Area Under Plasma Concentration-time Curve Research Articles

Drug-drug interactions and dose management of BTK inhibitors when initiating nirmatrelvir/ritonavir (paxlovid) based on physiologically-based pharmacokinetic models

ObjectiveCo-administration of Bruton's tyrosine kinase (BTK) inhibitors with nirmatrelvir/ritonavir is challenging because of potential drug-drug interactions (DDIs). However, clinical trials specifically evaluating such DDIs are absent. To evaluate and quantify the DDIs between them and provide rational dose management strategies of BTK inhibitors, we conducted this study using physiologically-based pharmacokinetic (PBPK) models. MethodsPhysicochemical properties and pharmacokinetic parameters were acquired from the published literature and databases. The PBPK models were developed using Simcyp® software. These models were validated by comparing with published literature values. The successfully validated PBPK models were used to simulate the plasma concentration-time profiles and DDIs in a virtual healthy population receiving BTK inhibitors alone or with ritonavir. ResultsSimulated plasma concentration-time profiles and pharmacokinetic parameters of each drug were in agreement with clinically observed values from literatures. Ritonavir increased ibrutinib maximum plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC) 33- and 53.88-fold, respectively, increased zanubrutinib Cmax and AUC 2.57- and 3.18-fold, respectively, and increased acalabrutinib Cmax and AUC 3.85- and 6.54-fold, respectively. Based on our simulations, dose-adjustment strategies may consist of ibrutinib at 25 mg q48h, zanubrutinib at 80 mg twice-daily and acalabrutinib at 25 mg twice-daily with nirmatrelvir/ritonavir. ConclusionsThe PBPK models predicted the in vivo pharmacokinetics and the DDIs of BTK inhibitors and ritonavir. The prospective simulations not only provided scientific evidence regarding rational dosing management strategies when initiating nirmatrelvir/ritonavir therapy but also provided a reference for the design of clinical DDIs study that may save resources and time. SummaryPaxlovid could increase Cmax and AUC0-τ of BTK inhibitors (ibrutinib, zanubrutinib and acalabrutinib), and dose adjustment strategy of ibrutinib (25 mg q48h), zanubrutinib (80 mg q12h) and acalabrutinib (25 mg q12h) should be considered when combination with nirmatrelvir/ritonavir.

Use of modeling and simulation to predict the influence of triazole antifungal agents on the pharmacokinetics of zanubrutinib and acalabrutinib.

Background: Bruton’s tyrosine kinase (BTK) inhibitors are commonly used in the targeted therapy of B-cell malignancies. It is reported that myelosuppression and fungal infections might occur during antitumor therapy of BTK inhibitors, therefore a combination therapy with triazole antifungals is usually required. Objective: To evaluate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on the pharmacokinetics of BTK inhibitors (zanubrutinib, acalabrutinib) and to quantify the drug-drug interactions (DDIs) between them. Methods: The physiologically-based pharmacokinetic (PBPK) models were developed based on pharmacokinetic parameters and physicochemical data using Simcyp® software. These models were validated using clinically observed plasma concentrations data which based on existing published studies. The successfully validated PBPK models were used to evaluate and predict potential DDIs between BTK inhibitors and different triazoles. BTK inhibitors and triazole antifungal agents were simulated by oral administration. Results: Simulated plasma concentration-time profiles of the zanubrutinib, acalabrutinib, voriconazole, fluconazole, and itraconazole are consistent with the clinically observed profiles which based on existing published studies, respectively. The exposures of BTK inhibitors increase by varying degrees when co-administered with different triazole antifungals. At multiple doses regimen, voriconazole, fluconazole and itraconazole may increase the area under plasma concentration-time curve (AUC) of zanubrutinib by 127%, 81%, and 48%, respectively, and may increase the AUC of acalabrutinib by 326%, 119%, and 264%, respectively. Conclusion: The PBPK models sufficiently characterized the pharmacokinetics of BTK inhibitors and triazole antifungals, and were used to predict untested clinical scenarios. Voriconazole exhibited the greatest influence on the exposures of BTK inhibitors. The dosage of zanubrutinib or acalabrutinib need to be reduced when co-administered with moderate CYP3A inhibitors.

