AUC 0-24h Research Articles

Vancomycin pharmacokinetic model development in patients on intermittent online hemodiafiltration

BackgroundVancomycin is frequently used in hemodialysis (HD) and in hemodiafiltration (HDF) patients and is usually administered in the last 30 or 60 minutes of a dialysis session. Vancomycin pharmacokinetics are not well described in HDF patients. The aim of this study is to develop a population pharmacokinetic (PPK) model and dosing regimen for vancomycin in HDF patients and to evaluate its applicability in low-flux (LF-HD) patients.MethodsTwo-compartment PPK models were developed using data from HDF patients (n = 17), and was parameterized as follows: non-renal clearance (CLm), renal clearance as a fraction of creatinine clearance (fr), central volume of distribution (V1), intercompartmental clearance (CL12), peripheral volume of distribution (V2) and extracorporeal extraction ratio (Eec). We evaluated the final model in a cohort of LF-HD patients (n = 21). Dosing schemes were developed for a vancomycin 24-h AUC of 400 mg*h/L.ResultsModel parameters (± SD) were: CLm = 0.473 (0.271) L/h, fr = 0.1 (fixed value), V1 = 0.278 (0.092) L/kgLBMc, CL12 = 9.96 L/h (fixed value), V2 = 0.686 (0.335) L/kgLBMc and Eec = 0.212 (0.069). The model reliably predicted serum levels of vancomycin in both HDF and LF-HD patients during and between dialysis sessions. The median of the prediction error (MDPE) as a measure of bias is -0.7% (95% CI: -3.4%-1.7%) and the median of the absolute values of the prediction errors (MDAPE) as a measure of precision is 7.9% (95% CI: 6.0%-9.8%). In both HDF and LF-HD, the optimal vancomycin loading dose for a typical patient weighing 70 kg is 1700 mg when administered during the last 60 minutes of the hemodialysis session. Maintenance dose is 700 mg if administered during the last 30 or 60 minutes of the hemodialysis session.ConclusionThe developed PPK model for HDF is also capable of predicting serum levels of vancomycin in patients on LF-HD. A dosing regimen was developed for the use of vancomycin in HDF and LF-HD.

Effects of Silymarin on the In Vivo Pharmacokinetics of Simvastatin and Its Active Metabolite in Rats.

Herein, the effect of silymarin pretreatment on the pharmacokinetics of simvastatin in rats was evaluated. To ensure the accuracy of the results, a rapid and sensitive UPLC–MS/MS method was established for simultaneous quantification of simvastatin (SV) and its active metabolite simvastatin acid (SVA). This method was applied for studying the pharmacokinetic interactions in rats after oral co-administration of silymarin (45 mg/kg) and different concentrations of SV. The major pharmacokinetic parameters, including Cmax, tmax, t1/2, mean residence time (MRT), elimination rate constant (λz) and area under the concentration-time curve (AUC0–12h), were calculated using the non-compartmental model. The results showed that the co-administration of silymarin and SV significantly increased the Cmax and AUC0–12h of SVA compared with SV alone, while there was no significant difference with regards to Tmax and t1/2. However, SV pharmacokinetic parameters were not significantly affected by silymarin pretreatment. Therefore, these changes indicated that drug-drug interactions may occur after co-administration of silymarin and SV.

Formulation and evaluation of cubosomes drug delivery system for treatment of glaucoma: Ex-vivo permeation and in-vivo pharmacodynamic study

Glaucoma, a chronic disease of elevated intraocular pressure, is considered as the first leading cause of blindness. Brimonidine tartrate (BRT), a hydrophilic drug with poor ocular bioavailability, is a glaucoma treatment that is used three times daily. The frequent administration of BRT hinders patient adherence to treatment. The aim of this work is to improve BRT ocular bioavailability and prolong its intraocular pressure lowering effect by the preparation of BRT loaded cubosomes. Cubosomal formulations were prepared according to a d-optimal design. The selected variables were the percent of the dispersed phase, the ratio of glyceryl monooleate to poloxamer 407, the type of surfactant and the surfactant concentration. The prepared formulations were characterized for their drug content, particle size, PDI, zeta potential and in-vitro release. The optimized formulation had a size of 157.2 ± 4.2 nm, PDI 0.22 ± 0.03, a zeta potential of −30.2 ± 0.6mv and showed a sustained release pattern over 24 h. Micrographs of the transmission electron microscope confirmed the cubic nanostructure of the optimized formulation. Ex-vivo corneal permeation showed 1.6 folds enhanced permeability compared to Alphagan®P. The in-vivo pharmacodynamic study showed a 4.6 folds increase in AUC0–24h and 9.1 folds increase in the mean residence time compared to the market product Alphagan®P.

