AUC0-t Values Research Articles

Pharmacokinetics and tolerability of intravenous ibuprofen injection in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study .

Recently a formulation of intravenous (IV) ibuprofen was developed in China for management of mild to moderate pain in patients who could not take oral medications or where intravenous administration was preferable. The aim of this study was to evaluate the pharmacokinetic properties and tolerability of single and multiple doses of ibuprofen injection in healthy Chinese volunteers. This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. In the single-dose phase, subjects were randomized to receive a single dose of ibuprofen injection 0.2, 0.4, or 0.8g administered as a 30-minute IV infusion with a 1-week washout between periods. Blood samples were collected at regular intervals from 0 to 12.5 hours after drug administration and were analyzed using a validated LC-MS/MS method. In the multiple-dose phase, subjects received 0.4g ibuprofen every 6hours for 9doses. Blood samples were obtained before the 7^th, 8^th, and 9^th administration to determine the C_min at steady state; on the 9^th intravenous administration, blood samples were also collected for 12.5hours after drug administration. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). A total of 12 healthy male (n=6) and female (n=6) Chinese volunteers were enrolled and completed the trial. After IV administration of single dose, the mean (SD) C_max value increased from 35.77 (6.98) to 117.12 (19.78)µg/mL, and the mean (SD) AUC_0-t value increased from 67.63(10.30) to 230.50(33.55)µg×h/mL in the range of 0.2-g to 0.8-g dose. The terminal half-life in plasma was ~2.0 hours. After IV administration of 9 doses of ibuprofen 400mg every 6 hours, the mean (SD) C_max was 66.49 (8.49) µg/mL, the AUC_0-t was 135.65 (26.91) µg×h/mL, the t_1/2 was 2.14 (0.34) hours, the Cl/F was 3.34 (0.68) L/h, and the Vz/F was 10.32 (2.69) L, which were comparable with those after single dosing. The accumulation index was 1.17 (0.06), and the fluctuation was 304.0 (57.7) %. Results of the t-tests of C_max and AUC found no significant differences between the male and female groups. No serious AEs were reported, and there were no discontinuations due to AEs. The pharmacokinetics of ibuprofen exhibited dose-related kinetics from the 0.2- to the 0.8-g dose. After multiple doses, the pharmacokinetic parameters of ibuprofen were consistent with those after single doses. There was no accumulation in ibuprofen exposure in healthy Chinese between multiple doses and single dose. At the doses studied, ibuprofen appeared to be well tolerated in these healthy volunteers. .

Tertiary amine mediated targeted therapy against metastatic lung cancer

In this work, two tertiary amine-derived 4′-demethylepipodophyllotoxin (DMEP) conjugates (DC and DP) have been designed and synthesized using N,N,N′-trimethyl-N′-(4-carboxyl benzyl)-1,3-propanediamine (CPDM) and 4-(4-methylpiperazinomethyl)benzoic acid (PBA) as the targeting ligands. Both DC and DP exhibited strong in vitro cytotoxicity against small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines. Cellular uptake efficiencies of DC and DP in human alveolar type II epithelial cells were significantly enhanced compared to DMEP and etoposide (VP-16), which were demonstrated to be concentration-, time- and energy-dependent. The active transport process of DC and DP might be mediated by organic cation transporters (OCTs). After systemic administration in mice, both DC and DP selectively accumulated in the lung, displaying the highest Cmax and AUC0-t values of all tested tissues. Compared with DMEP and VP-16, DC and DP remarkably reduced the lung weight and the number of lung metastases of B16 melanoma in mice, and further prolonged the survival of tumor-bearing mice. Also, DC and DP exhibited comparable levels of cell cycle arrest and cell apoptosis. Furthermore, DC and DP demonstrated minimum toxicity towards vital organs and reduced gastrointestinal injury compared to DMEP and VP-16. Taken together, tertiary amine-derived moieties such as CPDM and PBA represent an efficient yet safe strategy to achieve lung-targeted drug delivery.

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.

BackgroundA 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 methodsA 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.ResultsThe 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.ConclusionAn 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.