Pharmacokinetics and Bioequivalence of 2 Safinamide Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

To assess the bioequivalence of a generic safinamide tablet (test) vs a brand-name safinamide tablet (reference) and effects of food on the pharmacokinetics of safinamide in healthy Chinese subjects, a single-center, single-dose, randomized, open-label, 2-preparation, 2-period study with a 15-day washout period was undertaken. A total of 56 healthy subjects were recruited in this study (fasting, n = 28; fed, n = 28). A single dose of a 100-mg test or reference safinamide tablet was administered to each subject in a randomized sequence. Blood samples were obtained at 5minutes before drug administration and during the 120hours after dosing. The safinamide concentration in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed with noncompartmental methods. Safety was also monitored. The major pharmacokinetic parameters including maximum plasma drug concentration, area under plasma concentration-time curve (AUC) from zero to time t (AUC0-t ), and AUC from time 0 to infinity (AUC0-∞ ) were similar between the test and reference tablets under fasting and fed conditions. The 90% CIs of the test/reference ratios of log-transformed maximum plasma drug concentration, AUC from zero to time t, and AUC from time 0 to infinity all fell within the equivalence interval (80.0%-125%) whether under fasting condition or fed condition. In conclusion, the 2 formulations of safinamide tablets were bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese volunteers. High-fat food delayed the absorption of safinamide but did not affect the final bioavailability.

Pharmacokinetics, pharmacodynamics, and safety of verinurad with and without allopurinol in healthy Asian, Chinese, and non-Asian participants.

Verinurad is a selective inhibitor of uric acid transporter 1 (URAT1). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol and verinurad monotherapy in healthy participants. Studies 1 (NCT03836599) and 2 (NCT02608710) were randomized Phase 1 studies. In Study 1, 12 healthy Asian participants received 24 mg verinurad + 300 mg allopurinol or placebo, and 9 healthy Chinese participants received 12 mg verinurad + 300 mg allopurinol. In Study 2, 24 healthy non‐Asian male participants received 12 mg verinurad. Safety analyses included assessment of adverse events (AEs). Pharmacokinetic parameters included maximum concentration (Cmax) and area under plasma concentration‐time curve (AUC) over 24 h (AUCτ). Pharmacodynamic parameters included percentage change from baseline (day –1) in serum uric acid (sUA) and urinary uric acid (uUA). There were no serious AEs or deaths in either study. In Study 1, steady‐state geometric mean (gCV%) Cmax and AUCτ values of verinurad after 7 days’ dosing were 73.6 (29.0) ng/mL and 478 (18.4) ng·h/mL, respectively, in healthy Asian participants, and 42.0 (40.1) ng/mL and 264 (36.1) ng·h/mL, respectively, in healthy Chinese participants; in Study 2, gCV% values were 36.3 (36.5) ng/mL and 271 (31.0) ng·h/mL, respectively. sUA decreased and uUA excretion increased compared with baseline following verinurad + allopurinol (Study 1) or verinurad (Study 2). When accounting for dose, the steady‐state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non‐Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing.

Quantitative prediction of breast cancer resistant protein mediated drug-drug interactions using physiologically-based pharmacokinetic modeling.