Tadalafil nanocomposites as a dry powder formulation for inhalation, a new strategy for pulmonary arterial hypertension treatment

Tadalafil (a phosphodiesterase-5 inhibitor) is a choice for treatment of pulmonary arterial hypertension (PAH) that is known as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest and ≥30 mmHg during exercise with reduced cardiac output. The aim of this study was to prepare inhalable tadalafil nanocomposites as a dry powder formulation by spray drying technique for increasing bioavailability and treatment efficacy, as well as decreasing systemic side effects.The D-optimal design was used for optimization of formulation parameters. Microparticle size, morphology, crystallinity, density, solubility, redispersion (%), and in-vitro inhalation performance of tadalafil nanocomposites were investigated as physicochemical characteristics. Pharmacokinetic parameters were also evaluated in plasma and lung tissue of Wistar rats after intratracheal insufflation and compared with a control group receiving an oral tadalafil marketed product (dose = 10 mg/kg).The suggested optimum formulation contained stable amorphous particles with almost rounded shape and corrugated surface that were completely redispersed in the lung simulated medium with the mass median geometric diameter of 3.2 μm, density of 1.4 g/cm3, fine particle fraction based on emitted dose (%) of 57.2 ± 6.5%, and 13.7-fold enhancement in dissolution rate. In-vivo studies showed that the ratio of AUC0–24h lung/AUC0–24h plasma, achieved in the treated group after intratracheal insufflation, was significantly higher than the control group that means high local drug concentration and more efficacy. Besides, plasma data analysis indicated high value of MRT (2.3-fold) and tmax (3.7-fold) after intratracheal insufflation of tadalafil nanocomposites in comparison with the conventional oral route, indicating longer retention of tadalafil molecules in the lungs and their slower entry to the systemic blood circulation. In conclusion, it seems that inhalable tadalafil nanocomposites can be introduced as an alternative to oral tadalafil in the treatment of PAH.

Development and validation of a sensitive LC-MS/MS method for the determination of 6-hydroxykynurenic acid in rat plasma and its application to pharmacokinetics study

A sensitive and specific bioanalytical method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of 6-hydroxykynurenic acid (6-HKA) in a small quantity of rat plasma has been developed and comprehensively validated. Tolbutamide (Tol) was used as the internal standard (IS). An aliquot of 50 μL rat plasma sample was deproteinized by 150 μL methanol, and then 100 μL of its supernatant was mixed with 100 μL water after centrifugation. Chromatographic separation was performed on a ZORBAX Eclipse Plus C18 Rapid Resolution HD column (2.1 mm × 100 mm, 1.8 μm) with a gradient mobile phase consisting of water containing 2 mM ammonium formate and methanol at a flow rate of 0.2 mL/min over a total run time of 5.0 min. The mass spectrometer was operated under multiple reactions monitoring (MRM) mode with the transitions m/z 206.1 → 160.0 for 6-HKA and m/z 269.0 → 170.0 for Tol. The linear range was 2.5–250 ng/mL with the square regression coefficient (r2) of 0.997. The lower limit of quantification (LLOQ) was 2.5 ng/mL (Relative Error, RE +1.6% and RSD 4.8%, n = 5). The intra- and inter-day precision and accuracy was <13.3%. The mean recovery of 6-HKA in rat plasma was between the range of 99.3–103.4%. This method was successfully applied to study the pharmacokinetics of 6-HKA in rats after oral administration at a single dose of 20.0 mg/kg and after tail intravenous injection at a single dose of 2.0 mg/kg. Pharmacokinetic parameters bioavailability, Cmax, oral, Tmax, oral, AUC0–24h, oral, AUC0–∞, oral, AUC0–24h, iv and AUC0–∞, iv were 3.96%, 152.0 ± 85.5 ng/mL, 0.4 ± 0.1 h, 340.0 ± 136.3 ng/mL ∗ h, 369.5 ± 135.0 ng/mL ∗ h, 906.6 ± 324.1 ng/mL*h and 932.9 ± 336.5 ng/mL ∗ h, respectively.

