Single-dose Pharmacokinetic Profile Research Articles

Intramuscular and oral single-dose pharmacokinetic profiles and multi-tissue distribution of thiamphenicol in Chinese soft-shelled turtle (Trionyx sinensis)

The aim of this investigation was to reveal the pattern of disposal process of thiamphenicol (TAP) in Chinese soft-shelled turtle after oral (PO) and intramuscular (IM) administration routes. TAP concentration levels in Chinese soft-shelled turtle plasma and multi-tissues were measured by HPLC-MS/MS. Pharmacokinetic (PK) parameters of TAP were estimated using WinNolin software based on the non-compartmental analysis. Compared with IM route, higher absorption, longer elimination time and greater AUC0-∞ value for TAP in plasma were observed after PO treatment. It indicated that Chinese soft-shelled turtle has a higher bioavailability for TAP following PO administration than IM medication. For tissue distribution, higher TAP concentrations were also found following PO medication than IM administration. The prescribed medication dosage of TAP (17.5 mg/kg bw) against susceptible strains with MIC should be below 0.22 mg/L (PO) and 0.13 mg/L (IM) based on the values of Cmax/MIC >10 and AUC0–24 h/MIC >125. TAP elimination pattern was investigated, and skirt was suggested as residual target tissue. Withdrawal time (WT) of TAP was calculated using WT 1.4 software, and the recommended WT was 17 d (391 ℃-day). The present investigation can serve as reference data for TAP use in Chinese soft-shelled turtle.

Subconjunctival Delivery of Sorafenib-Tosylate-Loaded Cubosomes for Facilitated Diabetic Retinopathy Treatment: Formulation Development, Evaluation, Pharmacokinetic and Pharmacodynamic (PKPD) Studies.

Diabetic retinopathy (DR) is a microvascular complication associated with vascular endothelial growth factor (VEGF) overexpression. Therapeutic delivery to the retina is a challenging phenomenon due to ocular biological barriers. Sorafenib tosylate (ST) is a lipophilic drug with low molecular weight, making it ineffective at bypassing the blood-retinal barrier (BRB) to reach the target site. Cubosomes are potential nanocarriers for encapsulating and releasing such drugs in a sustained manner. The present research aimed to compare the effects of sorafenib-tosylate-loaded cubosome nanocarriers (ST-CUBs) and a sorafenib tosylate suspension (ST-Suspension) via subconjunctival route in an experimental DR model. In this research, ST-CUBs were prepared using the melt dispersion emulsification technique. The distribution of prepared nanoparticles into the posterior eye segments was studied with confocal microscopy. The ST-CUBs were introduced into rats' left eye via subconjunctival injection (SCJ) and compared with ST-Suspension to estimate the single-dose pharmacokinetic profile. Streptozotocin (STZ)-induced diabetic albino rats were treated with ST-CUBs and ST-Suspension through the SCJ route once a week for 28 days to measure the inhibitory effect of ST on the diabetic retina using histopathology and immunohistochemistry (IHC) examinations. Confocal microscopy and pharmacokinetic studies showed an improved concentration of ST from ST-CUBs in the retina. In the DR model, ST-CUB treatment using the SCJ route exhibited decreased expression levels of VEGF, pro-inflammatory cytokines, and adhesion molecules compared to ST-Suspension. From the noted research findings, it was concluded that the CUBs potentially enhanced the ST bioavailability. The study outcomes established that the developed nanocarriers were ideal for delivering the ST-CUBs via the SCJ route to target the retina for facilitated DR management.

A Physiological-Based Pharmacokinetic Model Embedded with a Target-Mediated Drug Disposition Mechanism Can Characterize Single-Dose Warfarin Pharmacokinetic Profiles in Subjects with Various CYP2C9 Genotypes under Different Cotreatments.

