Unveiling Pharmacokinetics and Drug Interaction of Linagliptin and Pioglitazone HCl in Rat Plasma Using LC-MS/MS.

The linagliptin (LIN) and pioglitazone HCl (PIO) combination, currently undergoing phase III clinical trials for diabetes mellitus treatment, demonstrated significant improvements in glycemic control. However, the absence of an analytical method for simultaneous determination in biological fluids highlights a crucial gap. This underscores the pressing need for sensitive bioanalytical methods, emphasizing the paramount importance of developing such tools to advance diabetes management strategies and enhance patient care. Herein, a sensitive reverse-phase high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for simultaneous determination of LIN and PIO in rat plasma using alogliptin as an internal standard. Chromatographic separation was performed on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 µm) using an isocratic mobile phase system consisting of ammonium formate (pH 4.5) and methanol using an acetonitrile-induced protein precipitation technique for sample preparation. Multiple reaction monitoring in positive ion mode was used for quantitation of the precursor to production at m/z 473.2 → 419.9 for LIN, 357.1 → 134.2 for PIO, and 340.3 → 116.1 for ALO. The linearity range was 0.5 to 100 and 1 to 2000 ng/mL for LIN and PIO, respectively. The developed method was validated as per US-FDA guidelines and successfully applied to clinical pharmacokinetic and drug-drug interaction studies with a single oral administration of LIN and PIO in rat plasma. Pharmacokinetic parameters of LIN were significantly influenced by the concomitant administration of PIO and vice versa. Molecular modeling revealed the significant interaction of LIN and PIO with P-glycoprotein. Therefore, the drug-drug interaction between LIN and PIO deserves further study to improve drug therapy and prevent dangerous adverse effects.

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.

Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging.

We have employed a bespoke setup combining confocal Raman microscopy and an ultraviolet-visible (UV-Vis) spectroscopy flow cell to investigate the effect of excipients on the disproportionation kinetics of Pioglitazone HCl (PioHCl) in tablets during dissolution. Three binary formulations of PioHCl, containing citric acid monohydrate (CA), lactose monohydrate (LM), or magnesium stearate (MgSt), respectively, were used as models to study the influence of excipients' physicochemical properties on the rate of salt disproportionation kinetics and dissolution performance in different aqueous pH environments. It was found that formulation excipients can induce or prevent salt disproportionation by modulating the microenvironmental pH regardless of the pH of the dissolution media. Incorporating CA in PioHCl tablets preserves the salt form and enhances the dissolution performance of the salt in the acidic medium (pH = 1.2). In contrast, LM and MgSt had a detrimental effect on in vitro drug performance by inducing salt disproportionation in the tablet during dissolution in the same acidic medium. Dissolution in the neutral medium (pH = 6.8) showed rapid formation of the free base upon contact with the dissolution medium. The Raman maps of the cross-sectioned tablets revealed the formation of a shell consisting of the free base around the edge of the tablet. This shell decreased the rate of penetration of the dissolution medium into the tablet, which had significant implications on the release of the API into the surrounding solution, as shown by the UV-vis absorption spectroscopy drug release data. Our findings highlight the utility of the Raman/UV-vis flow cell analytical platform as an advanced analytical technique to investigate the effect of excipients and dissolution media on salt disproportionation in real time. This methodology will be used to enhance our understanding of salt stability studies that may pave the way for more stable multicomponent formulations.

Investigating the Utility of Humanized Pregnane X Receptor-Constitutive Androstane Receptor-CYP3A4/7 Mouse Model to Assess CYP3A-Mediated Induction.

Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight because of species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologs were developed. The aim of this work was to investigate the utility of mouse models expressing human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz, and pioglitazone, which were employed to represent strong, moderate, and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. After the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction of clinic induction was recapitulated as rifampin yielded the greatest inductive effect followed by efavirenz and pioglitazone. Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity. Conversely, there was no difference between in vivo and in vitro CYP3A activity with efavirenz. These findings are consistent with the report that, although rifampin exhibits differential inductive effects between the intestines and liver, efavirenz does not. These data highlight the promise of transgenic models, such as Tg-Composite, to complement human hepatocytes to enhance the translatability of clinical induction as well as become a powerful tool to further study mechanisms of drug disposition. SIGNIFICANCE STATEMENT: Underprediction of the magnitude of clinical induction when using human hepatocytes has been reported, and transgenic models may improve clinical translatability. The work presented here showcases the human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 model, which was able to recapitulate the magnitude of clinical induction and to differentiate tissue-dependent induction observed with rifampin but not with efavirenz. These results not only foreshadow the potential application of such transgenic models in assessing clinical induction but also in further investigation of the mechanism of drug disposition.

In Vitro Sensitivity Analysis of the Gastrointestinal Dissolution Profile of Weakly Basic Drugs in the Stomach-to-Intestine Fluid Changing System: Explanation for Variable Plasma Exposure after Oral Administration.

An in vitro methodology for simulating the change in the pH and composition of gastrointestinal fluid associated with the transition of orally administered drugs from the stomach to the small intestine was developed (the stomach-to-intestine fluid changing system (the SIFC system)). This system was applied to in vitro sensitivity analysis on the dissolution of weakly basic drugs, and the obtained results were discussed in relation to the intrasubject variability in the plasma exposure in human bioequivalence (BE) study. Three types of protocols were employed (steep pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, gradual pH change: pH 1.6 FaSSGF → pH 6.5 FaSSIF, and high gastric pH: pH 4.0 FaSSGF → pH 6.5 FaSSIF). Regardless of the protocols and the forms of drug applied in active pharmaceutical ingredient powder or formulation, dissolution profiles of pioglitazone after fluid shift were similar and the final concentrations in FaSSIF were approximately equal to the saturation solubility in FaSSIF, supporting its small intrasubject variance in human BE study. In contrast, dissolved concentration of terbinafine in the SIFC system became less than half in the high gastric pH protocol than that in other protocols, suggesting the fluctuation of gastric pH as one of the factors of high intrasubject variance of terbinafine in human. Plasma exposure of telmisartan was highly variable especially at the high dose. Although the dissolution of telmisartan in the SIFC system was greatly improved by formulation, it considerably fluctuated during fluid shift especially at the high dose, which corresponds well to in vivo results.

Caffeine modulates pharmacokinetic and pharmacodynamic profiles of pioglitazone in diabetic rats: Impact on therapeutics.

OBJECTIVES: To determine the influence of caffeine on pharmacokinetics and pharmacodynamics of pioglitazone (PIO) in diabetic rats. METHODS: This was a preclinical study conducted in the College of Pharmacy, Najran University, Saudi Arabia, using 5 groups of Wistar rats: normal rats, untreated diabetic rats, diabetic rats + caffeine (20 mg/kg), diabetic rats + PIO (10 mg/kg), and diabetic rats + PIO (10 mg/kg) + caffeine (20 mg/kg). The drugs were administered for 14 days, and fasting plasma glucose concentrations were determined on the first day, and thereafter at weekly intervals. On day 14, rat sacrifice was followed with assay of levels of biomarkers. To estimate the pharmacokinetic parameters, the diabetic animals were assigned to 2 groups: one group received PIO (10 mg/kg), while the other received PIO + caffeine (20 mg/kg). Blood samples were drawn from the retro-orbital plexus at different time intervals, and pharmacokinetic parameters were measured using high performance liquid chromatography. RESULTS: Caffeine caused statistically marked increases in area under the curve, Cmax, Tmax, and half-life of PIO, and decreased clearance. Combination of PIO and caffeine produced a synergistic effect on percentage reduction in blood glucose, with 67.1% reductions observed on day 7 and 68.9% reductions observed on day 14. Liver and cardiac biomarkers were significantly decreased, suggesting cardioprotective and hepatoprotective effects. CONCLUSION: Co-administration of PIO with caffeine enhances its antidiabetic effect, probably due to enhanced bioavailability of PIO, leading to clinical benefits in diabetic patients.

Pharmacokinetic/Pharmacodynamic Interaction Between Evogliptin and Pioglitazone in Healthy Male Subjects.

AIM: Evogliptin is a newly developed oral glucose-lowering medication of the dipeptidyl peptidase 4 (DPP-4) inhibitor class for type 2 diabetes mellitus. The combination of a DPP-4 inhibitor with pioglitazone is a promising therapeutic option. The aim of the present study was to evaluate the pharmacokinetic and pharmacodynamic interaction between evogliptin and pioglitazone. MATERIALS AND METHODS: A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence crossover study was conducted in healthy Korean male subjects. All subjects received evogliptin 5 mg once daily for 7 days (EVO), pioglitazone 30 mg once daily for 7 days (PIO) and co-administration of evogliptin 5 mg and pioglitazone 30 mg once daily for 7 days (EVO+PIO) according to the assigned sequence and period. Serial blood samples were collected for 24 hours for pharmacokinetic analysis and 3 hours after the oral glucose tolerance test for the pharmacodynamic analysis. RESULTS: Thirty-four subjects completed the study. EVO+PIO and EVO showed a similar maximum plasma concentration at steady state (Cmax,ss) and area under the concentration-time curve during the dosing interval at the steady state (AUCτ,ss) of evogliptin, with geometric mean ratios (GMRs) (90% confidence interval (CI)) of 1.01 (0.97-1.05) and 1.01 (0.98-1.04), respectively. EVO+PIO and PIO showed a similar Cmax,ss and AUCτ,ss of pioglitazone, with GMRs (90% CI) of 1.07 (0.99-1.17) and 1.08 (0.99-1.17), respectively. Reduction of the glucose level after EVO+PIO was larger compared to PIO and similar with EVO. CONCLUSION: Concomitant administration of evogliptin and pioglitazone showed similar glucose-lowering effects with those of evogliptin alone without pharmacokinetic interactions when compared to the intake of each drug alone.

Co-stabilization of pioglitazone HCL nanoparticles prepared by planetary ball milling: in-vitro and in-vivo evaluation.

Pioglitazone (PGZ) is an oral antidiabetic agent that increases cell resistance to insulin, thereby decreasing blood glucose levels. PGZ is a class II drug. Because of its pH-dependent solubility, it precipitates at the intestinal pH, resulting in an erratic and incomplete absorption following oral administration, which causes fluctuations in its plasma concentration. A nanoparticle drug delivery system offers a solution to enhance the dissolution rate of this poorly water-soluble drug. PGZ nanoparticles were formulated by the wet milling technique using a planetary ball mill. The effects of the steric stabilizer (Pluronic F-127, PL F-127), electrostatic stabilizer (sodium deoxycholate, SDC), and number of milling cycles were optimized using a Box-Behnken factorial design. The results showed that the ratio of PL F-127: SDC significantly affected the zeta potential and the dissolution efficiency (DE%) of PGZ. The optimized PGZ nanoparticle formulation enhanced the dissolution to reach 100% after 5 min. The in-vivo results showed significant enhancement in Cmax (1.3-fold) compared to that of the raw powder, and both AUC0-24 and AUC0-∞ were significantly (p < 0.05) enhanced. In conclusion, PGZ nanoparticle formulation had enhanced dissolution rate in the alkaline media, which improved its drug bioavailability relative to that of the untreated drug.

Simultaneous Pharmacokinetics Estimation of Nateglinide and Pioglitazone by RP-HPLC: Computational Study to Unlock the Synergism.

Nateglinide (NAT) and Pioglitazone (PIO) are an antidiabetic drugs combination and currently under clinical trial in countries like Japan. In this study, an alternative, a simple, sensitive high-performance liquid chromatography method has been developed (limit of detection: 15 ng/mL and limit of quantification: 50 ng/mL) for simultaneous estimation of this drug combination in rat plasma. Most remarkably, bioavailability of NAT has been increased markedly on coadministration with PIO, than when it was administered alone. Thus, PIO is assumed to retard the catabolism of NAT by inhibiting metabolic liver-microsomal enzyme, especially CYP2C9. Using a Waters Nova-Pak C 18 column (150 × 3.9 mm, 4 µm) and a mobile phase of acetonitrile: 10 mM KH2PO4 (60: 40, V/V (volume by volume)) pH 3.5, the analysis was performed at 210 nm with a flow rate of 1.5 mL/min. In silico docking via molecular dynamics simulation revealed that NAT-CYP2C9 binding affinity may be reduced after PIO attachment, presumably due to the binding site overlapping of the two drugs. Thus, it has been proposed that NAT and PIO may be an efficient synergistic fixed dose combination against diabetes mellitus, and the above method can foster a simple but highly sensitive bioanalytical estimation for routine analysis.

Determination of pioglitazone, its metabolite and alogliptin in human plasma by a novel LC-MS/MS method; application to a pharmacokinetic study.

A novel, high throughput and sensitive LC-MS/MS assay method was developed and fully validated for quantitative determination of pioglitazone, its hydroxyl metabolite and alogliptin in human plasma. A simple and rapid sample preparation procedure based on protein precipitation technique with acetonitrile was utilized. Chromatographic separation was achieved on C8 (50 × 4.6 mm, 5 µm) Kinetex® analytical column using methanol and 0.1% formic acid in a gradient elution mode at a flow rate of 0.7 mL/min with injection volume of 8 µL. Detection was performed on a triple quadrupole mass spectrometer accompanied with electrospray ionization (ESI) technique in positive mode, operating in multiple reaction monitoring, with the transitions of 357.2 → 119.1, 373.1 → 150.1, 340.3 → 116.1, 361.1 → 138.1 and 343.2 → 116.1 m/z for pioglitazone, its hydroxyl metabolite, alogliptin, pioglitazone-d4 (IS-1) and alogliptin-d3 (IS-2), in order. Analysis was achieved within 4 min over a linear concentration range of 10-3000 ng/mL, 5-2000 ng/mL and 3-300 ng/mL, for pioglitazone, hydroxyl pioglitazone and alogliptin, in order. The method was fully validated according to FDA guidelines. The developed method was used for estimation of the three studied analytes in human plasma and pharmacokinetic parameters were demonstrated after oral dose administration of Oseni® tablets to Egyptian healthy volunteers.

Liquid chromatography tandem mass spectrometry for the simultaneous determination of metformin and pioglitazone in rat plasma: Application to pharmacokinetic and drug-drug interaction studies.

Failure to attain and sustain long term glycemic control is an ongoing challenge in diabetes therapy. The trend to use a combined therapy and the risk of drug-drug interaction (DDI) are elevated and thus the need for sensitive analytical methods is of great significance. Herein, a simple, robust, and sensitive reverse phase high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (ESI-MS/MS) method for simultaneous determination of metformin (MET) and pioglitazone (PGT) in rat plasma using canagliflozin (CAN) as internal standards (IS) was developed and fully validated. Prior Chromatographic separation on an Agilent Eclipse Plus C18 (4.6 × 100 mm, 3.5 µm) using gradient mobile phase system consisting of ammonium formate pH 4.5 and acetonitrile at a flow rate of 0.5 mL min-1, within a run time of 14 min, the antidiabetic drugs were extracted from rat plasma using acetonitrile-induced protein precipitation technique. Multiple reaction monitoring in positive ion mode was used for quantitation of precursor to production at m/z 130.1 → 71.0 & 60 for MET, 357.2 → 134.2 for PGT, and 462.16 → 191.1 for CAN. Method linearity was obeyed in the range of 1 to 5000 and 1 to 2500 ng mL-1 for MET and PGT, respectively. The developed method was validated in terms of accuracy, precision, selectivity, recovery, matrix effects, and stability as per US-FDA bioanalytical guidelines and successfully applied to clinical pharmacokinetic and DDI studies with a single oral administration of target compounds. The peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of MET was significantly influenced by the concomitant administration of PGT at equal concentration and vice versa. PGT affected the absorption and elimination rate of MET via inhibition of organic cationic transporter (OCT). Molecular modeling study revealed the significant interaction of PGT with OCT. A potential DDI in type 2 diabetic patient receiving chronic treatment with MET and PGT deserves further attention and study to improve drug therapy and prevent adverse effects.

Physiologically Based Pharmacokinetic Models for Prediction of Complex CYP2C8 and OATP1B1 (SLCO1B1) Drug-Drug-Gene Interactions: A Modeling Network of Gemfibrozil, Repaglinide, Pioglitazone, Rifampicin, Clarithromycin and Itraconazole.

BACKGROUND: Drug-drug interactions (DDIs) and drug-gene interactions (DGIs) pose a serious health risk that can be avoided by dose adaptation. These interactions are investigated in strictly controlled setups, quantifying the effect of one perpetrator drug or polymorphism at a time, but in real life patients frequently take more than two medications and are very heterogenous regarding their genetic background. OBJECTIVES: The first objective of this study was to provide whole-body physiologically based pharmacokinetic (PBPK) models of important cytochrome P450 (CYP) 2C8 perpetrator and victim drugs, built and evaluated for DDI and DGI studies. The second objective was to apply these models to describe complex interactions with more than two interacting partners. METHODS: PBPK models of the CYP2C8 and organic-anion-transporting polypeptide (OATP) 1B1 perpetrator drug gemfibrozil (parent-metabolite model) and the CYP2C8 victim drugs repaglinide (also an OATP1B1 substrate) and pioglitazone were developed using a total of 103 clinical studies. For evaluation, these models were applied to predict 34 different DDI studies, establishing a CYP2C8 and OATP1B1 PBPK DDI modeling network. RESULTS: The newly developed models show a good performance, accurately describing plasma concentration-time profiles, area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) values, DDI studies as well as DGI studies. All 34 of the modeled DDI AUC ratios (AUC during DDI/AUC control) and DDI Cmax ratios (Cmax during DDI/Cmax control) are within twofold of the observed values. CONCLUSIONS: Whole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.