Impact of Curcumin (with or without Piperine) on the Pharmacokinetics of Tamoxifen.

Tamoxifen is a prodrug that is primarily metabolized into the pharmacologically active metabolite endoxifen and eventually into inactive metabolites. The herb curcumin may increase endoxifen exposure by affecting phase II metabolism. We compared endoxifen and tamoxifen exposure in breast cancer patients with or without curcumin, and with addition of the bio-enhancer piperine. Tamoxifen (20–30mg per day (q.d.)) was either given alone, or combined with curcumin (1200 mg three times daily (t.i.d.)) +/− piperine (10 mg t.i.d.). The primary endpoint of this study was the difference in geometric means for the area under the curve (AUC) of endoxifen. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. The endoxifen AUC0–24h decreased with 7.7% (95%CI: −15.4 to 0.7%; p = 0.07) with curcumin and 12.4% (95%CI: −21.9 to −1.9%; p = 0.02) with curcumin and piperine, compared to tamoxifen alone. Tamoxifen AUC0–24h showed similar results. For patients with an extensive CYP2D6 metabolism phenotype (EM), effects were more pronounced than for intermediate CYP2D6 metabolizers (IMs). In conclusion, the exposure to tamoxifen and endoxifen was significantly decreased by concomitant use of curcumin (+/− piperine). Therefore, co-treatment with curcumin could lower endoxifen concentrations below the threshold for efficacy (potentially 20–40% of the patients), especially in EM patients.

Solidified phospholipid-TPGS as an effective oral delivery system for improving the bioavailability of resveratrol

Resveratrol (RES), a compound with a variety of pharmacological activities, is reported to be poorly soluble in water and has limited absorption in vivo. And so its application is limited. In this study, a solidified RES phospholipid (PL) complex solid dispersion, containing RES-PL complex (RPC) and Sylysia 350 (S350) together with D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) (RPC-SDT) was prepared by simple solvent evaporation. The RPC-SDT was characterized by DSC, PXRD, SEM and IR analysis. All the data obtained confirmed that RES in RPC-SDT was in an amorphous state. The dissolution profile in vitro proved that RPC-SDT was able to markedly improve the dissolution rate. Single-pass intestinal perfusion studies showed that RPC improved the absorption slightly while TPGS increased the absorption nearly 2-fold. Finally, a pharmacokinetic study of RES and RPC-SDT in rats was investigated when it was found that RPC-SDT exhibited a higher peak plasma concentration (2392.8 vs. 702.3 ng mL−1), and increased AUC0–8h (3606.5 vs. 2188.5 ng mL−1 h）when compared with the raw RES, suggesting improved drug bioavailability. All the results obtained demonstrated that RPC-SDT significantly improved the bioavailability of RES by increasing both the dissolution rate and absorption.

Pharmacokinetics and muscle residue depletion of amoxicillin in cage cultured hybrid red tilapia (Oreochromis mossambicus × Oreochromis niloticus)

Amoxicillin (AMX) is commonly used to treat Streptococcus spp. infection in hybrid red tilapia (Oreochromis mossambicus × Oreochromis niloticus), despite the lack of plasma pharmacokinetic data, and suitable edible tissue residue withdrawal time estimations. The aim of this study was therefore to investigate plasma pharmacokinetics and muscle tissue residues depletion of AMX in hybrid red tilapia raised in cages. Cage raised hybrid red tilapia (223 ± 11.5 g) from Southern Vietnam were treated with medicated feed containing AMX at a dose of 5000 mg/kg feed (equal to 50 mg/kg body weight fish) for five consecutive days. During administration of the medicated feed, fish muscle (including skin) samples were taken at days 1 and 5 (each time at 2 h, 12 h and 24 h after feeding) and at 3, 7 and 14 days after the cessation of medicated feed administration. Plasma was collected at 30 min, and at 1, 2, 6, 12 and 24 h after the first medication and at 2, 12 and 24 h after administration of medicated feed on day 2, 3, 4 and 5. AMX levels were determined by liquid chromatography coupled to tandem mass spectrometry. Results showed that AMX depleted rapidly in fish muscle and skin and was below the limit of quantification (5 μg/kg) within 24 h after five consecutive days of medication. Noncompartmental pharmacokinetic analysis of AMX revealed that maximum plasma concentration (Cmax) on day 1 was 2.75 ± 0.98 μg/mL (Tmax, 1 h), whereas it ranged from 0.81 to 0.97 μg/mL (day 2 to 4) and decreased to 0.27 ± 0.07 μg/mL (Tmax 2–12 h) on day five of medication. Also, the highest area under the plasma concentration-time curve from time 0 to 24 h (AUC0–24h; 28.06 ± 3.32 h·μg/mL) was found on the first day of treatment and decreased on the following days. The elimination rate constant (kel) was 0.17 h−1 and elimination half-life (T1/2el) was 4.1 h. Our results show that AMX is depleted from edible muscle tissue in a short time period, which suggests a low, if any, food safety hazard associated with common treatment regimes. However, further research is needed to define a well-suited therapeutic dose.