Warfarin, a commonly prescribed oral anticoagulant medication, is highly effective in treating deep vein thrombosis and pulmonary embolism. However, the clinical dosing of warfarin is complicated by high interindividual variability in drug exposure and response and its narrow therapeutic index. CYP2C9 genetic polymorphism and drug-drug interactions (DDIs) are substantial contributors to this high variability of warfarin pharmacokinetics (PK), among numerous factors. Building a physiology-based pharmacokinetic (PBPK) model for warfarin is not only critical for a mechanistic characterization of warfarin PK but also useful for investigating the complicated dose-exposure relationship of warfarin. Thus, the objective of this study was to develop a PBPK model for warfarin that integrates information regarding CYP2C9 genetic polymorphisms and their impact on DDIs. Generic PBPK models for both S- and R-warfarin, the two enantiomers of warfarin, were constructed in R with the mrgsolve package. As expected, a generic PBPK model structure did not adequately characterize the warfarin PK profile collected up to 15 days following the administration of a single oral dose of warfarin, especially for S-warfarin. However, following the integration of an empirical target-mediated drug disposition (TMDD) component, the PBPK-TMDD model well characterized the PK profiles collected for both S- and R-warfarin in subjects with different CYP2C9 genotypes. Following the integration of enzyme inhibition and induction effects, the PBPK-TMDD model also characterized the PK profiles of both S- and R-warfarin in various DDI settings. The developed mathematic framework may be useful in building algorithms to better inform the clinical dosing of warfarin. SIGNIFICANCE STATEMENT: The present study found that a traditional physiology-based pharmacokinetic (PBPK) model cannot sufficiently characterize the pharmacokinetic profiles of warfarin enantiomers when warfarin is administered as a single dose, but a PBPK model with a target-mediated drug disposition mechanism can. After incorporating CYP2C9 genotypes and drug-drug interaction information, the developed model is anticipated to facilitate the understanding of warfarin disposition in subjects with different CYP2C9 genotypes in the absence and presence of both cytochrome P450 inhibitors and cytochrome P450 inducers.

Mouse pharmacokinetics and metabolism of the phenylurea thiocarbamate NSC 161128

NSC 161128, a phenylurea thiocarbamate, displays activity against the NCI60 anti-cancer cell line panel and xenograft models. The metabolite N-methyl-N'-phenylurea (M10) has been detected in animal plasma; however, detection and quantification of other putative NSC 161128 metabolites have not been undertaken. The purpose of this study was to characterize the pharmacokinetics and metabolism of NSC 161128 in mice and under in vitro conditions. An LC-MS/MS assay was developed to evaluate stability and in vitro metabolism of NSC 161128 in liver microsomes and S9 fractions. Single-dose pharmacokinetic profiles for NSC 161128 and its metabolite M10 were obtained following intraperitoneal (I.P.) administration. A sensitive and specific positive ionization LC-MS/MS method for measuring NSC 161128 and its metabolites was developed. HPLC separation was achieved under gradient elution using an aqueous methanol mobile phase containing 0.05% formic acid and 0.05% ammonium hydroxide. The assay was linear over the range 1.0-1000ng/mL. NSC 161128 was stable in aqueous solution and tissue culture media, but not in plasma, where rapid degradation of NSC 161128 to the metabolite M10 was observed. Following I.P. administration of a 200mg/kg dose to male CD1 mice, the peak plasma concentration of NSC 161128 was 255ng/mL after 5min with a plasma half-life of 138min. Potential bioactivation of NSC 161128 was explored using mouse S9. An analytical LC-MS/MS method was successfully developed for the detection and quantification of NSC 161128 and its metabolites. These results increase the understanding of NSC 161128 pharmacokinetic and metabolic properties.

Dose Finding and Food Effect Studies of a Novel Abiraterone Acetate Formulation for Oral Suspension in Comparison to a Reference Formulation in Healthy Male Subjects.

Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.

The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study

PurposePamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP–DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors.MethodsIn this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3–11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3–8). Primary endpoints included pamiparib maximum observed concentration (Cmax), and area under the plasma concentration–time curve from zero to last quantifiable concentration (AUC0–tlast) and infinity (AUC0–inf). Secondary endpoints included safety and tolerability.ResultsRifampin coadministration did not affect pamiparib Cmax (geometric least-squares [GLS] mean ratio 0.94; 90% confidence interval 0.83–1.06), but reduced its AUC0–tlast (0.62 [0.54–0.70]) and AUC0–inf (0.57 [0.48–0.69]). Itraconazole coadministration did not affect pamiparib Cmax (1.05 [0.95–1.15]), AUC0–tlast (0.99 [0.91–1.09]), or AUC0–inf (0.99 [0.90–1.09]). There were no serious treatment-related adverse events.ConclusionsPamiparib plasma exposure was reduced 38–43% with rifampin coadministration but was unaffected by itraconazole coadministration. Pamiparib dose modifications are not considered necessary when coadministered with CYP3A inhibitors. Clinical safety and efficacy data will be used with these results to recommend dose modifications when pamiparib is coadministered with CYP3A inducers.