Delamanid Coadministered with Antiretroviral Drugs or Antituberculosis Drugs Shows No Clinically Relevant Drug-Drug Interactions in Healthy Subjects

Delamanid is a medicinal product approved for treatment of multidrug-resistant tuberculosis. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs, including ritonavir, a strong inhibitor of CYP3A4, and selected anti-TB drugs, including rifampin, a strong inducer of cytochrome P450 (CYP) isozymes. Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analyzed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means and 90% confidence intervals. Coadministration of delamanid with tenofovir or efavirenz did not affect the PK characteristics of delamanid. Coadministration of Kaletra (lopinavir/ritonavir) with delamanid resulted in an approximately 25% higher delamanid area under the concentration-time curve from time 0 to the end of the dosing interval (AUCτ). Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs (ethambutol plus Rifater [rifampin, pyrazinamide, and isoniazid]) resulted in lower delamanid exposures (47 and 42% for the AUCτ and Cmax [maximum concentration of a drug in plasma] values, respectively), as well as decreased exposure of three primary metabolites (approximately 30 to 50% lower AUCτ values). Delamanid did not affect rifampin, pyrazinamide, and isoniazid exposure; the ethambutol AUCτ and Cmax values were about 25% higher with delamanid coadministration. The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. Although there was a decrease in the delamanid concentrations when coadministered with ethambutol plus Rifater, this is likely related to decreased delamanid absorption and not to CYP induction.

Development and Evaluation of a Gentamicin Pharmacokinetic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitoring in Neonates and Infants.

Trough gentamicin therapeutic drug monitoring (TDM) is time-consuming, disruptive to neonatal clinical care, and a patient safety issue. Bayesian models could allow TDM to be performed opportunistically at the time of routine blood tests. This study aimed to develop and prospectively evaluate a new gentamicin model and a novel Bayesian computer tool (neoGent) for TDM use in neonatal intensive care. We also evaluated model performance for predicting peak concentrations and the area under the concentration-time curve from time 0 h to time t h (AUC0- t). A pharmacokinetic meta-analysis was performed on pooled data from three studies (1,325 concentrations from 205 patients). A 3-compartment model was used with the following covariates: allometric weight scaling, postmenstrual and postnatal age, and serum creatinine concentration. Final parameter estimates (standard errors) were as follows: clearance, 6.2 (0.3) liters/h/70 kg of body weight; central volume (V), 26.5 (0.6) liters/70 kg; intercompartmental disposition (Q), 2.2 (0.3) liters/h/70 kg; peripheral volume V2, 21.2 (1.5) liters/70 kg; intercompartmental disposition (Q2), 0.3 (0.05) liters/h/70 kg; peripheral volume V3, 148 (52.0) liters/70 kg. The model's ability to predict trough concentrations from an opportunistic sample was evaluated in a prospective observational cohort study that included data from 163 patients and 483 concentrations collected in five hospitals. Unbiased trough predictions were obtained; the median (95% confidence interval [CI]) prediction error was 0.0004 (-1.07, 0.84) mg/liter. Results also showed that peaks and AUC0- t values could be predicted (from one randomly selected sample) with little bias but relative imprecision, with median (95% CI) prediction errors being 0.16 (-4.76, 5.01) mg/liter and 10.8 (-24.9, 62.2) mg · h/liter, respectively. neoGent was implemented in R/NONMEM and in the freely available TDMx software.

A pharmacokinetic study of Isatin in Beagles' bodies.

Isatin are marine active drugs that exert anti-cancer effects, have a cancer-prevention function, and possess many pharmacological activities. The study aimed to examine the pharmacokinetics of a single intravenous injection and oral medication of Isatin given to Beagles. Nine male and nine female Beagles were injected with 30 mg/kg of 2,3-indole quinones. The animals were divided into 3 groups (n=6 per group) and lavaged with a dose of 15, 30 and 60 mg/kg, respectively. Blood samples were collected prior to the medicine delivery (0 h) and 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post-medicine delivery. The blood plasma samples were analyzed using the liquid chromatography-mass spectrometry (MS)/MS method following pretreatment for the protein precipitation. Pharmacokinetics software was applied to calculate relevant pharmacokinetic parameters through the atrioventricular model. The drug concentration in plasma decreased rapidly following the intravenous injection of Isatin. After 8 h, the prototype drugs could not be tested in the plasma and only trace amounts of drugs were tested in one dog, which was considered to be an endogenous drug. Indole quinone was absorbed following lavage into Beagles and peaked in <1 h, and the drug concentration in the plasma decreased rapidly. After 8 h, the prototype drugs could not be tested in the plasma. The elimination of the two drugs in the body had no evident gender differences. In conclusion, Isatin is rapidly absorbed in bodies of Beagles. Within the dose range of 15–60 mg/kg, no linear relationship was observed for the increase in Cmax and AUC0-t values with the increased dose.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 μg (range, 270-1720 μg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers.

The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and Cmax (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The tmax (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80%–125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt® Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics.

Bioequivalence of Two Different Nicotine Chewing Gum Formulations of Two Different Strengths (2 mg and 4 mg) in Indian Healthy Adult Human Male Smoker Subjects

Nicotine Mint Flavored Chewing Gums are used to aid smokers wishing to quit or reduce prior to quitting. The aim of these two studies was to determine the bioequivalence of two test and two reference formulations of Nicotine 2 mg and 4 mg Mint Flavored Chewing Gum. Both of these two studies were single dose, randomized, 2-period, 2‑sequence, laboratory-blinded, crossover design conducted in two different set of 54 healthy adult Indian male subjects each under fasting conditions with a washout period of 8 days (for 2 mg study) and 9 days (for 4 mg study). Study formulations were administered after a 10-hour overnight fast. Blood samples for pharmacokinetic profiling were taken post-dose up to 24 hours. Safety was evaluated through the assessment of adverse events, and laboratory tests. Plasma concentrations of Nicotine were determined with a validated LC-MS/MS method. Bioequivalence between the products was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax and AUC0-t values for the test and reference products, using logarithmic transformed data. The 90% CI of Nicotine were 93.71-113.45, 89.95-112.68 and 92.90-115.98 for Cmax, AUC0-t and AUC0-∞ respectively for Nicotine 2 mg Mint Flavored Chewing Gum study. The 90% CI of Nicotine were 88.68-102.76, 91.48-109.00 and 91.14-111.66 for Cmax, AUC0-t and AUC0-∞ respectively for Nicotine 4 mg Mint Flavored Chewing Gum study. Since the 90% CI for Cmax and AUC0-t were within the 80-125% interval, it was concluded that the two test and two reference formulations of Nicotine 2 mg and 4 mg Mint Flavored Chewing Gum are bioequivalent in their rate and extent of absorption.

Abstract A135: Physiologically-based pharmacokinetic modeling to support clinical investigation of the EZH2 inhibitor, tazemetostat (EPZ-6438) in INI1-deficient pediatric tumors

Abstract Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2, which has been implicated in the pathogenesis of a variety of malignancies, including B-cell non-Hodgkin lymphoma and INI1-deficient tumors. INI1-negative malignant rhabdoid tumors, for instance, occur mainly in young children. Tazemetostat pharmacokinetic (PK) data from the first in human phase I clinical study (CT.gov: NCT01897571), across the dose range of 100 mg (suspension) and 100, 200, 400, 800 and 1600 mg (tablet) p.o. twice daily (BID), together with in vitro data including plasma protein binding, blood partitioning, metabolic stability and P450 phenotyping were used to simulate adult exposures by physiologically-based PK (PBPK) modeling (GastroPlus™ 8.5, Simulations Plus, Inc.). A model fit of the adult exposures (n = 24) that, based on visual inspection, adequately described the time-concentration profiles of tazemetostat resulted in prediction of mean steady-state AUC0-t and oral clearance (CL/F) within ±30% of the observed results across the dose range. In addition, mean steady-state Cmax were predicted ≤2-fold of the observed values, for both suspension and tablet formulations. The resultant model was then used to simulate tazemetostat steady-state exposures in discrete pediatric age ranges (6 month to 1 year (yr), &amp;gt;1-2 yrs, &amp;gt;2-6 yrs, &amp;gt;6-12 yrs, &amp;gt;12-18 yrs) following BID administration of an oral suspension. In addition to pediatric physiology, the simulations accounted for ontogeny in hematocrit, plasma protein levels and CYP expression. Using this exposure-based analysis, pediatric doses which afforded the target AUC (80% of adult steady-state AUC0-t at 800 mg or 390 mg/m2 BID) were identified. On a body surface area normalized basis, the projected doses were comparable across the age range (1 to 18 yrs), from 270 to 305 mg/m2 BID, with a slightly lower projected dose of 230 mg/m2BID, for the 6 month to 1 yr old group. As the projected doses by age were comparable, population simulations were performed to determine the corresponding exposures for each age range, at a fixed 300 mg/m2 BID dose. At this dose, mean steady-state AUC0-t values ranged from approximately 80% to 100% of that observed in adults at 800 mg BID. Mean steady-state Cmax was projected to range between 895 and 1550 ng/mL (110% to 190% of Cmax,ss at 800 mg BID in adult), but within the safe and efficacious exposure range defined in adult at doses up to 1600 mg BID. This study demonstrates the prospective application of PBPK early in clinical development to support clinical trial design in special populations, and has provided dosing recommendations for future tazemetostat trials in pediatric patients, ages 6 months to 18 years. Citation Format: Nathalie Rioux, Heike Keilhack, Blythe Thomson, Richard Chesworth, Robert A. Copeland, Eric Hedrick, Peter Ho, Nigel J. Waters. Physiologically-based pharmacokinetic modeling to support clinical investigation of the EZH2 inhibitor, tazemetostat (EPZ-6438) in INI1-deficient pediatric tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A135.

Pharmacokinetics of Five Different Types of Safflower Constituents in Rat Plasma after Oral Administration of Safflower Powder

The petals of Carthamus tinctorius L. (safflower) is an important traditional medicine for promoting blood circulation and removing blood stasis. The pharmacokinetic properties of multiple safflower constituents have not been fully understood. In the present research, an ultra-high-performance liquid chromatography-triple quadrupole mass method in dynamic multiple reaction monitoring mode was developed and validated to simultaneously quantify in rat plasma of five different characteristic types of safflower constituents, including chalcone, poly-acetylene, glycoside of 6-hydroxykaempferol, etc. All the five constituents, hydroxysafflor yellow A, bidenoside C, 6-hydroxykaempferol-3,6-diglucoside, chlorogenic acid, and p-coumaric acid were detected in rat plasma after oral administration of safflower powder. p-Coumaric acid was the most quickly absorbed one with Tmax of 0.1 hr. The poly-acetylene constituent, bidenoside C, displayed the largest AUC0-t value (2177.796 ng · h/L) followed by hydroxysafflor yellow A (1564.1 ng · h/L). The impressively favorable pharmacokinetic behavior of bidenoside C reported herein for the first time rendered the importance for paying more attention to its role in the in vivo pharmacologic effects of safflower.

Enhancement of Bioavailability and Pharmacodynamic Effects of Thymoquinone Via Nanostructured Lipid Carrier (NLC) Formulation

Thymoquinone (TQ), obtained from black cumin (Nigella sativa), is a natural product with anti-oxidant, anti-inflammatory, and hepatoprotective effects but unfortunately with poor bioavailability. Aiming to improve its poor oral bioavailability, TQ-loaded nanostructured lipid carriers (NLCs) were prepared by high-speed homogenization followed by ultrasonication and evaluated in vitro. Bioavailability and pharmacodynamic studies were also performed. The resultant NLCs showed poor physical homogeneity in Compritol 888 ATO Pluronic F127 system which consequently produced larger particle size and polydispersity index, smaller zeta potential values, and lower short-term (30days) physical stability than other systems. Encapsulation efficiency percentage (EE%) lied between 84.6 ± 5% and 96.2 ± 1.6%. TQ AUC0-t values were higher in animals treated with NLCs, with a relative bioavailability of 2.03- and 3.97-fold (for F9 and F12, respectively) higher than TQ suspension, indicating bioavailability enhancement by NLC formulation. Hepatoprotective effects of F12 showed significant (P < 0.05) decrease in both serum alanine amino transferase and aspartate amino transferase to reach 305.0 ± 24.88 and 304.7 ± 23.55U/ml, respectively, when compared with untreated toxic group. Anti-oxidant efficacy of F12 showed significant (P < 0.05) decline of malondialdehyde and elevation of reduced glutatione. This improvement was also confirmed histopathologically.

Simultaneous improvement of solubility and permeability by fabricating binary glassy materials of Talinolol with Naringin: Solid state characterization, in-vivo in-situ evaluation

The aim of the current study was to prepare binary amorphous forms of Talinolol (TLN) by using Naringin (NRG) as a stabilizing agent. The secondary objective of this study was to study the effect of P-gp inhibitor NRG on the P-gp probe drug TLN. The binary amorphous samples were prepared by quench cooling technique in the molar ratios TLN:NRG (1:1), TLN:NRG (1:2), TLN:NRG (2:1). The prepared samples were characterized by DSC, FTIR and XRD. Amorphicity of the prepared binary amorphous samples was confirmed by spotting diffuse halo in the diffractograms and further corroborated by detecting glass transition event (Tg) in the thermograms of the respective samples. The Tgs for all prepared systems were found above room temperature, the highest being 45.43°C. The systems were found physically stable at 25°C and 40°C at dry conditions for 60days. The temperature stability of prepared amorphous forms may be attributed to strong intermolecular hydrogen bond interaction between TLN and NRG, which was confirmed by Gordon–Taylor calculations and FTIR data. The solubility of TLN in amorphous form was increased by approximately 9-fold as compared to its crystalline counterpart. The in-vivo bioavailability study conducted on wistar rats demonstrated 5.4-fold increase in the AUC0-t value for TLN as compared to its crystalline counterpart. Further to learn the contribution of P-gp inhibition by NRG on the permeability of TLN, In-vitro single pass perfusion studies were conducted on the ileum of wistar rats. The permeability of TLN in rat ileum in the presence of NRG was significantly increased to 3.16×10−5cm/s as compare to control value 2.48×10−5cm/s. The current study demonstrated the ability of binary amorphous technology to simultaneously overcome both the BCS barriers i.e. solubility and permeability.

Disposition of Astragaloside IV via Enterohepatic Circulation Is Affected by the Activity of the Intestinal Microbiome.

Astragaloside IV (ASIV) is a typical bioactive constituent of Radix Astragali. The study aimed to investigate the enterohepatic circulation of ASIV and evaluate the impact of activity of intestinal microbiota on the deposition of ASIV. The amounts of ASIV and its metabolites were quantified by an LC-MS/MS method. ASIV was metabolized by intestinal bacteria to form brachyoside B (Bra B), cyclogaleginoside B (Cyc B), cycloastragenol (CA), iso-cycloastragenol (iso-CA), and dehydrogenated metabolite of CA (CA-2H). CA and iso-CA circulated in blood besides ASIV when rats received ASIV intragastrically or intravenously. After rats were intragastrically administered 10 mg/kg ASIV, the AUC0-t values of ASIV, CA, and iso-CA were 109 ± 55, 26.8 ± 17.9, and 77.9 ± 35.1 nM·h, respectively. The plasma distribution of ASIV was significantly affected by bile duct drainage when ASIV was administered through the duodenum. ASIV, Bra B, and Cyc B were secreted from bile after duodenal administration of ASIV. Antibiotics markedly inhibited the metabolism of ASIV in intestinal microbiota. After rats were pretreated with antibiotics, the AUC0-t of iso-CA was 4.8 times less than that in control rats and the concentration of CA became undetectable. Variations in intestinal microbiota may change the disposition of ASIV and subsequently influence its potential health benefits.

Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c) (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product) and Levaquin(c) (Janssen-Cilag Farmacêutica Ltda, Brazil, test product) was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c) and Levaquin(c) are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies.

A Bioequivalence Study of Nicotine 2 Mg Lozenges in Indian Healthy Adult Human Male Smoker Subjects

Nicotine Lozenges are used to aid smokers wishing to quit or reduce prior to quitting. The aim of this study was to determine the bioequivalence of a test and reference formulation of Nicotine 2 mg Lozenge. This single dose, randomized, 2-period, 2‑sequence, laboratory-blinded, crossover design study was conducted in 28 healthy adult Indian male subjects under fasting conditions with a washout period of 7 days. Study formulations were administered after a 10-hour overnight fast. Blood samples for pharmacokinetic profiling were taken post-dose up to 16 hours. Safety was evaluated through the assessment of adverse events, and laboratory tests. Plasma concentration of Nicotine was determined with a validated LC-MS/MS method. Bioequivalence between the products was determined by calculating 90% confidence intervals (90% CI) for the ratio of AUC0-t and Cmax values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals of Nicotine were 96.16-119.10 and 92.16-111.51 respectively. Since the 90% confidence intervals for Cmax and AUC0-t were within the 80 – 125% interval, it was concluded that the two formulations of Nicotine 2 mg Lozenge are bioequivalent in their rate and extent of absorption.

Bioequivalence Study of Nicotine 4 Mg Lozenges in Indian Healthy Adult Human Male Smoker Subjects

Nicotine Lozenges are used to aid smokers wishing to quit or reduce prior to quitting. The aim of this study was to determine the bioequivalence of a test and reference formulation of Nicotine 4 mg Lozenge. This single dose, randomized, 2-period, 2‑sequence, laboratory-blinded, crossover design study was conducted in 28 Indian healthy adult human male smoker subjects under fasting conditions with a washout period of 7 days. Study formulations were administered after a 10 hrs overnight fast. Blood samples for pharmacokinetic profiling were taken postdose up to 16 hrs. Safety was evaluated through the assessment of adverse events, and laboratory tests. Plasma concentrations of Nicotine were determined with a validated LC-MS/MS method. Bioequivalence between the products was determined by calculating 90% confidence interval (90% CI) for the ratio of Cmax and AUC0-t values for the test and reference products, using logarithmic transformed data. The 90% CI of Nicotine were 109.85-123.32 and 101.48-115.41 for Cmax and AUC0-t respectively. Since the 90% CI for Cmax and AUC0-t were within the 80-125% interval, it was concluded that the two formulations of Nicotine 4 mg Lozenge are bioequivalent in their rate and extent of absorption.

Evaluation of the pharmacokinetics of the DPP-4 inhibitor gemigliptin when coadministered with rosuvastatin or irbesartan to healthy subjects

Objective:Gemigliptin is a selective DPP4 inhibitor used to treat type 2 diabetes. The objective of this study was to evaluate the pharmacokinetics (PKs) of gemigliptin, rosuvastatin, and irbesartan monotherapies and combination therapies.Research design and methods:Randomized, open-label, three-treatment, six-sequence, three-period, crossover studies were performed on healthy male volunteers. The three treatments were: 50 mg gemigliptin alone; 20 mg rosuvastatin (part A) or 300 mg irbesartan alone (part B); and rosuvastatin or irbesartan with concomitant gemigliptin. Each drug was administered as part of once daily, 7 day, repeated dosing regimens with a 14 day washout period.Clinical trial registration:NCT01823133 (part A) and NCT01825850 (part B).Main outcome measures:The primary PK parameters – Cmax and AUCτ – were compared to the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) that were determined for the combination therapies and monotherapies.Results:A total of 60 participants were administered the study drugs, and 52 participants (27 participants in part A; 25 participants in part B) were analyzed as part of the PK dataset. In part A, the GMRs (gemigliptin + rosuvastatin/gemigliptin) of the Cmax and AUCτ values of gemigliptin were 0.955 (90% CI = 0.874–1.044) and 1.023 (90% CI = 0.991–1.057), and those of rosuvastatin were 1.012 (90% CI = 0.946–1.084) and 1.086 (90% CI = 1.032–1.142), respectively. In part B, the GMRs of the Cmax and AUCτ values of gemigliptin were 1.046 (90% CI = 0.964–1.134) and 1.035 (90% CI = 1.005–1.065), and those of irbesartan were 0.966 (90% CI = 0.897–1.040) and 1.050 (90% CI = 0.993–1.111), respectively. The limitations of this study include its relatively short treatment period and small sample size, as only healthy participants were included.Conclusions:Gemigliptin does not affect the PK properties of rosuvastatin or irbesartan; also, rosuvastatin and irbesartan do not affect the PKs of gemigliptin.

Investigation of mutual pharmacokinetic interactions between macitentan, a novel endothelin receptor antagonist, and sildenafil in healthy subjects.

To study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects. In this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration-time profiles of macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally. The pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by macitentan. All treatments were well tolerated. A minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil.

Reduced bioavailability of cyclosporine A in rats by mung bean seed coat extract

Mung bean seed coat (MBSC) is a healthcare product in Asian countries. The aim of this study was to investigate the effect of an MBSC ethanol extract on the bioavailability of cyclosporine A (CsA) in rats. Rats were orally dosed with CsA alone or in combination with MBSC ethanol extracts (500 mg/kg, p.o.). The blood levels of CsA were assayed by liquid chromatography with an electrospray ionization source and tandem mass spectrometry (LC-MS/MS). The everted rat intestinal sac technique was used to determine the influence of MBSC on the absorption of CsA. The results reveal that combined CsA intake with MBSC decreased the Cmax, AUC0-t, t1/2z and MRT0-t values of CsA by 24.96%, 47.28%, 34.73% and 23.58%, respectively (P&lt;0.05), and significantly raised the CL/F by 51.97% (P&lt;0.01). The in vitro results demonstrated that significantly less CsA was absorbed (P&lt;0.05). The overall results indicate that after being concomitantly ingested, MBSC reduced the bioavailability of CsA, at least partially, in the absorption phase.