Bioavailability of the diterpenoid 14-deoxy-11,12-didehydroandrographolide in rats and up-regulation of hepatic drug-metabolizing enzyme and drug transporter expression

Background14-Deoxy-11,12-didehydroandrographolide (deAND) is the second most abundant diterpenoid in Andrographis paniculata (Burm. f.) Nees, a traditional medicine used in Asia. To date, the biological activity of deAND has not been clearly investigated. PurposeIn this study, we intended to examine the modulatory effect of deAND on hepatic drug metabolism as well as its bioavailability. Study designdeAND prepared from A. paniculata was orally given to Sprague-Dawley rats and changes in plasma deNAD were determined by HPLC-MS. Modulation of deAND on drug-metabolizing enzyme and drug transporter expression as well as the possible mechanism involved was examined in primary rat hepatocytes. ResultsAfter a single oral administration of 50 mg/kg deAND to rats, the maximum plasma concentration (Cmax), time to reach the Cmax, area under the curve (AUC0–24h), mean retention time, and half-life (t1/2) of deAND were 2.65 ± 0.68 μg/ml, 0.29 ± 0.15 h, 6.30 ± 1.66 μg/ml•h, 5.55 ± 2.52 h, and 3.56 ± 1.05 h, respectively. The oral bioavailability was 3.42%. In primary rat hepatocytes treated with up to 10 μM deAND, a dose-dependent increase was noted in the expression of cytochrome P450 (CYP) 1A1/2, CYP2C6, and CYP3A1/2; UDP-glucuronosyltransferase (UGT) 1A1, NAD(P)H:quinone oxidoreductase (NQO1), π form of GSH S-transferase (GSTP), multidrug resistance-associated protein 2, p-glycoprotein, and organic anion transporter protein 2B1. Immunoblotting assay and EMSA revealed that deAND increases the nuclear translocation and DNA binding activity of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and nuclear factor erythroid-derived 2-related factor 2 (Nrf2). Knockdown of AhR and Nrf2 expression abolished deAND induction of CYP isozymes and UGT1A1, NQO1, and GSTP expression, respectively. ConclusionThese results indicate that deAND quickly passes through enterocytes in rats and effectively up-regulates hepatic drug-metabolizing enzyme and drug transporter expression in an AhR-, PXR-, and Nrf2-dependent manner.

Epsilon-poly-l-lysine decorated ordered mesoporous silica contributes to the synergistic antifungal effect and enhanced solubility of a lipophilic drug