Pharmacokinetic profile of a single dose of an oral pradofloxacin suspension administered to eastern long-necked turtles (Chelodina longicollis).

The pharmacokinetics of fluoroquinolones in chelonians are well described but this does not extend to pradofloxacin, a broad-spectrum veterinary fluoroquinolone available as an oral suspension for cats and dogs. The aim of this study was to investigate the single-dose pharmacokinetic profile of pradofloxacin oral suspension at 7.5mg/kg in eastern long-necked turtles (Chelodina longicollis). Eight treated turtles were sampled at multiple time points up to 168hr. Plasma concentrations were measured using high-performance liquid chromatography. Pradofloxacin was quantifiable for up to 48hr after drug administration. The Tmax (9.0hr) and T½ to 48hr (13.16hr) were longer, and the Cmax (0.2μg/ml) and AUC0-24 (2.2hr*μg/ml) lower, than previously reported in cats and dogs. Pradofloxacin was measurable in tank water samples for up to 48hr. No adverse effects were observed in six turtles administered 7.5mg/kg sid for 7days. Using mammalian MIC data, the AUC0-24 /MIC ratios for a range of bacterial isolates suggest that this dose of pradofloxacin in turtles is unlikely to be effective against many bacterial pathogens.

Lorlatinib in previously treated anaplastic lymphoma kinase‐rearranged non–small cell lung cancer: Japanese subgroup analysis of a global study

Lorlatinib is a potent, brain‐penetrant, third‐generation anaplastic lymphoma kinase (ALK)/ROS proto‐oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK‐rearranged/ROS1‐rearranged advanced non–small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC‐ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK‐rearranged/ROS1‐rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty‐one ALK‐rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC‐ORR. The ORR and the IC‐ORR for Japanese patients in EXP2‐5 were 54.8% (95% confidence interval [CI]: 36.0‐72.7) and 46.7% (95% CI: 21.3‐73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9‐81.6). The most common treatment‐related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single‐dose and multiple‐dose pharmacokinetic profiles among Japanese patients were similar to those in non–Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK‐rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.

Plasma concentrations of itraconazole following a single oral dose in juvenile California sea lions (Zalophus californianus).

The objective of this study was to establish a single-dose pharmacokinetic profile for orally administered itraconazole in California sea lions (Zalophus californianus). Twenty healthy rehabilitated juvenile California sea lions were included in this study. Itraconazole capsules were administered orally with food at a target dose of 5-10mg/kg. Blood samples were collected from each animal at 0hr and attwo of the following timepoints: 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72hr. Quantitative analysis of itraconazole in plasma samples was performed by high-performance liquid chromatography. An average maximum concentration of 0.22µg/ml±0.11 was detected 4hr after administration. The average concentration fell to 0.12µg/ml±0.11 by 6hr and 0.02µg/ml±0.02 at 12hr. At no point did concentrations reach 0.5µg/ml, the concentration commonly accepted for therapeutic efficacy. While this formulation was well tolerated by the sea lions, oral absorption was poor and highly variable among individuals. These data indicate that a single oral dose of itraconazole given as a capsule at 5-10mg/kg, under the conditions used in this study, does not achieve therapeutic plasma concentrations in California sea lions.

Metabolism and pharmacokinetics characterization of metarrestin in multiple species.

Metarrestin is a first-in-class pyrrolo-pyrimidine-derived small molecule targeting a marker of genome organization associated with metastasis and is currently in preclinical development as an anti-cancer agent. Here, we report the in vitro ADME characteristics and in vivo pharmacokinetic behavior of metarrestin. Solubility, permeability, and efflux ratio as well as in vitro metabolism of metarrestin in hepatocytes, liver microsomes and S9 fractions, recombinant cytochrome P450 (CYP) enzymes, and potential for CYP inhibition were evaluated. Single dose pharmacokinetic profiles after intravenous and oral administration in mice, rat, dog, monkey, and mini-pig were obtained. Simple allometric scaling was applied to predict human pharmacokinetics. Metarrestin had an aqueous solubility of 150µM at pH 7.4, high permeability in PAMPA and moderate efflux ratio in Caco-2 assays. The compound was metabolically stable in liver microsomes, S9 fractions, and hepatocytes from six species, including human. Metarrestin is a CYP3A4 substrate and, in mini-pigs, is also directly glucuronidated. Metarrestin did not show cytochrome P450 inhibitory activity. Plasma concentration-time profiles showed low to moderate clearance, ranging from 0.6mL/min/kg in monkeys to 48mL/min/kg in mice and moderate to high volume of distribution, ranging from 1.5 L/kg in monkeys to 17 L/kg in mice. Metarrestin has greater than 80% oral bioavailability in all species tested. The excretion of unchanged parent drug in urine was < 5% in dogs and < 1% in monkeys over collection periods of ≥ 144h; in bile-duct cannulated rats, the excretion of unchanged drug was < 1% in urine and < 2% in bile over a collection period of 48h. Metarrestin is a low clearance compound which has good bioavailability and large biodistribution after oral administration. Biotransformation appearsto be the major elimination process for the parent drug. In vitro data suggest a low drug-drug interaction potential on CYP-mediated metabolism. Overall favorable ADME and PK properties support metarrestin's progression to clinical investigation.

