin production; however, it may induce a whitening effect by inhibiting melanin transport. CONCLUSIONS: Taken together, our findings indicate that CVP could be used as an active and safe cosmeceutical ingredient for antiaging applications.

Combination of PD-1 Checkpoint Blockade and Botulinum Toxin Type A1 Improves Antitumor Responses in Mouse Tumor Models of Melanoma and Colon Carcinoma.

BACKGROUND: Tumor innervation has been shown to be utilized by some solid cancers to support tumor initiation, growth, progression, and metastasis, as well as confer resistance to immune checkpoint blockade through suppression of antitumor immunologic responses. Since botulinum neurotoxin type A1 (BoNT/A1) blocks neuronal cholinergic signaling, its potential use as an anticancer drug in combination with anti-PD-1 therapy was investigated in four different syngeneic mouse tumor models. METHODS: Mice implanted with breast (4T1), lung (LLC1), colon (MC38), and melanoma (B16-F10) tumors were administered a single intratumoral injection of 15 U/kg BoNT/A1, repeated intraperitoneal injections of 5 mg/kg anti-PD-1 (RMP1-14), or both. RESULTS: Compared to the single-agent treatments, anti-PD-1 and BoNT/A1 combination treatment elicited significant reduction in tumor growth among B16-F10 and MC38 tumor-bearing mice. The combination treatment also lowered serum exosome levels in these mice compared to the placebo control group. In the B16-F10 syngeneic mouse tumor model, anti-PD-1 + BoNT/A1 combination treatment lowered the proportion of MDSCs, negated the increased proportion of Treg cells, and elicited a higher number of tumor-infiltrating CD4+ and CD8+ T lymphocytes into the tumor microenvironment compared to anti-PD-1 treatment alone. CONCLUSION: Our findings demonstrate the synergistic antitumor effects of BoNT/A1 and PD-1 checkpoint blockade in mouse tumor models of melanoma and colon carcinoma. These findings provide some evidence on the potential application of BoNT/A1 as an anticancer drug in combination with immune checkpoint blockade and should be further explored.

A compatibility evaluation between the physiologically based pharmacokinetic (PBPK) model and the compartmental PK model using the lumping method with real cases.

Pharmacokinetic (PK) modeling is a useful method for investigating drug absorption, distribution, metabolism, and excretion. The most commonly used mathematical models in PK modeling are the compartment model and physiologically based pharmacokinetic (PBPK) model. Although the theoretical characteristics of each model are well known, there have been few comparative studies of the compatibility of the models. Therefore, we evaluated the compatibility of PBPK and compartment models using the lumping method with 20 model compounds. The PBPK model was theoretically reduced to the lumped model using the principle of grouping tissues and organs that show similar kinetic behaviors. The area under the concentration-time curve (AUC) based on the simulated concentration and PK parameters (drug clearance [CL], central volume of distribution [Vc], peripheral volume of distribution [Vp]) in each model were compared, assuming administration to humans. The AUC and PK parameters in the PBPK model were similar to those in the lumped model within the 2-fold range for 17 of 20 model compounds (85%). In addition, the relationship of the calculated Vd/fu (volume of distribution [Vd], drug-unbound fraction [fu]) and the accuracy of AUC between the lumped model and compartment model confirmed their compatibility. Accordingly, the compatibility between PBPK and compartment models was confirmed by the lumping method. This method can be applied depending on the requirement of compatibility between the two models.

Comparative Pharmacodynamics of Three Different Botulinum Toxin Type A Preparations following Repeated Intramuscular Administration in Mice.

Botulinum neurotoxin type A (BoNT/A) causes muscle paralysis by blocking cholinergic signaling at neuromuscular junctions and is widely used to temporarily correct spasticity-related disorders and deformities. The paralytic effects of BoNT/A are time-limited and require repeated injections at regular intervals to achieve long-term therapeutic benefits. Differences in the level and duration of effectivity among various BoNT/A products can be attributed to their unique manufacturing processes, formulation, and noninterchangeable potency units. Herein, we compared the pharmacodynamics of three BoNT/A formulations, i.e., Botox® (onabotulinumtoxinA), Xeomin® (incobotulinumtoxinA), and Coretox®, following repeated intramuscular (IM) injections in mice. Three IM injections of BoNT/A formulations (12 U/kg per dose), 12-weeks apart, were administered at the right gastrocnemius. Local paresis and chemodenervation efficacy were evaluated over 36 weeks using the digit abduction score (DAS) and compound muscle action potential (CMAP), respectively. One week after administration, all three BoNT/A formulations induced peak DAS and maximal reduction of CMAP amplitudes. Among the three BoNT/A formulations, only Coretox® afforded a significant increase in paretic effects and chemodenervation with a prolonged duration of action after repeated injections. These findings suggest that Coretox® may offer a better overall therapeutic performance in clinical settings.