The emergence of drug-resistant fungal strains remains a severe threat for the public health, which prompts strict restrictions on the uses of antifungal drugs. However, the majority of lipophilic fungistatic agents are poorly water soluble with a low oral adsorption characteristic posing challenges for the precise prescriptions. In this study, a natural antimicrobial cationic peptide of epsilon-poly-l-lysine (EPL) decorated ordered mesoporous silica (SBA-15) was facilely prepared for the efficient loading of antifungal itraconazole (ITZ) drugs. The characterized mesoporous SBA-15/EPL/ITZ composite exhibited remarkable antifungal performance against Aspergillus fumigatus as a model mold, which was attributed to synergistic antifungal activities of ITZ and EPL in the mesopores. Moreover, the in vitro release behaviors of ITZ in the composite nanoexcipients both in simulated gastric fluid and fasted state simulated intestinal fluid were studied. The observed release kinetics of ITZ demonstrated a contributing role of SBA-15/EPL to enhance the solubility of ITZ and thereby may promote its flux across the gastrointestinal epithelium, which is beneficial for the absorption of drugs. Additionally, SBA-15/EPL/ITZ composites showed desirable biocompatibility toward mammalian red blood cells, human cervical cancer cells (Hela) and human embryonic kidney cells (HEK-293T). Furthermore, the pharmacokinetic profiles of obtained nano-formulations were assessed in rats, among which the improved adsorption of SBA-15/EPL/ITZ composites (AUC0–24h sum: 8381.7 nM·h) was identified compared with that of pure ITZ (525.1 nM·h) and the commercial drug of Sporanox (7516.6 nM·h). Collectively, the prepared SBA-15/EPL/ITZ provides an ecofriendly and integrated nanocomposite with enhanced solubility of lipophilic drugs to combat proliferations of infectious fungi.

Pharmacokinetics of mycophenolate mofetil in juvenile patients with autoimmune diseases

Objectives: This study aimed to determine the association between the dosage and pharmacokinetics of mycophenolate mofetil (MMF) in juvenile patients with autoimmune diseases.Methods: Totally, 29 patients were administered oral MMF. The blood concentrations of mycophenolate acid (MPA) at seven points, the area under the time–concentration curve (MPA–AUC0–12h), the peak concentration (Cmax), and the time to peak concentration (Tmax) were measured. To obtain a dose-normalized MPA–AUC0–12h value, the actual measured MPA–AUC0–12h value was divided by the dose value of the morning administration corrected for body weight (BW) or body surface area (BSA). The patients were classified into three age groups (group 1, ≤10 years; group 2, >10–≤15 years; and group 3, >15 years), and pharmacokinetic parameters were compared among the groups.Results: In total, we obtained 37 measurements. The actual measured MPA–AUC0–12h values and the MPA–AUC0–12h values corrected for dose per BW and Tmax were lower in young patients. The MPA–AUC0–12h values corrected for dose per BSA and Cmax were comparable among all the groups.Conclusion: In patients with juvenile autoimmune diseases, determining MMF administration dosage according to BSA may facilitate MPA–AUC0–12h value prediction.

Strategy for the Prediction of Steady-State Exposure of Digoxin to Determine Drug–Drug Interaction Potential of Digoxin With Other Drugs in Digitalization Therapy

Digoxin, a narrow therapeutic index drug, is widely used in congestive heart failure. However, the digitalization therapy involves dose titration and can exhibit drug-drug interaction. Ctrough versus area under the plasma concentration versus time curve in a dosing interval of 24 hours (AUC0-24h) and Cmax versus AUC0-24h for digoxin were established by linear regression. The predictions of digoxin AUC0-24h values were performed using published Ctrough or Cmax with appropriate regression lines. The fold difference, defined as the quotient of the observed/predicted AUC0-24h values, was evaluated. The mean square error and root mean square error, correlation coefficient (r), and goodness of the fold prediction were used to evaluate the models. Both Ctrough versus AUC0-24h (r = 0.9215) and Cmax versus AUC0-24h models for digoxin (r = 0.7781) showed strong correlations. Approximately 93.8% of the predicted digoxin AUC0-24h values were within 0.76-fold to 1.25-fold difference for Ctrough model. In sharp contrast, the Cmax model showed larger variability with only 51.6% of AUC0-24h predictions within 0.76-1.25-fold difference. The r value for observed versus predicted AUC0-24h for Ctrough (r = 0.9551; n = 177; P < 0.001) was superior to the Cmax (r = 0.6134; n = 275; P < 0.001) model. The mean square error and root mean square error (%) for the Ctrough model were 11.95% and 16.2% as compared to 67.17% and 42.3% obtained for the Cmax model. Simple linear regression models for Ctrough/Cmax versus AUC0-24h were derived for digoxin. On the basis of statistical evaluation, Ctrough was superior to Cmax model for the prediction of digoxin AUC0-24h and can be potentially used in a prospective setting for predicting drug-drug interaction or lack of it.