Quantitative assessment of drug‐drug interactions (DDIs) involving breast cancer resistance protein (BCRP) inhibition is challenged by overlapping substrate/inhibitor specificity. This study used physiologically‐based pharmacokinetic (PBPK) modeling to delineate the effects of inhibitor drugs on BCRP‐ and organic anion transporting polypeptide (OATP)1B‐mediated disposition of rosuvastatin, which is a recommended BCRP clinical probe. Initial static model analysis using in vitro inhibition data suggested BCRP/OATP1B DDI risk while considering regulatory cutoff criteria for a majority of inhibitors assessed (25 of 27), which increased rosuvastatin plasma exposure to varying degree (~ 0–600%). However, rosuvastatin area under plasma concentration‐time curve (AUC) was minimally impacted by BCRP inhibitors with calculated G‐value (= gut concentration/inhibition potency) below 100. A comprehensive PBPK model accounting for intestinal (OATP2B1 and BCRP), hepatic (OATP1B, BCRP, and MRP4), and renal (OAT3) transport mechanisms was developed for rosuvastatin. Adopting in vitro inhibition data, rosuvastatin plasma AUC changes were predicted within 25% error for 9 of 12 inhibitors evaluated via PBPK modeling. This study illustrates the adequacy and utility of a mechanistic model‐informed approach in quantitatively assessing BCRP‐mediated DDIs.

A Bioequivalence Study of Avanafil in Healthy Chinese Male Subjects Under Fasting and Fed Conditions: Results of a Randomized, Open-Label, Single-Dose, 2-Sequence, 2-Period Crossover Study.

This bioequivalence study was conducted to determine the pharmacokinetics and safety profiles of an originator and a generic avanafil formulation in Chinese male subjects under fed and fasting conditions. Each eligible subject was initially randomly given avanafil (200 mg) in a test‐reference or reference‐test order, before being switched to another study drug sequence after 7 drug‐free days. The bioequivalence of test and reference avanafil were determined if the 90%CIs of the geometric mean ratio (GMR) for the area under plasma concentration‐time curve (AUC) from time 0 to infinity (AUC0‐∞), AUC from time 0 to the last detectable concentration (AUC0‐t), and the maximum plasma concentration (Cmax) fell within the range 80%‐125%. Under fasting/fed conditions, the 90%CIs of GMR for AUC0‐∞, AUC0‐t, and Cmax were 98.9% to 109.5%/96.0% to 101.2%, 99.6% to 110.3%/96.6% to 102.4%, and 99.3% to 116.8%/94.3% to 106.7%, respectively, which were all within the 80%‐125% range. Adverse events (AEs) occurred in 20.8% of subjects under fasting conditions and 20.7% of subjects under fed conditions, with a severity of grade 1. No significant difference was found in the rate of occurrence of AEs and drug‐related AEs in the test and reference‐avanafil groups (all P > .05). We concluded that the test and reference avanafil were bioequivalent in healthy Chinese male subjects under fasting and fed conditions.

Application of smart solid lipid nanoparticles to enhance the efficacy of 5-fluorouracil in the treatment of colorectal cancer

5-Fluorouracil (5-FU) is a standard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability (short half-life) has hindered its therapeutic efficacy. The objective of this study was to develop a novel drug delivery system, solid lipid nanoparticle (SLN), capable of delivering high payload of 5-FU to treat CRC. The rational was to improve 5FU-nanocarrier compatibility and therapeutic efficacy. The SLN-loaded 5-FU was developed by utilizing a Strategic and unique Method to Advance and Refine the Treatment (SMART) of CRC through hot and cold homogenization approach. The SLN was made of unique PEGylated lipids and combination of the surfactants. Cytotoxicity studies, clonogenic assay, flow cytometry and confocal imaging were conducted to evaluate the effectiveness and cellular uptake of 5FU-SLN4 in HCT-116 cancer cells. Pharmacokinetic (PK) parameters and receptor expressions were determined while tumor efficacy studies were conducted on mouse bearing subcutaneous HCT-116 cancer. Among the all the formulations, 5FU-SLN4 was the most effective with particle size of was 263 ± 3 nm, zeta potential was 0.1 ± 0.02 and entrapment efficiency of 81 ± 10%. The IC50 value of 5FU-SLN4 (7.4 ± 0.02 µM) was 2.3 fold low compared with 5-FU (17.7 ± 0.03 µM). For tumor efficacy studies, 5FU-SLN4 significantly inhibited tumor growth in comparison to 5-FU while area-under plasma concentration-time curve (AUC) of 5FU-SLN4 was 3.6 fold high compared with 5-FU. HER2 receptors expression were markedly reduced in 5-FU-SLN4 treated mice compared with 5FU and liver and kidney tissues showed no toxicity at dose of 20 mg/kg. 5FU-SLN4 was highly cytotoxic against HCT-116 cells and significantly inhibited subcutaneous tumor growth in mice compared with 5-FU. This emphasizes the significance of developing a smart nano-delivery system to optimize the delivery efficiency of anticancer drugs to tumors.

Absence of OATP1B (Organic Anion-Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression.

Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4β-hydroxycholesterol (4βHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4βHC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity.

Pharmacokinetic study of oral amitriptyline in horses.

The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (Cmax ) of amitriptyline was 30.7ng/ml, time to maximum plasma concentration (Tmax ) 1-2hr, elimination half-life (t1/2 ) 17.2hr, area under plasma concentration-time curve (AUC) 487.4ngml-1 hr-1 , apparent clearance (Cl/F) 2.6Lhr-1 kg-1 , and apparent volume of distribution (Vd/F) 60.1L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p<.05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations.

LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats.

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6–20.5, from (LC478 concentration in intestine, 9.37–12.3 μM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 μM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

Effects of Orotic Acid-Induced Non-Alcoholic Fatty Liver on the Pharmacokinetics of Metoprolol and its Metabolites in Rats.

Preliminary study results have shown that rats with non-alcoholic fatty liver disease (NAFLD) induced by 1% orotic acid-containing diet have decreased hepatic CYP2D activity. This study aims to evaluate the possible pharmacokinetic changes in NAFLD as a result of reduced metabolic activity of CYP2D. The pharmacokinetics of metoprolol and its metabolites, O-desmethyl metoprolol (DMM) and α-hydroxy metoprolol (HM), was investigated in NAFLD and control rats following intravenous (1 mg/kg) and oral (2 mg/kg) administration of metoprolol. The hepatic CYP2D expression was also investigated. NAFLD rats had lower CYP2D expression (by 36.6%) and slower intrinsic clearance (CLint) of metoprolol and formation of HM (by 40.1% and 37.2%, respectively). There were no significant changes in the pharmacokinetics of metoprolol and its metabolites following intravenous administration. In contrast, oral administration of metoprolol resulted in significantly increased total area under plasma concentration-time curve (AUC) of metoprolol (by 127%) and decreased metabolite formation ratios (AUCDMM/AUCMetoprolol [by 42.8%], AUCHM/AUCMetoprolol [by 35.0%]) in NAFLD rats. Moreover, these changes were well correlated with severity of steatosis as quantified by hepatic triglyceride contents. NALFD can lead to a reduction in the hepatic CLint of a drug if it is a substrate of the CYP2D subfamily. The decreased clearance may result in elevated drug concentrations and increased exposure.

Optimization of Extended-Release ZL-004 Nanosuspensions for In Vivo Pharmacokinetic Study to Enhance Low Solubility and Compliance.

ZL-004, a promising small molecule that increases white blood cell counts, was developed for extended-release nanosuspensions to improve low solubility and compliance of patients. In vivo pharmacokinetic studies of nanosuspensions with different particle sizes and administration volumes were conducted. Unexpectedly, Cmax of NS-PC-L (1156 nm) was 1.3 fold higher than NS-PB-L (836 nm), and area under plasma concentration-time curve (AUC) was similar. It suggested that in vivo behavior of nanosuspensions was influenced significantly by the original dissolved drug, which did not only rely on the particle size but also the amount of the free stabilizers. In addition, smaller administration volume (0.1 mL) achieved significantly lower Cmax and AUC than the higher volume (0.5 mL), due to the reduced amount of dissolved drug. DSC and XPRD demonstrated that the crystal forms of nanosuspensions prepared by the precipitation method and high-pressure homogenization were similar; therefore, in vivo behaviors did not show significant differences. An additional 0.15% PEG 4000 enhanced the redispersity and maintained the particle size for 3 months. Finally, a nanosuspensions with the desired initial release was achieved, which lasted approximately 32 days steadily after a single dose. AUC and t1/2 were 161.2 fold and 22.9 fold higher than oral administration.

Compatibility with Panax notoginseng and Rehmannia glutinosa Alleviates the Hepatotoxicity and Nephrotoxicity of Tripterygium wilfordii via Modulating the Pharmacokinetics of Triptolide.

Tripterygium wilfordii (TW) and the representative active component triptolide show positive therapeutic effect on the autoimmune disorders and simultaneously ineluctable hepatotoxicity and nephrotoxicity. Combinational application of Panax notoginseng (PN) and Rehmannia glutinosa (RG) weakens the toxicity of TW according the clinical application of traditional Chinese medicine. This article was aimed at the mechanism of decreasing toxicity of TW by the combinational application of PN and RG. Biochemical and pathohistological analysis were utilized to assess the toxicity on liver and kidney in rats administrated with TW, TW-PN, TW-RG and TW-PN-RG for 3 and 7 days. Meanwhile, the pharmacokinetics profiling of triptolide and wilforlide A was determined based on the plasma concentration analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). TW-induced alkaline phosphatase (ALP), the marker for liver injury, was enhanced from 22.83 ± 1.29 to 40.73 ± 1.42 King’s unit/100 mL (p < 0.01) at day 7. TW-PN-RG decreased the serum ALP of TW-treated rats at 30.15 ± 1.27 King’s unit/100 mL (p < 0.01). For nephrotoxicity, TW pronouncedly elevated serum creatinine (SCr) in rats from 20.33 ± 1.77 to 49.82 ± 2.35 μmol/L (p < 0.01). However, rats treated with TW-PN-RG showed lower SCr at 30.48 ± 1.98 μmol/L (p < 0.01). Moreover, TW-PN-RG significantly decreased the TW-induced elevation of total bilirubin (T-BIL), alanine amino transferase (ALT), aspartate amino transferase (AST), blood urea nitrogen (Bun), and reversed the TW-resulted pathohistological characteristics of liver and kidney. The delayed time to reach Cmax (Tmax) and reduced maximum concentration (Cmax) and area under plasma concentration-time curve (AUC) of triptolide and wilforlide A were explored in rats with combinational formulas. Synergism of PN and RG obviously prolonged the half-life (t1/2) and apparent volume of distribution (Vd), but exerted no action on the clearance rate. The compatibility of TW, PN and RG influences intracorporal process of both triptolide and wilforlide A on the steps of absorption and tissue distribution contributing to less toxicity of TW on liver and kidney.

Pharmacokinetic food-effect study of abiraterone acetate (AA) in patients with metastatic castration resistant prostate cancer (mCRPC): The ABIFOOD trial (EudraCt number: 2012-003226-25).

227 Background: A.A has been approved for the treatment of mCRPC before and after docetaxel. The standard regime consists on daily A.A. 1.000 mg in a fasting state along with prednisone 10mg q.d. However, data from pharmacokinetic (PK) studies in patients (pts) and healthy volunteers has revealed a significant food-effect with up to 7-10 folder increase in area under plasma concentration-time curve (AUC) when A.A is given with food, specially with fat content, [Chi KN, J Clin Pharmacol 2015]. Methods: ABIFOOD is a phase I, randomized trial to evaluate the short and long-term effect of diet on the PKs of A.A. in pts with mCRPC who have progressed to docetaxel. Eligible pts include men ≥ 18 years old with mCRPC, ECOG performance status (PS) &lt; 2 and an adequate organ function. Pts are randomly assigned to receive 4-weekly cycles of 250 mg A.A with standard meal (Arm A), 250 mg A.A with high-fat meal (Arm B) or 1000 mg A.A in fasting conditions (Arm C). PK analyses are conducted at week 1 (W1) and cycle 5. Results: Fifteen pts (5, 3 and 7 in arms A, B and C respectively) have been included and 6 are still on treatment. Median age is 72, 97% have ECOG-PS 1. Gleason Score is &gt; 8 in 6 (40%) pts.Geometric mean abiraterone [AUC (ng.h/ml) (IQR)] at W1 did not significantly differ between treatment arms [arm A: 404.68 (368.4 - 488.2), arm B: 372 (334.6 - 440.5) arm C: 656.51 (387.8 – 1144.5) p 0.15]. PK data did not influence activity or toxicity. Progression free survival was 8.50, 6.33 and 4.86 months in Arms A, B and C respectively (p 0.53). One patient in arm A is still on treatment after 17 cycles. Conclusions: The administration of lower doses of A.A with food [regardless the fat content], might achieve comparable plasma levels to standard dosing with no detriment in efficacy or toxicity parameters. The study is actively recruiting and data on additional pts and long term PK parameters will be presented. Clinical trial information: EudraCt number: 2012-003226-25.

Modulation of Cytochrome P450 Activity by 18β-Glycyrrhetic Acid and its Consequence on Buspirone Pharmacokinetics in Rats.

The aim of this study was to elucidate the inhibition mechanism of 18β-glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC50 of 20.1 ± 10.7 μM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration-time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12-1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A-mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A-mediated drug metabolism in vivo. Copyright © 2015 John Wiley & Sons, Ltd.

Bioequivalence of fixed-dose combination RIN®-150 to each reference drug in loose combination.

RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis. This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore. To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination. This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC). Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study. The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.

Enhanced oral bioavailability of quercetin by nanostructured lipid carriers (1044.24)

Background: Quercetin, a flavonoid found in fruits, vegetables and grains, has been shown to have many biological activities and pharmacological actions, however, because of its high hydrophobicity, low stability, and low oral bioavailability, the clinical application of quercetin is greatly restricted. We have successful synthesized biocompatible and biodegradable quercetin loaded nanostructured lipid carriers (QNLCs) and chitosan‐coated QNLCs (CS‐QNLCs), which may improve the solubility, stability and bioavailability of quercetin.Methods: The solubility of quercetin in water and its stabilities in plasma and different gastric‐intestinal solutions were measured using a HPLC system in vitro. Native quercetin, QNLCs and CS‐QNLCs were given through intravenous or oral administration to male SD rats. Quercetin concentrations in blood at different time points were measured using a HPLC system.Results: As compared to native quercetin, QNLCs and CS‐QNLCs increased quercetin stability in plasma and gastric‐intestinal solutions. Q‐NLCs and CS‐QNLCs significantly increased AUC (area under plasma concentration‐time curve) values with prolonged blood circulation time compared with native Q.Conclusion: Nanoencapsulation significantly increased quercetin aqueous solubility, stabilities in plasma and gastric‐intestinal solutions, and bioavailability.Grant Funding Source: Texas Tech University

Bioequivalence of Omeprazole Delayed-Release Capsules in Healthy Filipino Subjects

Study background: Omeprazole is indicated for the treatment of various acid-related gastrointestinal disorders. It is acid labile and therefore administered orally as enteric-coated granules in capsules. Methods: This randomized, open-label, single dose, two-way cross-over clinical pharmacology study in healthy adult Filipino subjects evaluated the bioequivalence of a new 40 mg delayed-release (enteric-film coated) capsule formulation of omeprazole (Pfizer Inc., US) relative to the reference marketed Losec® capsule (2x20 mg; AstraZeneca, Sweden; enteric-coated granules in capsule) under fasted conditions. Pharmacokinetic blood sampling was carried out at various time points for 12 h post-dose and plasma samples were analysed using a fully validated ultra performance liquid chromatography with tandem Mass Spectrometry technology. The primary endpoints were area under plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast) and maximum plasma concentration (Cmax) for omeprazole. Results: Twenty five subjects (12 females and 13 males; mean age 26 years; mean body mass index 24 kg/ m2) completed the study. When administered as one omeprazole 40 mg delayed-release capsule, the ratios of the adjusted geometric means of the primary endpoints, AUClast and Cmax, were contained within the established bioequivalence limits of 80 to 125% compared with two Losec® 20 mg capsules: 100.4% (90% confidence interval: 90.8–110.9%) and 90.4% (90% confidence interval: 81.2–100.6%), respectively. The two omeprazole formulations were well tolerated and no serious adverse event or other significant adverse event was noted. Conclusion: Based on the results of this study in healthy adult Filipino subjects, the new omeprazole 40 mg delayed-release capsule and the established marketed Losec® capsule (2x20 mg) are bioequivalent. Omeprazole 40 mg delayed-release capsule was safe and well tolerated.

Bioequivalence of fixed-dose combination Myrin®-P Forte and reference drugs in loose combination

Myrin®-P Forte is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg), isoniazid (INH, 75 mg), ethambutol (EMB) hydrochloride (275 mg) and pyrazinamide (PZA, 400 mg) developed for the treatment of tuberculosis (TB). This study was conducted at a single centre--the Pfizer Clinical Research Unit in Singapore. To demonstrate the bioequivalence of each drug component of the Myrin-P Forte FDC and the individual product in loose combination. In a randomized, open-label, single-dose, two-way, crossover study, subjects received single doses of Myrin-P Forte or four individual products under fasting conditions in a crossover fashion with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (C(max)) and the area under plasma concentration-time curve (AUC). Of 36 subjects enrolled, 35 completed the study. The adjusted geometric mean ratios and 90% confidence intervals for C(max) and AUC values were completely contained within bioequivalence limits (80%, 125%) for all four drugs in both formulations. Both treatments were generally well tolerated in the study. The Myrin-P Forte FDC tablet formulation is bioequivalent to the four single-drug references for RMP, INH, EMB hydrochloride and PZA at equivalent doses.

Effect of Tacrolimus on the Pharmacokinetics and Glucuronidation of SN-38, an Active Metabolite of Irinotecan

The present study has investigated the effect of tacrolimus on the pharmacokinetics of an active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide (SN-38G) in rats. The effect of tacrolimus on SN-38 glucuronidation was also investigated in human and rat liver microsomes. When tacrolimus (0.5 mg/kg) was intravenously injected in rats 15 min before intravenous injection of CPT-11 (5 mg/kg), tacrolimus decreased the plasma concentration of SN-38G. Tacrolimus significantly decreased the area under plasma concentration-time curve (AUC) of SN-38G without change in the mean residence time. On the contrary, significant changes in the pharmacokinetic parameters of SN-38 were not observed. SN-38 glucuronidation in human and rat liver microsomes was inhibited dose-dependently by the presence of tacrolimus and the 50% inhibition concentration (IC50) values of tacrolimus in rat and human liver microsomes were 10.33 μM and 3.58 μM, respectively. When the inhibition type was determined by Lineweaver-Burk and Dixon plots, the inhibition was noncompetitive and the calculated inhibition constant (Ki) values for rat and human liver microsomes were 12.57 μM and 3.88 μM, respectively. These findings suggest that tacrolimus inhibits UGT1A1-mediated SN-38 glucuronidation. Considering the IC50 and Ki values for tacrolimus, it is likely that tacrolimus does not alter the pharmacokinetics of SN-38 and SN-38G at the clinically used dosages, suggesting the possibility that tacrolimus can use safely for cancer patients with irinotecan chemotherapy.