&lt;p&gt;Population Pharmacokinetic Modeling Of On-Demand And Surgical Use Of Nonacog Beta Pegol (N9-GP) And rFIXFc Based Upon The paradigm 7 Comparative Pharmacokinetic Study&lt;/p&gt;

Aim/objectiveUnderstanding pharmacokinetic (PK) differences between standard and extended half-life (EHL) products is important, particularly for factor IX (FIX), where differences are more significant than for factor VIII. Two single-dose PK trials showed N9-GP achieves higher FIX levels and greater area-under-the-curve than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. In paradigm 7, N9-GP demonstrated consistently favorable PK characteristics compared with rFIXFc. Collins et al explored population PK differences between N9-GP and pdFIX/rFIX based upon paradigm 1 data. This analysis uses population PK models based upon the paradigm 7 trial.Methods15 patients (21–65 years) with hemophilia B received single 50-IU/kg doses of N9-GP and rFIXFc ≥21 days apart. A population PK model developed from single-dose PK profiles simulated plasma FIX activity following dosing for surgery and on-demand treatment of bleeds. Simulations explored doses and frequencies required to sustain target World Federation of Hemophilia (WFH) factor activity levels.ResultsPK profiles of N9-GP and rFIXFc were described by one- and three-compartment models, respectively. Simulations predicted significantly reduced dosing frequency and consumption for N9-GP than rFIXFc. For severe bleeds, a single N9-GP dose (80 IU/kg) is sufficient to maintain WFH-recommended FIX levels, whereas multiple rFIXFc doses are required. For surgery, redosing in the first week with N9-GP is modeled at day 6 vs rFIXFc dosing at 6, 30, 54, 78, and 126 hrs. For life-threatening bleeds, N9-GP is required at days 0, 3, 6, 13, and 18 vs rFIXFc redosing after 6 hrs with 10 additional doses at 24-, 48-, and 72 hr intervals.ConclusionPK modeling approaches based upon direct comparative studies offer insights into PK differences between EHL FIX products. Model simulations show N9-GP may allow on-demand treatment and perioperative management with 55–75% fewer injections and 65–74% lower overall factor concentrate consumption than rFIXFc.

A New Model to Describe the Single-dose Pharmacokinetics of Bevacizumab and Predict Its Multiple-Dose Pharmacokinetics in Beagle Dogs.

Complex pharmacokinetic (PK) properties including nonlinear elimination were encountered by some monoclonal antibodies (mAbs), and classic compartment models sometimes failed to appropriately describe those properties. In this work, a new model was built on a comprehensive analysis of the complex elimination of mAbs. This new model was firstly utilized to fit with the single-dose plasma concentration data of bevacizumab in beagle dogs receiving an intravenous administration of 2.5 mg/kg bevacizumab. Then, the optimal PK parameters from fitting with the single-dose PK data were employed into the multiple-dose mathematical expressions to predict bevacizumab’s multiple-dose PK profiles. One-compartment model recommended as the optimal classic model by DAS 2.0 software was set as a control. As a result, new model fitted better with the single-dose PK profiles of bevacizumab with smaller weighted residual sum of squares and higher fitting degree compared with the classic model. Importantly, new model also accurately predicted the multiple-dose PK profiles of bevacizumab and performed well at the single-to-multiple transition. In conclusion, the new model reasonably explained the complex elimination of bevacizumab, and it might play a big role in the PK studies of bevacizumab and other mAbs.