Arsenic trioxide encapsulated liposomes prepared via copper acetate gradient loading method and its antitumor efficiency

In this study, arsenic trioxide (ATO) was encapsulated in liposomes via copper acetate (Cu(OAc)2) gradients and high entrapment efficiency of over 80% was obtained. The average particle size and the zeta-potential of the liposomes were detected to be 115.1 ± 29.1 nm and −21.97 ± 0.6 mV, respectively. The TEM images showed rod-like precipitates in the inner aqueous phase, which was supposed be due to the formation of insoluble ATOCu complex. The in vitro drug release of ATOCu liposomes exhibited a sustained release over 72 h, and the release rates decreased with the increase of the pH of release media. Pharmacokinetic and tissue distribution studies of ATO liposomes showed significantly reduced plasma clearance rate, increased AUC0–12h and T1/2, and improved tumor distribution of As compared to iv administration of ATO solution. The anti-tumor effect of ATO loaded liposomes to S180 tumor-bearing mice was significantly improved with a tumor inhibition rate of 61.2%, meanwhile the toxicity of encapsulated ATO was greatly decreased. In conclusion, ATO can be effectively encapsulated into liposomes by remote loading method via Cu(OAc)2 gradients; the co-administration of ATO and Cu(II) via liposomal formulation may find wide applications in the treatment of various tumors.

Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats.

Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0–24h) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223.

Effects of a Self–micro-emulsifying Delivery System Formulation Versus a Standard ω-3 Acid Ethyl Ester Product on the Bioavailability of Eicosapentaenoic Acid and Docosahexaenoic Acid: A Study in Healthy Men and Women in a Fasted State

PurposeIntakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with several potential health benefits, but standard ethyl ester (EE) formulations of these ω-3 fatty acids require the co-ingestion of fat for adequate absorption. The objective of this research was to assess the relative bioavailability of EPA and DHA administered in a proprietary self–micro-emulsifying delivery system (SMEDS) formulation compared with EPA and DHA in a standard ω-3 acid EE product in healthy men and women in a fasted state. MethodsThis randomized crossover study investigated the bioavailability of 2 encapsulated formulations of EPA and DHA, a capsule containing 500 mg EPA + DHA administered in a SMEDS formulation (SMEDS treatment), and a capsule containing 840 mg EPA + DHA in a standard ω-3 acid EE formulation (EE treatment). Subjects consumed a single dose of their assigned capsule in a fasting state, and plasma was collected before and for 24 h after dosing. Subjects underwent a ≥14-day washout and were crossed over to the other treatment condition. Plasma concentrations of EPA, DHA, and EPA + DHA were assessed. FindingsTwenty-three subjects (11 women, 12 men; mean [SEM] age, 33.8 [2.1] years; and body mass index, 24.9 [0.7] kg/m2) completed the trial. The baseline-adjusted, dose-normalized, arithmetic means (SD) of the incremental (i)-AUC0–24h for EPA + DHA were 543 (266) and 102 (88.2) h · μg/mL/g for the SMEDS and EE formulations, respectively (P < 0.001). The iAUC0–24h least-squares geometric mean ratio (90% CI) for SMEDS:standard EE was 475/58 = 8.2 (4.8–13.9), indicating markedly higher bioavailability of EPA + DHA with the SMEDS formulation compared to the standard EE formulation. This finding was also true for EPA (geometric mean ratio [90% CI], 18.2 [11.3–29.3]) and DHA (geometric mean ratio [90% CI], 4.5 [2.9–7.0]). ImplicationsThe SMEDS delivery system markedly enhanced appearance in plasma of EPA and DHA, compared to a standard EE formulation, when ingested in the fasting state. ClinicalTrials.gov identifier: NCT03443076.

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

PurposeMetarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.MethodsPK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.ResultsMetarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.ConclusionsMetarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.

Identification of beagle food taking patterns and protocol for food effects evaluation on bioavailability

Food is a known primary role to the exposure of the drugs orally administered. Since each animal may have unique food taking pattern and it is difficult to manipulate the food taking to animals, there lacks rationalized protocol for the food effects in pre-clinic study. The objective of this study was to identify the beagle food taking patterns and demonstrate their effects on bioavailability in valsartan. Herein, four types of food taking patterns of beagle were identified via inter-day and intra-day analysis, and named as Persisting, Pulsing, Postponing, Pushing (“4P Modes”), respectively, which were also validated by principal component analysis (PCA). Interestingly, food intake resulted in a reduced area under the concentration-time curve (AUC0–12h), maximum concentration (Cmax) and absorption rate, whilst the reduction varied in “4P Modes” of food taking. General considerations in the design of experiment for food effect to the bioavailability in beagles have been established as: to recognize the food taking patterns in each animal, to confirm the inter-day stability of the food taking behaviors, to trace the food taking patterns in parallel with plasma sampling. In conclusion, the right animals with proper food taking patterns should be assessed and selected for pre-clinic bioavailability evaluations.