Correction: Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits.

[This corrects the article DOI: 10.1371/journal.pone.0256869.].

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits.

Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.

Evaluation for Potential Drug-Drug Interaction of MT921 Using In Vitro Studies and Physiologically-Based Pharmacokinetic Models.

MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug-drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

Comparative Analyses of Inflammatory Response and Tissue Integration of 14 Hyaluronic Acid-Based Fillers in Mini Pigs.

PURPOSE: Hyaluronic acid (HA)-based dermal fillers have been approved for various clinical indications, both cosmetic and medical. Previous studies that have assessed the performance of HA dermal fillers have primarily focused on evaluating filler durability, and only a few have studied their distribution within the tissues. The present study aimed to compare tissue integration of various types of HA dermal fillers having different clinical indications and varying injection depths. METHODS: To examine the local inflammatory response and distribution pattern of 14 HA dermal fillers (six Neuramis [NEU], one Belotero [BEL], three Juvéderm [JUV], and four Restylane [RES]), each product was injected intradermally and subcutaneously at the backs of two male miniature pigs. Histopathological evaluation and visual examination of the tissue sections were conducted 1 and 4 weeks after injection. RESULTS: Mean inflammatory cell infiltration scores tended to be lower in response to fillers from the NEU and BEL series than to those from the JUV and RES series after intradermal and subcutaneous injection. Furthermore, the inflammatory response to fillers with higher physicochemical properties specifically designed for injection into deeper layers of the skin tended to be slightly higher than those designated for injection into more superficial layers. There was no significant difference in tissue integration according to clinical indication and injection depth, although fillers from the NEU and BEL series exhibited better tissue integration than those from the JUV and RES series. CONCLUSION: Our findings not only suggest that the local inflammatory response and tissue integration differ across HA dermal filler products, but also that these parameters could vary according to the recommended clinical indication and injection depth of the products.

Comparative Analysis of Hyaluronidase-Mediated Degradation Among Seven Hyaluronic Acid Fillers in Hairless Mice.

PURPOSE: Hyaluronic acid (HA) is the most common injectable dermal filler used for soft-tissue augmentation, and can be removed non-surgically by directly injecting hyaluronidase. In this study, the hyaluronidase-mediated degradation of different types of HA fillers implanted subcutaneously at the back of hairless mice having filler residence time of four days or three months were compared. METHODS: Two sites at the back of female hairless mice were subcutaneously implanted with 0.1-mL of one of the seven HA fillers (NLL, NL, NDL, NVL, and ND, JUVX+, and RESLYFT) and injected with 30 IU or 60 IU hyaluronidase per 0.1-mL filler after reaching a filler residence time of 4 or 91 days, respectively. Filler bolus projection was measured using three-dimensional optical imaging over a 72 h period, and the implantation sites were histologically examined 2 weeks after hyaluronidase injection. RESULTS: Following hyaluronidase injection, all seven HA fillers showed a rapid decrease of filler volume within 24 h, and complete degradation was confirmed by histological examination after 2 weeks. There was no significant difference in filler volume reduction rate among the seven HA fillers, and no evidence of macroscopic or microscopic adverse effects were observed at the implantation sites. CONCLUSION: All seven HA fillers show comparable susceptibility to hyaluronidase-mediated degradation. HA fillers with prolonged filler residence time may require a higher dose of hyaluronidase to achieve efficient degradation owing to tissue integration.

Population Pharmacokinetic Method to Predict Within-Subject Variability Using Single-Period Clinical Data.