Integration of in vitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products

Bioequivalence implementation in developing countries where a high proportion of similar drug products are being marketed has found several obstacles, impeding regulatory agencies to move forward with this policy. Biopharmaceutical quality of these products, several of which are massively prescribed, remains unknown. In this context, an in vitro-in silico-in vivo approach is proposed as a mean to screen product performance and target specific formulations for bioequivalence assessment. By coupling in vitro biorelevant dissolution testing in USP-4 Apparatus (flow-through cell) with physiologically-based pharmacokinetic (PBPK) modeling in PK-Sim® software (Bayer, Germany), the performance of seven similar products of carvedilol tablets containing 25 mg available in the Uruguayan market were compared with the brand-name drug Dilatrend®. In silico simulations for Dilatrend® were compared with published results of bioequivalence studies performed in fasting conditions allowing model development through a learning and confirming process. Single-dose pharmacokinetic profiles were then simulated for the brand-name drug and two similar drug products selected according to in vitro observations, in a virtual Caucasian population of 1000 subjects (50% male, aged between 18 and 50 years with standard body-weights). Population bioequivalence ratios were estimated revealing that in vitro differences in drug release would have a major impact in carvedilol maximum plasma concentration, leading to a non-bioequivalence outcome. Predictions support the need to perform in vivo bioequivalence for these products of extensive use. Application of the in vitro-in silico-in vivo approach stands as an interesting alternative to tackle and reduce drug product variability in biopharmaceutical quality.

Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis

Background: This study aimed to characterize the single-dose pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban 15 mg administered before and after dialysis in subjects with end-stage renal disease (ESRD), and to compare this profile in subjects with ESRD to that in healthy control subjects (creatinine clearance ≥80 ml/min). Methods: This was an open-label, single-dose, single-center, parallel-group study of rivaroxaban in ESRD subjects who had been clinically stable on maintenance hemodialysis for ≥3 months. In 8 subjects with ESRD, a 15-mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7-14 days later at 3 h after a 4-h hemodialysis session. Eight healthy control subjects, matched for age, sex, and body mass index, received one 15-mg rivaroxaban dose. Results: Compared to healthy subjects, area under the rivaroxaban plasma concentration versus time curve (AUC) increased by 56% following post-dialysis administration. Assuming similar bioavailability between groups, this reflects an approximate 35% decrease in overall drug clearance in ESRD subjects. Pre-dialysis dosing resulted in only 5% lowering of AUC versus post-dialysis dosing, confirming the minimal impact of dialysis on the PK of rivaroxaban. PD effects, as assessed by change in prothrombin time, percent factor Xa inhibition, and anti-Xa activity, were generally concordant with observed changes in plasma PK. Conclusions: Changes in PK and PD parameters in chronic dialysis patients were generally comparable to changes observed previously in patients with moderate-to-severe renal impairment who were not undergoing dialysis, and support use of a 15-mg dose in this patient population.

A novel pharmacokinetic model based on the complex elimination of monoclonal antibodies for bevacizumab pharmacokinetic study in rabbits

Monoclonal antibodies (mAbs) complex pharmacokinetic (PK) properties including a nonlinear pharmacokinetics and a significant variation in individual PK process cannot be appropriately described by classic PK models, probably derived form a poor understanding of the complex elimination of mAbs. In this study, a novel PK model based on mAbs' complex drug elimination was established. Subsequently, this new model was used to fit bevacizumab plasma concentration data from PK rabbits, and the outcomes of model fitting were compared with those came from a fit with classic models. In addition, the variations existing in the parameters set in the new model were analyzed. As a result, this novel model reasonably described the single-dose PK profiles of bevacizumab in rabbits, and its fitting efficiency was greatly improved compared with those fitted with classic PK models in terms of the weighted residual sum of squares. Moreover, the variations existing in the new model's parameters CA(antibody) and K0 could reasonably explain the individual variations of bevacizumab's PK profiles. In conclusion, the novel model reasonably explained the elimination of bevacizumab, and exhibited a potential as a useful tool for the PK studies of bevacizumab and other mAbs in practice.

Abstract 1752: 6-Methoxyethylamino-numonafide (MEAN) inhibits hepatocellular carcinoma as a single agent or in combination with sorafenib

Abstract Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide and the incidence is increasing rapidly in the United States, tripling over the past 3 decades. Unfortunately, chemotherapeutic treatment strategies against localized and metastatic HCC are very ineffective, leading to a high mortality from the disease. Sorafenib is the sole FDA approved chemotherapeutic currently used clinically for the disease and it shows limited efficacy and substantial toxicity. We have developed a small molecule, 6-methoxyethylamino-numonafide (MEAN), which is highly effective in two murine xenograph models of human HCC. MEAN is more effective in tumor growth inhibition and less toxic than sorafenib at the same concentration. MEAN, at efficacious doses, does not significantly affect animal body weight and does not significantly induce liver damage as determined by the serum levels of liver enzymes at the experimental endpoint. NCI60 cell assay analyses using the COMPARE algorithm indicate that, at IC50 concentration, MEAN does not significantly correlate with any of the small molecules in the 60 cell assay database (correlation&amp;lt;0.5), suggesting novel modes of action in tumor inhibition. MEAN suppresses some of the well-known oncogene expression and enhances the expression of a subset of tumor suppressors. MEAN remains effective against cancer cells that are drug resistant due to expression of P-glycoprotein drug efflux pumps and has a favorable single dose pharmacokinetic profile. In summary, MEAN is effective against HCC tumor growth and is an excellent candidate for future development as therapeutic agent for management of HCC. Citation Format: Yanning Liu, Guohua Lou, John Norton, Chen Wang, Irawati Kandela, Shuai Tang, Min Huang, Michael Avram, Richard Green, Andrew Mazar, Daniel Appella, Zhi Chen, Sui Huang. 6-Methoxyethylamino-numonafide (MEAN) inhibits hepatocellular carcinoma as a single agent or in combination with sorafenib. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1752. doi:10.1158/1538-7445.AM2015-1752

Development of Sustained Release "NanoFDC (Fixed Dose Combination)" for Hypertension - An Experimental Study.

ObjectivesThe present study was planned to formulate, characterize and evaluate the pharmacokinetics of a novel “NanoFDC” comprising three commonly prescribed anti-hypertensive drugs, hydrochlorothiazide (a diuretic), candesartan (ARB) and amlodipine (a calcium channel blocker).Basic MethodsThe candidate drugs were loaded in Poly (DL-lactide-co-gycolide) (PLGA) by emulsion- diffusion-evaporation method. The formulations were evaluated for their size, morphology, drug loading and in vitro release individually. Single dose pharmacokinetic profiles of the nanoformulations alone and in combination, as a NanoFDC, were evaluated in Wistar rats.ResultsThe candidate drugs encapsulated inside PLGA showed entrapment efficiencies ranging from 30%, 33.5% and 32% for hydrochlorothiazide, candesartan and amlodipine respectively. The nanoparticles ranged in size from 110 to 180 nm. In vitro release profile of the nanoformulation showed 100% release by day 6 in the physiological pH 7.4 set up with PBS (phosphate buffer saline) and by day 4-5 in the intestinal pH 1.2 and 8.0 set up SGF (simulated gastric fluid) and SIF (simulated intestinal fluid) respectively. In pharmacokinetic analysis a sustained-release for 6 days and significant increase in the mean residence time (MRT), as compared to the respective free drugs was noted [MRT of amlodipine, hydrochlorothiazide and candesartan changed from 8.9 to 80.59 hours, 11 to 69.20 hours and 9 to 101.49 hours respectively].ConclusionWe have shown for the first time that encapsulating amlodipine, hydrochlorothiazide and candesartan into a single nanoformulation, to get the “NanoFDC (Fixed Dose Combination)” is a feasible strategy which aims to decrease pill burden.

Application of a method used to deconstruct a single dose pharmacokinetic profile from multiple dose data.

With traditional non-compartmental methods, it is challenging to deconstruct plasma concentration versus time curves to assess the influence of individual doses. This study describes the application of a mathematical approach used to deconstruct a single dose curve using data derived from the second, third, fourth or nth dosing interval. Using data from a prospective clinical trial it is demonstrated that this approach reliably estimates pharmacokinetic parameters measured following two doses of zolpidem tartrate. Additionally, the study demonstrates the application of this approach using previously published data from a single- and multiple-dose pharmacokinetic study of the antibiotic gatifloxacin. Copyright © 2015 John Wiley & Sons, Ltd.