Effect of food on the pharmacokinetics of YH4808, a potassium-competitive acid blocker, after single- and multiple-oral dosing in healthy subjects.

YH4808 is a potassium-competitive acid blocker, developed for the treatment of acid-related disorders. Two clinical studies in healthy male subjects were conducted to evaluate the effect of food on the pharmacokinetics of YH4808. The first study, a randomized, three-treatment, three-period, crossover study, compared pharmacokinetics of YH4808 (300mg) after a single dose at fed state with a standard or a high-fat meal to those at fasted state. The second study, a randomized, two-treatment, two-period, crossover study, investigated pharmacokinetics at fasted or fed state with a standard meal after twice daily dose of YH4808 (100mg) for 7days. Bloods for pharmacokinetic evaluation were sampled up to 48h post-dose and 24h post-dose at steady state, respectively. The pharmacokinetic parameters were estimated by non-compartmental method. After single dosing, the geometric means of maximum plasma concentration increased by 1.2 and 2.1 times in the fed states with a standard meal and a high-fat meal, respectively, of that in fasted state. Corresponding values of area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time point increased by 1.8 and 2.8 times, respectively. After multiple dosing, the geometric mean for 24-h AUC at steady state slightly increased in fed state by 1.1 times of that in fasted state. As fat content of the food increased, the systemic exposure of YH4808 after single dosing increased. However, systemic exposures at steady state after multiple dosing between fasted and fed states were similar. ClinicalTrials.gov registry no.: NCT01520012.

Further Studies to Support the Use of Coproporphyrin I and III as Novel Clinical Biomarkers for Evaluating the Potential for Organic Anion Transporting Polypeptide 1B1 and OATP1B3 Inhibition.

In a recent study, limited to South Asian Indian subjects (n = 12), coproporphyrin (CP) I and CPIII demonstrated properties appropriate for an organic anion-transporting polypeptide (OATP) 1B endogenous probe. The current studies were conducted in healthy volunteers of mixed ethnicities, including black, white, and Hispanic subjects, to better understand the utility of these biomarkers in broader populations. After oral administration with 600 mg rifampin, AUC(0-24h) values were 2.8-, 3.7-, and 3.6-fold higher than predose levels for CPI and 2.6-, 3.1-, and 2.4-fold higher for CPIII, for the three populations, respectively. These changes in response to rifampin were consistent with previous results. The sensitivity toward OATP1B inhibition was also investigated by evaluating changes of plasma CP levels in the presence of diltiazem and itraconazole [administered as part of an unrelated drug-drug interaction (DDI) investigation], two compounds that were predicted to have minimal inhibitory effect on OATP1B. Administration of diltiazem and itraconazole did not increase plasma CPI and CPIII concentrations relative to prestudy levels, in agreement with predictions from in vitro parameters. Additionally, the basal CP concentrations in subjects with SLCO1B1 c.521TT genotype were comparable to those with SLCO1B1 c.521TC genotype, similar to studies with probe substrates. However, subjects with SLCO1B1 c.388AG and c.388GG genotypes (i.e., increased OATP1B1 transport activity for certain substrates) had lower concentrations of CPI than those with SLCO1B1 c.388AA. Collectively, these findings provide further evidence supporting the translational value of CPI and CPIII as suitable endogenous clinical probes to gauge OATP1B activity and potential for OATP1B-mediated DDIs.

Evaluation of dried blood spot sampling for pharmacokinetic research and therapeutic drug monitoring of anti-tuberculosis drugs in children

BackgroundDried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters. MethodsParaguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing–Bablok regression, Bland–Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for Cmax and AUC0–24h were calculated. ResultsAfter use of a conversion factor, Passing–Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland–Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of Cmax target attainment was 62.5% for isoniazid, 25% for rifampicin, 100% for pyrazinamide and 75% for ethambutol. ConclusionFor rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.