Sample sizes for single-period clinical trials, including pharmacokinetic studies, are statistically determined by within-subject variability (WSV). However, it is difficult to determine WSV without replicate-designed clinical trial data, and statisticians typically estimate optimal sample sizes using total variability, not WSV. We have developed an efficient population-based method to predict WSV accurately with single-period clinical trial data and demonstrate method performance with eperisone. We simulated 1000 virtual pharmacokinetic clinical trial datasets based on single-period and dense sampling studies, with various study sizes and levels of WSV and interindividual variabilities (IIVs). The estimated residual variability (RV) resulting from population pharmacokinetic methods were compared with WSV values. In addition, 3 × 3 bioequivalence results of eperisone were used to evaluate method performance with a real clinical dataset. With WSV of 40% or less, regardless of IIV magnitude, RV was well approximated by WSV for sample sizes greater than 18 subjects. RV was underestimated at WSV of 50% or greater, even with datasets having low IIV and numerous subjects. Using the eperisone dataset, RV was 44% to 48%, close to the true value of 50%. In conclusion, the estimated RV accurately predicted WSV in single-period studies, validating this method for sample size estimation in clinical trials.

Model-Based Prediction to Evaluate Residence Time of Hyaluronic Acid Based Dermal Fillers.

Dermal fillers are gel-type substances for nonsurgical medical-device use to achieve facial rejuvenation. Currently, the most widely used skin fillers are hyaluronic-acid-based dermal fillers. This study aimed to explain the change in the volume of injected dermal fillers by developing a mathematical kinetic model for various dermal fillers. The kinetics of the injected fillers were separated by a biphasic phenomenon. We attributed an increase in filler volume to the hydration of hyaluronic acid molecules and injection-site reaction and a decrease in volume to enzyme-mediated degradation. To explain these in vivo characteristics of dermal fillers, we proposed a two-compartment model, divided into a depot compartment (where the filler was injected) and a subcutaneous compartment (an observation compartment where the fillers swell and degrade), assuming that the swelling and degradation occurred in accordance with the swelling and degradation rate constants, respectively. The model was developed using five hyaluronic-acid-based dermal fillers and NONMEM. We determined that the rate-limiting step for the complete degradation of the dermal fillers in vivo was the swelling phase, as described by the swelling rate constant (Kswell). This study could enable scientists developing novel dermal fillers to predict the in vivo behavior of fillers.

Model-Based Anticancer Effect of Botulinum Neurotoxin Type A1 on Syngeneic Melanoma Mice.

In recent, Botulinum Neurotoxin A1 (BoNT/A1) has been suggested as a potential anticancer agent due to neuronal innervation in tumor cells. Although potential BoNT/A1's mechanism of action for the tumor suppression has been gradually revealed so far, there were no reports to figure out the exposure-response relationships because of the difficulty of its quantitation in the biological matrix. The main objectives of this study were to measure the anticancer effect of BoNT/A1 using a syngeneic mouse model transplanted with melanoma cells (B16-F10) and developed a kinetic-pharmacodynamic (K-PD) model for quantitative exposure-response evaluation. To overcome the lack of exposure information, the K-PD model was implemented by the virtual pharmacokinetic compartment link to the pharmacodynamic compartment of Simeoni's tumor growth inhibition model and evaluated using curve-fitting for the tumor growth-time profile after intratumoral injection of BoNT/A1. The final K-PD model was adequately explained for a pattern of tumor growth depending on represented exposure parameters and simulation studies were conducted to determine the optimal dose under various scenarios considering dose strength and frequency. The optimal dose range and regimen of ≥13.8 units kg-1 once a week or once every 3 days was predicted using the final model in B16-F10 syngeneic model and it was demonstrated with an extra in-vivo experiment. In conclusion, the K-PD model of BoNT/A1 was well developed to optimize the dosing regimen for evaluation of anticancer effect and this approach could be expandable to figure out quantitative interpretation of BoNT/A1's efficacy in various xenograft and/or syngeneic models.

Development of a Pharmacokinetic Model Describing Neonatal Fc Receptor-Mediated Recycling of HL2351, a Novel Hybrid Fc-Fused Interleukin-1 Receptor Antagonist, to Optimize Dosage Regimen.