Lack of inhibition of CYP2C8 by saroglitazar magnesium: In vivo assessment using montelukast, rosiglitazone, pioglitazone, repaglinide and paclitaxel as victim drugs in Wistar rats.

Saroglitazar, a PPAR αÒ® agonist, is currently undergoing global development for the treatment of NASH and other indications. Saroglitazar showed CYP2C8 inhibition in human liver microsomes (IC50: 2.9 µM). The aim was to carry out drug-drug interaction (DDI) studies in Wistar rats using saroglitazar (perpetrator drug) with five CYP2C8 substrates. Also, the in vitro CYP2C8 inhibitory potential of saroglitazar in rat liver microsomes (RLM) was evaluated to justify use of preclinical model. The oral pharmacokinetics of various CYP2C8 substrates; montelukast, rosiglitazone, pioglitazone, repaglinide and intravenous pharmacokinetics of paclitaxel was assessed in the presence/absence of oral saroglitazar (4 mg/kg) in Wistar rats. A separate study was performed to assess the oral pharmacokinetics of saroglitazar. Serial blood samples were collected from all studies and the harvested plasma were stored frozen until bioanalysis. LC-MS/MS was used for the analysis of various analytes; concentration data was subjected to noncompartmental pharmacokinetic analysis. Statistical tests (unpaired t-test) were employed to judge the level of DDI. Generally, the pharmacokinetics of CYP2C8 substrates was not affected by the concomitant intake of saroglitazar as judged by the overall exposure (AUC0-last and AUC0-inf) and elimination half-life. The CYP2C8 IC50 of 4.5 µM in RLM for saroglitazar, supported the use of rats for this DDI study. In conclusion, pharmacokinetic data of diverse CYP2C8 substrates suggested that coadministration of saroglitazar did not cause clinically relevant DDI.

Nanoparticle-mediated local delivery of pioglitazone attenuates bleomycin-induced skin fibrosis.

BACKGROUND: Nanoparticle-loaded delivery systems have attracted much attention recently. Poly(lactic-co-glycolic acid) (PLGA) is one of the most successful biodegradable polymers for biomedical applications. There are only a few studies on the treatment of dermal fibrosis with sustained-release drugs. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in endogenous anti-fibrotic defense mechanisms. Recent studies have suggested that pioglitazone, a synthetic PPAR-γ activator, has effects beyond reducing blood sugar and it can reduce fibrosis and inflammation when used systemically. OBJECTIVE: We aimed to assess the effects of local injections of pioglitazone-loaded PLGA nanoparticles (PGN-NP) on an experimental sclerosis and to demonstrate the in vivo pharmacokinetics of subcutaneously administered PLGA nanoparticles. METHODS: Locally injectable PGN-NP were prepared and subcutaneously administered to bleomycin (BLM)-induced scleroderma model mice. The effect of pioglitazone was also evaluated with cultured fibroblasts. Coumarin-6-loaded fluorescent PLGA nanoparticles (FL-NP) and silicon naphthalocyanine-loaded near-infrared PLGA nanoparticles (NIR-NP) were used to demonstrate in vitro cellular uptake by cultured fibroblasts and the in vivo pharmacokinetics of subcutaneously administered nanoparticles. RESULTS: Weekly subcutaneous injections of PGN-NP attenuated skin fibrosis in BLM-induced scleroderma model mice. Pioglitazone significantly suppressed migration ability and TGF-ß-mediated myofibroblast differentiation in cultured fibroblasts. FL-NP were internalized into cultured fibroblasts within 60 min, and PGN-NP-primed fibroblasts expressed anti-fibrotic phenotypes. Subcutaneously injected NIR-NP remained in the vicinity of the injection site more than non-particulate silicon naphthalocyanine. CONCLUSION: These results provide a basis for the development of new treatments for dermal fibrosis and a better understanding of the potential of PLGA nanoparticles in dermatology.

Effect of semicrystalline copolymers in solid dispersions of pioglitazone hydrochloride: in vitro-in vivo correlation.

OBJECTIVE: The study was aimed to improve the dissolution and bioavailability of developed stable amorphous solid dispersions (SDs) of pioglitazone hydrochloride (PGH), a poorly water-soluble drug. SIGNIFICANCE: Poor aqueous solubility of PGH was overcome by the design of SDs. Level A correlation demonstrated between in vitro release and bioavailability of PGH, suggest its biowaiver potential. METHODS: The effects of semicrystalline copolymers (poloxamer 407 and gelucire 50/13) and methods of preparations on dissolution behavior, in vivo performance, and stability of PGH SDs were investigated. All the SDs were characterized by FTIR, TGA, DSC, XRD, and SEM. RESULTS: FTIR and TGA showed the compatibility with the polymers. The significant change in melting pattern of the PGH observed in the DSC thermograms supported by XRD patterns & SEM indicated a change from a crystalline to an amorphous state. Gelucire 50/13 was observed to have greater ability to form SDs than poloxamer 407 in solvent evaporation method (SM). Prevention of recrystallization during storage suggested stability of the formulation. Gelucire 50/13 based SD, prepared by SM remarkably increased the dissolution within 15 min (87.27 ± 2.25%) and was supported by dissolution parameters (Q15, IDR, RDR, % DE, f1, f2). These SDs showed pH-dependent solubility. In vivo test showed significantly (p < .05) higher AUC0-t and Cmax, which were about 3.17 and 4.34 times that of the pure drug respectively. CONCLUSION: Gelucire 50/13 was found to be a suitable carrier for SM for preparation of SDs of PGH as evident from increased dissolution and bioavailability.

A pilot dose finding study of pioglitazone in autistic children.

Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations. Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old. Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily. Results: Maximum tolerated dose: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily.Safety: overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia.Early evidence of efficacy: statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders. Conclusions and relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted. Trial registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010.

Pioglitazone provides beneficial effect in metabolic syndrome rats via affecting intracellular Na+ Dyshomeostasis.

Metabolic syndrome, is associated impaired blood glucose level, insulin resistance, and dyslipidemia caused by abdominal obesity. Also, it is related with cardiovascular risk accumulation and cardiomyopathy. The hypothesis of this study was to examine the effect of thiazolidinediones such as pioglitazone on intracellular Na+ homeostasis in heart of metabolic syndrome male rats. Abdominal obesity and glucose intolerance had measured as a marker of metabolic syndrome. Intracellular Na+ concentration ([Na+]i) at rest and [Na+]i during pacing with electrical field stimulation were determined in freshly isolated cardiomyocytes. Also, TTX-sensitive Na+- channel current (INa) density and I-V characteristics of these channels were measured to understand [Na+]i homeostasis. We determined the protein levels of Na+/Ca2+ exchanger and Na+-K+ pump to understand the relation between [Na+]i homeostasis. High sucrose intake significantly increased body mass and blood glucose level of the rats in the metabolic syndrome group as compared with control group. There was a decrease in INa density and there were differences in points on activation curve of INa. Basal [Na+]i in metabolic syndrome group significantly increased but there was a significantly decrease in [Na+]i in stimulated cardiomyocytes in metabolic syndrome. Furthermore, pioglitazone induced decreases in the basal [Na+]i and preserved the decrease in INa and [Na+]i in stimulated cardiomyocytes to those of controls. Histologically, metabolic syndrome affected heart and associated tissues together with many other organs. Results of the present study suggest that pioglitazone has significant beneficial effects on metabolic syndrome associated disturbances in the heart via effecting Na+ homeostasis in cardiomyocytes.

Nanocrystalization of Pioglitazone by Precipitation Method.

BACKGROUND: Poor solubility in aqueous medium limits the use of many drugs. Different methods have been adopted to promote the rate of dissolution of slightly water soluble drugs. Crystallization improves solubility, and bioavailability by increasing the surface area of slightly water soluble drugs. Pioglitazone (PGZ), which is a class II Biopharmaceutical Classification System drug has a slight solubility in water and a slow rate of dissolution, which may have a negative effect on its metabolism leading to a therapeutic failure. AIM: The aim of this study was to improve the solubility of PGZ-HCl; an antidiabetic drug using precipitation method. MATERIALS AND METHODS: Formulations were prepared with polyethylene glycol 6000 and isomalt using different speed of homogenizer and quantity of solvent by precipitation method. Drug-polymer interactions were examined using differential scanning calorimetry (DSC), and Powder X-Ray Diffraction (PXRD). Surface structure were shown by SEM photographs. RESULTS: The particle size was significantly decreased and solubility was enhanced with increase speed, ethanol solvent and increase stabilizer, however very high amount of stabilizer resulted in a decrease in solubility. CONCLUSION: This result however showed that solid dispersion technique is a potential method for increasing dissolution profile of a poorly aqueous soluble agent.