Pharmacokinetic Properties of Once-Daily Oral Low-Dose Mesylate Salt of Paroxetine (LDMP 7.5 mg) Following Single and Multiple Doses in Healthy Postmenopausal Women

BackgroundLow-dose mesylate salt of paroxetine (LDMP 7.5 mg) is being investigated for the treatment of vasomotor symptoms associated with menopause. ObjectiveThis Phase I, open-label, single- and multiple-dose study evaluated the pharmacokinetic properties, safety and tolerability of LDMP in postmenopausal, nonsmoking women aged ≥40 years. MethodsAfter a 3-week screening period, subjects received LDMP 7.5-mg capsules as a single dose on day 1 and then as multiple doses (once daily for 14 days) on Days 6–19. Blood samples were collected predose and up to 120 hours postdose on day 1 (single-dose pharmacokinetic profile), at predose (after 12 doses) on day 18, and at predose and up to 24 hours postdose on day 19 (multiple-dose pharmacokinetic profile). Capsules were taken with 240 mL of water while subjects were fasted. Safety was evaluated throughout the study. ResultsTwenty-four women (mean age, 56 years) completed the study. On day 1, median Tmax was ~6 hours, and mean t1/2 was 17.30 hours. Mean plasma concentrations attained predose on days 18 and 19 (days 13 and 14 of multiple dosing) and at 24 hours postdose (day 20) were similar, suggesting that steady state was achieved by day 13 of multiple dosing after 12 daily doses. Mean AUC0–24 h at steady state (day 14 of multiple dosing) was ~3-fold greater than AUC0–∞ on day 1, indicating nonlinear pharmacokinetics. Mean Cmax on day 14 of multiple dosing was ~5-fold greater than that attained on day 1, and the accumulation index (AUCday 19/AUCday 1) at steady state was 9.71. Fluctuation index (calculated as [(Cmax – Cmin)/Cavg ss] × 100) was 75.8%. Most subjects (23/24 [95.8%]) experienced at least 1 treatment-emergent adverse event (AE); however, most AEs (67 events in 22/24 subjects [91.7%]) were mild, and the remainder were moderate. Seventeen subjects experienced 33 AEs that were deemed possibly or probably related to LDMP. No serious AEs were reported, and no clinically meaningful changes in laboratory values, vital signs, or ECGs were observed. ConclusionsOn multiple dosing, LDMP exhibited nonlinear pharmacokinetics and was well tolerated in these healthy postmenopausal women; the extent of accumulation was consistent with data from the published literature. ClinicalTrials.gov identifier: NCT01829919.

A Randomised, Two-Period, Cross-Over, Open-Label Study to Evaluate the Pharmacokinetic Profiles of Single Doses of Two Different Flurbiprofen 8.75-mg Lozenges in Healthy Volunteers

Aims: To compare the bioavailability of a new oromucosal formulation of flurbiprofen 8.75-mg lozenges, developed by Alfa Wassermann S.p.A. (test drug) to that of marketed flurbiprofen 8.75-mg lozenges (Benactiv Gola®, reference drug). Methods: This was an open, randomised, two-period, crossover, pharmacokinetic (PK) study in which flurbiprofen plasma levels were compared in 12 healthy volunteers after the administration of single doses (8.75 mg × 2) of two different oromucosal lozenges to be sucked and slowly dissolved in the mouth. A wash-out period of at least 7 days separated the two study periods. Blood samples were collected prior to dosing and at predefined intervals for 24 h after dose. Flurbiprofen plasma concentrations were determined by liquid chromatography/tandem mass spectrometry. PK parameters maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), area under the plasma concentration-time curve from time zero to 24 hours (AUC_0–t), area under the plasma concentration-time curve from time zero to infinity (AUC_0–∞) and half-life were calculated and compared by analysis of variance using treatment, period and sequence as sources of variation. Bioequivalence between the two formulations was based on 90% confidence intervals of the ratio of the geometric means of C_max and AUC falling within the 0.80–1.25 range as defined in bioequivalence guidelines by regulators. Tolerability of the two formulations was assessed by adverse event monitoring, routine laboratory tests, physical examination, electrocardiographic tracing and vital sign measurements. Results: All enrolled subjects completed the study. Bioequivalence without significant treatment effect was demonstrated between the test drug/reference drug ratios of mean C_max and AUCs. Moreover, mean T_max was superimposable. No safety parameter presented a clinically relevant variation after administration of either formulation that were therefore well tolerated. Conclusion: The new formulation of flurbiprofen 8.75-mg compressed lozenges developed by Alfa Wassermann S.p.A. is bioequivalent to the reference product flurbiprofen 8.75-mg lozenges (Benactiv Gola) in healthy volunteers.