HL2351 (hIL-1Ra-hyFc) is a novel recombinant protein formed by the fusion of two human interleukin-1 receptor antagonist components into one antibody-derived fragment crystallizable portion. Although HL2351 has a pharmacological mechanism of action similar to that of anakinra as a commercialized biopharmaceutical drug, HL2351 has been desired to reduce the dose frequency and improve therapeutic efficacy due to its long circulation half-life. In this study, we aimed to develop a population pharmacokinetic (PK) model for HL2351 using a neonatal Fc receptor (FcRn)-mediated recycling model based on a quasi-steady-state approximation of target-mediated drug disposition (TMDD) for the description of interactions between the drug and FcRn. FcRn recycling was expected in the case of HL2351 because of PK related to the antibody portion. A TMDD model was also applied to describe interactions of IL1R with HL2351 or anakinra. PK data were collected from a phase I study conducted in six groups (1, 2, 4, 8, 12 mg/kg HL2351 and 100 mg anakinra single subcutaneous administration; n = 8 per group). In consequence, the PK of anakinra and HL2351 following administration of multiple doses at different dosages were simulated. Optimized doses were considered based on average concentrations of IL1R bound to anakinra and HL2351. HL2351 at doses of 326 mg or 4.267, 4.982, 5.288, 5.458, or 5.748 mg/kg once weekly or HL2351 at 1726 mg or 21.92, 26.86, 29.10, 30.36, or 32.53 mg/kg once biweekly would have similar therapeutic effects with anakinra at a dose of 100 mg or 1, 2, 3, 4, or 8 mg/kg administered once daily, respectively.

Comparative Pharmacodynamics Study of 3 Different Botulinum Toxin Type A Preparations in Mice.

BACKGROUND: A new complexing protein-free botulinum toxin Type A (CBoNT) with the same mechanism of action as the botulinum toxin complex onabotulinumtoxinA (OBoNT) and complexing protein-free incobotulinumtoxinA (IBoNT) was recently developed. OBJECTIVE: To compare the local paresis and chemodenervation efficacy of 3 different botulinum toxin Type A preparations in mice. MATERIALS AND METHODS: Efficacy and duration of action of CBoNT, OBoNT, and IBoNT after a single intramuscular injection to the right gastrocnemius was evaluated by digit abduction score (DAS) and compound muscle action potential (CMAP) assays. RESULTS: Mouse DAS and CMAP responses were comparable between CBoNT and OBoNT, indicating similar paresis and chemodenervation efficacy, as well as duration of action. Both botulinum toxins showed significantly higher efficacy and longer duration of action than IBoNT. Similarly, mean DAS potency of CBoNT (ED50: 3.85 ± 0.34 U/kg) and OBoNT (ED50: 4.13 ± 0.07 U/kg) were significantly higher compared with IBoNT (ED50: 6.70 ± 0.83 U/kg). CONCLUSION: CBoNT displays the same efficacy as OBoNT as shown by their comparable chemodenervation and local paretic effects, and demonstrates superior efficacy and duration of action compared with IBoNT. Likewise, CBoNT has comparable DAS potency to OBoNT and is superior to IBoNT.

Simultaneous analysis of acetylcarnitine, proline, hydroxyproline, citrulline, and arginine as potential plasma biomarkers to evaluate NSAIDs-induced gastric injury by liquid chromatography-tandem mass spectrometry.

Although major adverse effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are gastric injury, assessment of NSAIDs-induced gastrointestinal adverse effects is mostly dependent on endoscopy due to the lack of plasma biomarkers. Several amino acids associated with collagenase activity and gastric mucosal mass have been suggested as plasma biomarker candidates for gastric injury. Therefore, this study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the plasma biomarker candidates, i.e., acetylcarnitine, proline, hydroxyproline, citrulline, and arginine and evaluate their potential as a biomarker for NSAIDs-induced gastric injury. The method utilized simple protein precipitation with methanol and D4-citrulline as an internal standard (IS). The assay resulted in the lower limit of quantification (LLOQ) of 0.1 µg/mL for acetylcarnitine and 1 µg/mL for proline, hydroxyproline, citrulline, and arginine in the surrogate blank plasma. The intra- and inter-day accuracy ranged 82.5-111.2% for acetylcarnitine, 95.4-103.3% for proline, 98.9-106.4% for hydroxyproline, 99.5-103.5% for citrulline, and 87.4-105.3% for arginine. The precision was within 6.17%, 3.63%, 6.20%, 6.31%, and 6.17% for acetylcarnitine, proline, hydroxyproline, citrulline, and arginine, respectively. The developed assay was successfully applied to monitor the changes of the plasma levels of the five amino acids in rats and Beagle dogs following repeated oral administrations of aceclofenac. In rats, plasma concentrations of proline, hydroxyproline, and citrulline were significantly reduced after 4 days of aceclofenac administration compared to the control group. In dogs, plasma concentrations of proline and citrulline were significantly decreased after 7 days of aceclofenac administration compared to those obtained after the first aceclofenac administration. These data indicate that plasma levels of proline, hydroxyproline, and citrulline may be used as quantitative biomarkers of NSAIDs-induced gastric damage. The present assay could also be utilized to monitor the changes of these amino acids as potential indicators for various physiological and pathophysiological conditions.

Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats.

This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by a novel liquid chromatography-tandem mass spectrometry method. Gastrointestinal damage was determined by measuring ulcer area and ulcer lesion index of the stomach. Oral administration of aceclofenac induced significant gastric ulceration, which was inhibited by esomeprazole administration. Following concurrent administration of aceclofenac and esomeprazole, overall pharmacokinetic profiles of aceclofenac and metabolic conversion to diclofenac were unaffected by esomeprazole. Aceclofenac metabolism and pharmacokinetics were not subject to significant food effects, whereas bioavailability of esomeprazole decreased in fed compared to fasting conditions. In contrast, the pharmacokinetics of aceclofenac and esomeprazole were significantly altered by different dosing vehicles. These results suggest that co-administration of esomeprazole with aceclofenac may reduce aceclofenac-induced gastrointestinal complications without significant pharmacokinetic interactions. The optimal combination and clinical significance of the benefits of the combination of aceclofenac and esomeprazole need to be further evaluated.

Modulation of microenvironmental pH for dual release and reduced in vivo gastrointestinal bleeding of aceclofenac using hydroxypropyl methylcellulose-based bilayered matrix tablet.

This study was designed to develop a once-daily controlled-release matrix tablet of aceclofenac 200mg (AFC-CR) with dual release characteristics and to investigate the role of an alkalizer in enhancing drug solubility and reducing the occurrence of gastroduodenal mucosal lesions. Two formulation approaches were employed, namely a monolithic matrix tablet and a bilayered tablet. In vitro dissolution studies of AFC-CR tablets were carried out in simulated intestinal fluid (pH6.8 buffer). The in vivo pharmacokinetic studies and drug safety of the immediate-release reference tablet Airtal® 100mg (Daewoong Co., Korea) and the optimized AFC-CR tablet were compared in beagle dogs under fasted condition. The optimally selected AFC-CR formulation displayed the desired dual release characteristics in simulated intestinal fluid with satisfactory micromeritic properties. The swelling action of the optimal matrix tablet, which was visualized by near-infrared (NIR) chemical imaging, occurred rapidly following hydration. Incorporation of sodium carbonate (Na2CO3) was found to enhance the release rate of the AFC-CR bilayered tablets at early stages and increase the microenvironmental pH (pHM). A pharmacokinetic study in beagle dogs indicated a higher drug plasma concentration and a sustained-release pattern for the AFC-CR tablet compared to the Airtal® tablet. AFC-CR was also superior to Airtal® in terms of in vivo drug safety, since no beagle dog receiving AFC-CR experienced gastrointestinal bleeding. The significant enhancement of drug safety was attributed to the size reduction and the increase of pHM of drug particles by means of incorporation of the alkalizer. These findings provide a scientific rationale for developing a novel controlled-release matrix tablet with enhanced patient compliance and better pain control.

Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study.

BACKGROUND: A fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects. SUBJECTS AND METHODS: A randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography-tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration (Cmax) and the area under the concentration curve from time zero to the last quantifiable time point (AUC0-t) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once. RESULTS: The PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the Cmax and AUC0-t were 0.98 (0.94-1.01) and 0.97 (0.93-1.01), respectively. The corresponding values for losartan were 0.91 (0.81-1.02) and 1.05 (0.98-1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated. CONCLUSION: An FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on Cmax and AUC0-t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects.