Reduction In Systemic Exposure Research Articles

Machine learning-aided design of composite mycotoxin detoxifier material for animal feed

The development of food and feed additives involves the design of materials with specific properties that enable the desired function while minimizing the adverse effects related with their interference with the concurrent complex biochemistry of the living organisms. Often, the development process is heavily dependent on costly and time-consuming in vitro and in vivo experiments. Herein, we present an approach to design clay-based composite materials for mycotoxin removal from animal feed. The approach can accommodate various material compositions and different toxin molecules. With application of machine learning trained on in vitro results of mycotoxin adsorption–desorption in the gastrointestinal tract, we have searched the space of possible composite material compositions to identify formulations with high removal capacity and gaining insights into their mode of action. An in vivo toxicokinetic study, based on the detection of biomarkers for mycotoxin-exposure in broilers, validated our findings by observing a significant reduction in systemic exposure to the challenging to be removed mycotoxin, i.e., deoxynivalenol (DON), when the optimal detoxifier is administrated to the animals. A mean reduction of 32% in the area under the plasma concentration–time curve of DON-sulphate was seen in the DON + detoxifier group compared to the DON group (P = 0.010).

Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly

Abstract Depot injection formulations of peptide somatostatin receptor ligands (SRLs) are routinely used to treat acromegaly and neuroendocrine tumors (NETs). Paltusotine (CRN00808), an orally administered small molecule nonpeptide selective somatostatin receptor 2 (SST2) agonist has been shown to maintain GH and IGF-1 levels in acromegaly patients previously on depot SRLs (ACROBAT Edge NCT03789656). In this study, a capsule formulation was used, which did not exhibit dose proportional pharmacokinetics (PK) at doses >40 mg, required a 2-hour post-dose fast in overnight fasted patients, and had the potential for reduced bioavailability when taken with proton-pump inhibitors (PPI). A spray-dried dispersion (SDD) tablet formulation was developed with improved solubility in the physiological pH range and its performance was evaluated in healthy volunteers. Male and female healthy volunteers who met inclusion/exclusion criteria were enrolled in a single-center Phase 1 study (ANZCTR registration ACTRN12619001562167). A Cohort of 12 subjects was administered a single dose of paltusotine in a four-period cross-over design. Periods 1 and 2 assessed the effect of lansoprazole (a PPI) on PK of 20 mg dose of paltusotine SDD tablets. In Period 3, 20 mg dose of paltusotine SDD tablets was co-administered with a high fat, high-calorie meal. In Period 4, a 60 mg dose of paltusotine SDD tablets was administered to assess dose proportionality. In a separate cohort of subjects (n=12; also, a 4-period cross-over design), the relative bioavailability of capsules and SDD tablets was assessed, and the effect of food administration 0.5, 1, and 2 hour post-dose was evaluated. Subsequently, in another cohort of 12 subjects (a 3-period cross-over design), dose proportionality of the SDD tablets was evaluated at 40 mg and 80 mg dose with a 1-hour post-dose fast. A 4 hours post-dose fast was also assessed for the 80 mg dose. Pharmacokinetics and safety of paltusotine were evaluated. Paltusotine was generally well tolerated in this study. SDD tablets exhibited dose proportional increase in total systemic exposure (AUC) up to a dose of 80 mg. Healthy volunteers pretreated with the PPI, lansoprazole (15 mg bid for 3 days), and co-administered with paltusotine SDD tablets exhibited a small decrease (approximately 25%) in systemic exposure to paltusotine compared with the same subjects that had washed out from the PPI-pretreatment. SDD tablets exhibited significant reduction in systemic exposure when co-administered with a high-fat, high-calorie meal. However, the SDD formulation was less sensitive to timing of post-dose food administration compared to the capsule formulation. These data suggest that the SDD tablet formulation of paltusotine improves flexibility in dose administration, can be co-administered with PPIs and other agents that increase stomach pH, and reduces the post-dose fasting requirement.

Immunogenicity and toxicokinetics assessment of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys

AimProtein therapeutics have potential to elicit immune responses resulting in undesirable anti-drug antibodies (ADA) that might affect product efficacy and patient safety, and should be assessed in animals before applying the treatment to humans. In this paper, we aim to assess the immunogenicity and toxicokinetics of the mono-PEGylated recombinant human interleukin-11 (rhIL-11), a novel protein therapeutic for the treatment of chemotherapy-induced thrombocytopenia, in repeated administration to cynomolgus monkeys. Main methodsEnzyme-linked immunosorbent assay (ELISA) methods were developed to measure ADA responses and plasma PEGylated IL-11 (PEG-IL11) concentration in monkeys. Assay parameters of immunogenicity and toxicokinetics methods were evaluated during validation in accordance with regulatory guidelines. We also employed cell-based assays to test the neutralizing activity of ADA provoked in monkeys. Key findingsThe results showed that weak immunogenicity occurred in some monkeys after receiving repeated dose of 0.1–0.3 mg/kg by subcutaneous administration and disappeared after the recovery period. More pronounced immunogenicity occurred at high dose of 0.9 mg/kg, with a higher positive rate and titer, and some ADAs had neutralizing activity, but it can be greatly reduced after recovery. Such ADAs generated in monkeys may be accounted for the plasma toxicokinetics changes of PEG-IL11 and a minor reduction in systemic exposure. SignificanceThese methods have been successfully applied to immunogenicity and toxicokinetic studies of PEG-IL11 in repeated dose toxicity following subcutaneous administration to monkeys, and could be successfully used in clinical trials after some modifications.

Synthesis and Characterization of PDMS-PMOXA-Based Polymersomes Sensitive to MMP-9 for Application in Breast Cancer.

Cytotoxic compounds used to treat cancer are often associated with adverse events. The development of formulations activated by tumor-specific triggers would allow a reduction of systemic exposure while maintaining therapeutic concentrations in the tumor. One enzyme with proteolytic activity reported to be involved in tumor progression and assumed to be enhanced in the tumor environment is the matrix metalloproteinase 9 (MMP-9). In our study, we aimed to develop surface-modified PDMS-PMOXA polymersomes able to release their cytotoxic payload upon digestion by MMP-9. To test the applicability of such a system in breast cancer, this tumor entity was assessed for MMP-9 expression, supporting breast cancer as a potential target. The surface-modified polymersomes were synthesized and formulated resulting in paclitaxel-loaded particles of about 320 ± 153.15 nm in size with a surface potential of 0.04 ± 0.007 mV. After the expression and activity of MMP-9 in MCF7 cells were verified, this cell line was used for further analysis. Treatment of MCF7 cells with the polymersomes significantly reduced cell viability, this effect was abolished after addition of MMP-inhibitors, suggesting proteolytic activation. In zebrafish embryos, the polymersomes were observed in the circulation with some enrichment in liver and agglomerates in the caudal veins. Importantly, in zebrafish embryos xenografted with mKate2-expressing MCF7 cells, the amount of tumor cells, quantified by detecting the copies of the heterologously expressed fluorescent protein, significantly decreased after treatment with PDMS-PMOXA-SRL-paclitaxel polymersomes. Taken together, our data suggest that polymersomes modified with an MMP-9 labile peptide and loaded with paclitaxel can be formulated, and that these particles exert pharmacological activity upon enzymatic digestion.

Clinical Pharmacology Profile of Pacritinib (PAC), a Novel JAK2/FLT3 Inhibitor

Introduction: PAC is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R that does not inhibit JAK1. PAC has demonstrated activity in phase (Ph) 1-3 clinical studies. Nonclinical and clinical pharmacokinetic (PK) and pharmacodynamic studies support a 400 mg QD oral dosing regimen in ongoing Ph 3 studies in myelofibrosis. Here we present PK data from a series of Ph 1 studies of PAC.Methods: Seven Ph 1 studies were conducted in healthy subjects receiving a single 100, 200, or 400 mg dose of PAC. In an ADME mass balance study, [14 C]-PAC was administered to characterize routes of disposition. Separate drug interaction studies were conducted to assess effects of a strong CYP3A4 inhibitor (clarithromycin) or strong pan-CYP450 inducer (rifampin) on PAC PK. Cardiac safety of PAC was evaluated in a thorough QT (TQT) study. Food-effect, dose proportionality, and relative bioavailability studies were also conducted.Results: 140 subjects across 7 studies received single doses of PAC 100-400 mg. PK parameters of PAC 400 mg are presented in the Table (n=12). Following administration of single 100-400 mg PAC doses under fasted conditions, systemic exposure increased in a linear, but less than dose proportional manner. Among identified metabolites, the 2 major metabolites (M1, M2) exhibit relatively low pharmacological potency and are unlikely to contribute to PAC activity. Following a 400 mg single dose of [14 C]-PAC, the parent compound was the predominant moiety in plasma. Mean radioactivity recovery in urine = 3.22% of administered dose with intact PAC excreted in urine = 0.12% of administered dose. Of all 9 metabolites formed, M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose) excreted in urine. Mean radioactivity recovery in feces = 85.46% of administered dose and M2 (O- dealkylation metabolite) was the predominant component (24.08% of administered dose). When co-administered with clarithromycin (CYP3A4 inhibitor), PAC exposure increased with mean Cmax and AUC approximately 1.3- and 1.8-fold higher, respectively, with a similar mean t1/2 vs PAC alone. Co-administration with rifampin, a strong CYP3A4 inducer, reduced mean PAC Cmax and AUC by 51% and 87%, respectively vs PAC alone. Median Tmax was similar when co-administered with rifampin vs PAC alone (5-6 h), but t1/2 was shortened by approximately 65% (PAC: 43.3 h; PAC + rifampin: 15.1 h). Administration of single oral doses of PAC 400 mg in a placebo- and moxifloxacin-controlled TQT study had no clinically relevant effects on ECG parameters, including heart rate. There was no effect on QT prolongation (mean QTcF change <10 msec) and a small but non-clinically significant shortening in the placebo-corrected change in QTcF below 0 msec in the first 12 h post-dose. Across all clinical pharmacology studies, PAC was tolerable (primarily grade 1 gastrointestinal AEs), consistent with the PAC clinical safety profile to date.Conclusions: PAC exhibits moderate oral bioavailability and is eliminated primarily through metabolism and biliary excretion. Minimal excretion occurs via renal clearance, indicating dosage adjustment is unlikely to be warranted in renal impairment. Increase in PAC exposure is limited when co-administered with a strong CYP3A4 inhibitor, unlikely necessitating dosage adjustments. There is marked reduction in systemic exposure when co-administered with a strong CYP450 inducer and co-administration should therefore be avoided due to potential for negative impact on efficacy. PAC was not found to cause QT prolongation, suggesting favorable cardiac safety. Single 100-400 mg doses of PAC were well tolerated in healthy volunteers in these studies. Overall, PAC exhibited a favorable clinical pharmacology profile supportive of its safety and tolerability at clinical dose levels.TablePK Parameter(Geometric Mean; n=12)PAC 400 mgCmax, μg/mL3.83AUC0-t, μg∙h/mL184t1/2, h37.5Tmaxa, h6.00λz, L/h0.0185CL/F, L/h2.08Vz/F, L112Oral bioavailability, %58.6aMedian for Tmax.λz, terminal elimination rate constant; AUC0-t, area under the plasma concentration curve from time 0 to time t; CL/F, apparent oral clearance; Cmax, maximum plasma concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Vz/F apparent volume of distribution during terminal phase. DisclosuresAl-Fayoumi:CTI Biopharma: Employment, Equity Ownership. Off Label Use: This abstract discusses off-label use of pacritinib. Campbell:CTI Biopharma: Equity Ownership. Amberg:BMS: Employment, Equity Ownership; Juno: Equity Ownership. Zhou:CTI Biopharma: Employment, Equity Ownership. Millard:CTI Biopharma Corp.: Employment. Dean:CTI Biopharma: Employment, Equity Ownership.

Pharmacokinetic interactions between artesunate-mefloquine and ritonavir-boosted lopinavir in healthy Thai adults.

BackgroundConcomitant use of anti-malarial and antiretroviral drugs is increasingly frequent in malaria and HIV endemic regions. The aim of the study was to investigate the pharmacokinetic interaction between the anti-malarial drugs, artesunate-mefloquine and the antiretroviral drug, lopinavir boosted with ritonavir (LPV/r).MethodsThe study was an open-label, three-way, sequential, cross-over, pharmacokinetic study in healthy Thai adults. Subjects received the following treatments: Period 1: standard 3-day artesunate-mefloquine combination; Period 2 (2 months wash-out): oral LPV/r 400 mg/100 mg twice a day for 14 days; and, Period 3: artesunate-mefloquine and LPV/r twice a day for 3 days. Sixteen subjects (eight females) were enrolled and pharmacokinetic parameters were determined by non-compartmental analysis.ResultsIn the presence of LPV/r, artesunate Cmax and systemic exposure were significantly increased by 45–80 %, while the metabolic ratio of dihydroartemisinin to artesunate was significantly reduced by 72 %. In addition, mefloquine Cmax and systemic exposure were significantly reduced by 19–37 %. In the presence of artesunate-mefloquine, lopinavir Cmax was significantly reduced by 22 % but without significant change in systemic drug exposure. The 90 % CI of the geometric mean ratio (GMR) of AUC0−∞ and Cmax were outside the acceptable bioequivalent range for each drug. Drug treatments were generally well tolerated with no serious adverse events. Vertigo, nausea and vomiting were the most common adverse events reported.ConclusionThe reduction in systemic exposure of all investigated drugs raises concerns of an increased risk of treatment failure rate in co-infected patients and should be further investigated.

Exposure of hairdressers to aromatic diamines: an interventional study confirming the protective effect of adequate glove use

ObjectivesMany hairdressers leave their profession due to health problems, including occupational hand eczema, which has been associated with skin exposure to sensitising hair dye components such as paraphenylenediamine (PPD) and...

An Open-Label Drug–Drug Interaction Study of the Steady-State Pharmacokinetics of Topiramate and Glyburide in Patients with Type 2 Diabetes Mellitus

Topiramate is approved for epilepsy and migraine headache management and has potential antidiabetic activity. Because topiramate and antidiabetic drugs may be co-administered, the potential drug-drug interactions between topiramate and glyburide (glibenclamide), a commonly used sulfonylurea antidiabetic agent, was evaluated at steady state in patients with type 2 diabetes mellitus (T2DM). This was a single-center, open-label, phase I, drug interaction study of topiramate (150 mg/day) and glyburide (5 mg/day alone and concomitantly) in patients with T2DM. The study consisted of 14-day screening, 48-day open-label treatment, and a 7-day follow-up phase. Serial blood and urine were obtained and analyzed by liquid chromatography coupled mass spectrometry/mass spectrometry for topiramate, glyburide, and its active metabolites M1 (4-trans-hydroxy-glyburide) and M2 (3-cis-hydroxy-glyburide) concentrations. Pharmacokinetic parameters were estimated by model-independent methods. Changes in fasting plasma glucose from baseline and safety parameters were monitored throughout the study. Of 28 enrolled patients, 24 completed the study. Co-administration of topiramate resulted in a significant (p < 0.05) decrease in the glyburide area under the concentration-time curve (25 %) and maximum plasma concentration (22 %), and reduction in systemic exposure of M1 (13 %) and M2 (15 %). Renal clearance of M1 (13 %) and M2 (12 %) increased during treatment with topiramate. Steady-state pharmacokinetics of topiramate were unaffected by co-administration of glyburide. Co-administration of topiramate and glyburide was generally tolerable in patients with T2DM. Glyburide did not affect the pharmacokinetics of topiramate. Co-administration of topiramate decreased systemic exposure of glyburide and its active metabolites; combined treatment may require dosing adjustments of glyburide as per clinical judgment and glycemic control.

Effects of Lepidium sativum, Nigella sativa and Trigonella foenum‐graceum on Phenytoin Pharmacokinetics in Beagle Dogs

The present work was designed to evaluate the effect of some commonly used herbs viz. garden cress (Lepidium sativum), black seed (Nigella sativa) and fenugreek (Trigonella foenum-graceum) on the disposition of phenytoin after oral administration in a dog model. Phenytoin was given orally at a dose of 50 mg, and blood samples were obtained for the determination of drug's pharmacokinetic parameters. After a suitable washout period, animals were commenced on a specific herb treatment for one week. Garden cress treatment caused a modest increase in maximum observed concentration (Cmax ) and terminal half-life (T1/2λ ) of phenytoin with a reduction in clearance by 33%. The effect of black seed therapy was more drastic on drug elimination and to a lesser extent on its volume of distribution at steady state (Vss ) with a consequent reduction in systemic exposure measured by area under the curve (AUC0-∞ ) by about 87%. The effect of fenugreek therapy resembled, albeit to a lesser extent, that of black seed with a significant reduction in AUC0-∞ by ~72%. In addition, there was a 73% increase in Vss . Our findings suggest that the phenytoin disposition can be significantly altered by the concurrent consumption of tested herbal products.

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase‐4 inhibitor, in healthy subjects

To investigate the effect of co-administration of rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) and pharmacodynamics (PD) of saxagliptin and 5-hydroxy saxagliptin in healthy subjects. Saxagliptin is metabolized by CYP3A4/3A5 to 5-hydroxy saxagliptin, its major pharmacologically active metabolite. In a non-randomized, open label, single sequence design, 14 healthy subjects received single oral doses of saxagliptin 5 mg with and without steady-state rifampicin (600 mg once daily for 6 days). PK (saxagliptin and 5-hydroxy saxagliptin) and PD (plasma DPP-4 activity) were measured for up to 24 h on days 1 and 7. Concomitant administration with rifampicin resulted in 53% (point estimate 0.47, 90% CI 0.38, 0.57) and 76% (point estimate 0.24, 90% CI 0.21, 0.27) decreases in the geometric mean C(max) and AUC values of saxagliptin, respectively, with a 39% (point estimate 1.39, 90% CI 1.23, 1.56) increase in the geometric mean C(max) and no change (point estimate 1.03, 90% CI 0.97, 1.09) in the AUC of 5-hydroxy saxagliptin. Similar maximum % inhibition and area under the % inhibition-time effect curve over 24 h for DPP-4 activity were observed when saxagliptin was administered alone or with rifampicin. The saxagliptin total active moieties exposure (AUC) decreased by 27% (point estimate 0.73, 90% CI 0.66, 0.81). Saxagliptin with or without rifampicin in this study was generally well tolerated. Lack of change of PD effect of saxagliptin is consistent with the observed 27% reduction in systemic exposure to the total active moieties, which is not considered clinically meaningful. Based on these findings, it is not necessary to adjust the saxagliptin dose when co-administered with rifampicin.

Novel microbially triggered colon specific delivery system of 5-Fluorouracil: Statistical optimization, in vitro, in vivo, cytotoxic and stability assessment

The present study aimed to statistically optimize a colon specific formulation of 5-Fluorouracil for the treatment of colon cancer. A 3 2 full factorial design was used for optimization. The independent variables employed were amount of pectin and amount of starch paste, each at three levels. The evaluated responses were hardness, percent cumulative drug release (% CDR) at 5th h and t 90% (time required for 90% of drug release). Drug release studies were carried out using change over media [pH 1.2, 7.4 and 6.5 in presence of 4% (w/v) rat caecal contents]. The optimized formulation was subjected to in vivo roentgenographic studies in New Zealand white rabbits to analyze the in vivo behaviour of the developed tablets. This formulation was also evaluated for cytotoxic potential using HT-29 human colon cancer cell lines. Pharmacokinetic studies in New Zealand white rabbits were conducted to determine the extent of systemic exposure provided by the developed formulation in comparison to an immediate release tablet. The optimized formulation consisting of pectin (66.67%, w/w) and starch paste (15%, w/w) released negligible amount of drug at pH 1.2 and pH 7.4 whereas significant ( p < 0.05) drug release was observed at pH 6.5 in presence of 4% (w/v) rat caecal contents. Roentgenographic studies corroborated the in vitro observations, thus providing the “proof of concept”. Pharmacokinetic studies revealed significant reduction in systemic exposure and cytotoxicity studies demonstrated enhanced cellular uptake of drug by the developed formulation. Shelf life of the formulation was found to be 2.83 years. The results of the study established pectin-based coated matrix tablet to be a promising system for the colon specific delivery of 5-FU so as to treat colon carcinoma.

Phospholipid binding improves plasma survival of factor VIII

Phospholipid binding improves plasma survival of factor VIII

Effect of eslicarbazepine acetate on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy subjects during a three-stage, open-label, multiple-dose, single-period study

Background: The anticoagulant warfarin, which is administered as a racemic mixture of R- and S-enantiomers, has been reported to interact with other drugs, including some antiepileptics. Eslicarbazepine acetate (ESL) is a once-daily voltage-gated sodium channel blocker that has been developed for the treatment of partial epilepsy and other indications. Objective: The aim of this work was to investigate whether multiple-dose administration of ESL had any effect on the steady-state pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers stabilized on warfarin at a subtherapeutic level. Methods: Subjects received ESL 1200 mg once daily for 8 days concomitantly with racemic warfarin, the dose of which had been individually optimized to a stable prothrombin international normalized ratio (INR) of 1.3 to 1.8 during a previous run-in phase (up to 21 days). Coadministration of ESL and warfarin was followed by a 7-day recovery period when warfarin was again administered alone. The effects of ESL on the steady-state pharmacokinetics of R- and S-warfarin and on the INR were assessed. For the R- and S-warfarin assay, blood sampling was to occur at stage 1 (run-in period), 3 days before starting ESL dosing; stage 2 (combined treatment period), on days 1 and 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 4, 6, and 7 at predose; and stage 3 (after the combined treatment period) on days 3, 5, and 7 predose, and on day 8 at 24 hours after the final warfarin dose. For determination of INR, blood sampling was to occur at stage 2 on days 1, 2, 4, 6, 7, and 8 at predose; and at stage 3 on days 1, 3, 5, and 7 at predose and on day 8 at 24 hours after the final warfarin dose. For the assay of the racemic mixture of the S- and the R-enantiomers (eslicarbazepine and R-licarbazepine), blood sampling was to occur at stage 2 on day 8 at predose and 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours postdose, and on days 2, 4, 6, and 7 at predose. C max and AUC 0-t were defined as primary pharmacokinetic parameters. Tolerability was evaluated by monitoring adverse events, clinical laboratory safety tests, vital signs, and 12-lead ECG. Results: Of the 15 subjects enrolled, 13 (7 men and 6 women) completed the study. The mean (SD) age was 28.1 (7.3) years (range, 20–42 years), mean weight was 67.3 (10.7) kg (range, 54.0–84.4 kg), and 14 subjects (93.3%) were white. Reductions in S-warfarin C max (test:reference geometric means ratio [GMR] = 0.81 [90% CI, 0.76 to 0.86] and in S-warfarin AUC ss (test:reference GMR = 0.77 [90% CI, 0.72 to 0.82]) were observed, without any clinically relevant changes in the INR. The mean INR was 1.45 (0.10) when warfarin was used alone in stage 1 (control) and 1.51 (0.25) when ESL was added to warfarin in stage 2. In relation to stage 1, a slight mean INR increase of 4.04% [90% CI, 1.03% to 9.12%] was reported in stage 2. In stage 3, following discontinuation of ESL administration, a change of −5.42% in the INR was found [90% CI, −8.85% to −1.98%]. ESL was not associated with any clinically relevant changes in R-warfarin pharmacokinetic parameters. No deaths, serious adverse events, or discontinuations due to adverse events were noted, and no clinically relevant findings were reported for the other safety variables. During the course of the study, 9 subjects (60%) reported a total of 32 adverse events. Catheter-site ecchymosis, venipuncturesite hematoma, dizziness, vasovagal reaction, and adhesive-tape allergy were the most common adverse events reported. During coadministration of ESL and warfarin, 7 subjects reported a total of 17 adverse events, of which 6 (epigastric discomfort, asthenia, dizziness, lipothymia, irritability, and macular rash) were considered possibly related to treatment; only lipothymia reached moderate intensity, and all symptoms subsided without sequelae after ESL was discontinued. Conclusions: In this short-term study in healthy subjects, coadministration of warfarin and ESL 1200 mg once daily was associated with a small, but statistically significant, reduction in systemic exposure to S-warfarin. There was no statistically significant effect on R-warfarin pharmacokinetics or on coagulation as measured by the INR. Protocol identifier: UFH/BIA-2093-108.

Passive Transfer of Polyethylene Glycol to Liposomal-Recombinant Human FVIII Enhances its Efficacy in a Murine Model for Hemophilia A

The replacement therapy using recombinant human FVIII (rFVIII) is the first line of therapy for hemophilia A. Approximately 15-30% of the patients develop inhibitory antibodies. Recently, we reported that liposomes composed of phosphatidylserine (PS) could reduce the immunogenicity of rFVIII. However, PS containing liposomal-rFVIII is likely to reduce the systemic exposure and efficacy of FVIII due to rapid uptake of the PS containing liposomes by the reticuloendothelial system (RES). Here, we investigated whether phosphatidylserine (PS) liposomes containing Polyethylene glycol (PEG) (PEGylated), could reduce the immunogenicity of rFVIII and reverse the reduction in systemic exposure of rFVIII. Animals given PEGylated liposomal-rFVIII had lower total and inhibitory anti-rFVIII antibody titers, compared to animals treated with rFVIII alone. The mean stimulation index of CD4+ T-cells from animals given PEGylated liposomal-rFVIII also was lower than for animals that were given rFVIII alone. Pharmacokinetic studies following intravenous dosing indicated that the systemic exposure (area under the activity curve, AUAC(0-24h)) of PEGylated liposomal-rFVIII was approximately 59 IU/mL x h and significantly higher than that of non-PEGylated liposomal-rFVIII (AUAC(0-24h) approximately 36 IU/mL x h). Based on these studies, we speculate that PEGylated PS-containing liposomal rFVIII may improve efficacy of rFVIII.

Design and evaluation of a novel series of 2,3-oxidosqualene cyclase inhibitors with low systemic exposure, relationship between pharmacokinetic properties and ocular toxicity

We describe the discovery of novel potent inhibitors of 2,3-oxidosqualene:lanosterol cyclase inhibitors (OSCi) from a focused pharmacophore-based screen. Optimization of the most tractable hits gave a series of compounds showing inhibition of cholesterol biosynthesis at 2 mg/kg in the rat with distinct pharmacokinetic profiles. Two compounds were selected for toxicological study in the rat for 21 days in order to test the hypothesis that low systemic exposure could be used as a strategy to avoid the ocular side effects previously described with OSCi. We demonstrate that for this series of inhibitors, a reduction of systemic exposure is not sufficient to circumvent cataract liabilities.

Identification of an alginate-based formulation of paraquat to reduce the exposure of the herbicide following oral ingestion

The herbicide paraquat has been widely used throughout the world for almost 50 years and is important in sustainable agriculture. When used correctly the chemical poses no known risk to human health. However, it is acutely toxic, and can be fatal, if the concentrated product is ingested orally. Despite many years of research there is no successful treatment for paraquat intoxication. In recent years we have turned our attention to understanding how we can make the product safer, if it is accidentally or intentionally consumed. We present in this paper a novel approach aimed at safening the paraquat product, Gramoxone. Following our previous research on the site and mechanism of paraquat absorption from the gastrointestinal tract we have identified a new formulation of paraquat, Gramoxone INTEON ® that reduces the absorption of paraquat into the blood. This new formulation contains the polysaccharide, alginate, a natural product extracted from sea-weed. We have designed a preparation of paraquat and alginate with surfactants that is herbicidally active but has the unique property that it gels on contact with gastric acid in the stomach. The resulting mixture slows the dispersion and delivery of the toxic chemical to its site of absorption in the small intestine. Alginates also protect the mucosa against the damaging influence of topical gastric irritants, like paraquat. Our studies have shown that increasing the loading of alginate between 7 and 17 g/L causes a dose-related reduction in paraquat absorption in vitro in isolated rat ileum. This is also observed in vivo, as measured by paraquat plasma kinetics in the rabbit where the Area Under Curve (AUC 0–24 h) was reduced from 33.8 ± 3 for Gramoxone to 12.5 ± 6 (μg/mL) h for a formulation containing 17 g/L alginate. Such a reduction in systemic exposure to paraquat is expected to reduce the acute oral toxicity of the formulation. This should be particularly effective in a vomiting species such as man since we have shown in this investigation that alginates not only reduce the peak plasma paraquat values but also delay the time to peak levels. This provides the opportunity for a more effective emetic response since the highly viscous gelled material should remain in the stomach for longer than the liquid Gramoxone. Further research is required to understand and optimise the safening and herbicidal characteristics of these alginate acid-triggered gel formulations of paraquat. However, we anticipate that this alginate technology in Gramoxone INTEON ® could have significant benefit in reducing human mortalities associated with the herbicide.

Pulmonary targeting of sustained release formulation of budesonide in neonatal rats

Systemic corticosteroids are widely used for the treatment/prevention of chronic lung disease (CLD) in premature infants. The use of the inhalation route for delivering corticosteroids has been widely recognized, however so far pre-term babies continue to be treated with oral glucocorticoids, such as dexamethasone. We hypothesize that the pulmonary administration of sustained release formulations of inhaled corticosteroids to pre-term infants will result in a higher benefit/risk ratio as compared to traditional inhalation therapy. To achieve a slow release formulation budesonide particles were coated with a very thin film of polylactic acid using a pulse laser ablation technique. Coated material was characterized with respect to the dissolution behavior and particle size. Ex vivo receptor binding studies were performed to monitor the cumulative lung, liver and brain receptor occupancies after adminstration in neonatal (10–11 days old) rats after intratracheal instillation of either uncoated budesonide or poly (l-lactic acid) (PLA) coated budesonide. The mean dissolution timed for the uncoated and the polymer coated formulations were 1.2 ± 0.5 and 4.7 ± 0.1 h, respectively (p < 0.05). No significant differences in the respirable fraction were found between coated and uncoated formulation (p>0.05). The average receptor occupancies in the lung, liver and brain after administration of uncoated budesonide were 58.4 ± 12.9, 56.4 ± 6.8 and 38.3 ± 6.7%, respectively. However, after administration of PLA coated budesonide, the average AUC estimates in the lung, liver and brain were 75.8 ± 3.7%, 46.6 ± 14.5 and 29 ± 7, respectively. The results from our study suggest sustained receptor occupancy in the lungs of neonatal rats after administration of PLA coated budesonide results in lower systemic exposure (as indicated by low liver receptor occupancy). The data strongly underscore the urgent need to develop sustained release pulmonary-targeted delivery systems of corticosteroids for the treatment of CLD in pre-term infants. The administration of inhaled corticosteroids using targeted drug-delivery systems will potentially result in higher local effects and a reduction in systemic exposure.

Effect of rifampin on the pharmacokinetics of SU11248 in healthy volunteers

3078 Background: SU11248 is a novel oral multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activity that specifically inhibits platelet derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and stem-cell factor receptor (c-kit). SU11248 is metabolized by CYP3A4 to an equipotent metabolite SU12662, which is further metabolized by CYP34A. SU11248 exposure could consequently decrease if it is co-administered with drugs that induce CYP3A4. Methods: This was an open-label two-way crossover drug-interaction study in healthy male subjects to assess the pharmacokinetics (PK) of SU11248 with and without rifampin (RMP), a potent CYP3A4 inducer. The study also compared the PK of SU11248 in Caucasian and Asian males with and without CYP3A4 induction by RMP. Thirteen Caucasian and 13 Japanese subjects were initially randomized to either Treatment A (1 x 50 mg SU11248, PO) or Treatment B (RMP 600 mg/day PO for 17 days, combined with 50 mg SU11248, PO on day 8 only) with a 2-week washout between treatments. Results: CYP3A4 induction with RMP caused a 4-fold reduction in SU11248 plasma exposure (AUClast and AUC0-∞) and a 2.5-fold reduction in SU11248 plasma Cmaxcompared with SU11248 alone in both ethnic groups. A 1.4-fold increase in SU12662 AUC was observed after CYP3A4 induction with RMP. SU11248 and SU12662 PK results after treatment either with SU11248 alone or with SU11248 plus RMP were similar in Caucasian and Japanese subjects. Conclusions: The reduction in systemic exposure of SU11248 when co-administered with RMP indicates that concomitant treatment with potent CYP3A4 inducers should be avoided when SU11248 is used in patients with cancer. The similarity of SU11248 PK in Caucasian and Japanese subjects supports a common starting dose and schedule of SU11248 in these populations. No significant financial relationships to disclose.

Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients.

Dyslipidaemia is more frequent in solid organ transplant recipients than in the general population, primarily as a result of immunosuppressive drug treatment. Both cyclosporin and corticosteroids are associated with dyslipidaemic adverse effects. In order to reduce the overall cardiovascular risk in these patients, lipid-lowering drugs have become widely used, especially HMG-CoA reductase inhibitors (statins). Cyclosporin, as well as most statins (lovastatin, simvastatin, atorvastatin and pravastatin) are metabolised by cytochrome P450 (CYP)3A4, so a bilateral pharmacokinetic interaction between these drugs is theoretically possible. However, results from several studies show that statins do not induce increased systemic exposure of cyclosporin. A small (but not clinically relevant) reduction in systemic exposure of cyclosporin has actually been shown in many studies. Cyclosporin-treated patients on the other hand show several-fold higher systemic exposure of all statins, both those that are metabolised by CYP3A4 and fluvastatin (metabolised by CYP2C9). Therefore, the mechanism for this interaction does not seem to be solely caused by inhibition of CYP3A4 metabolism, but it is probably also a result of inhibition of statin-transport in the liver, at least in part. Other lipid-lowering drugs, such as fibric acid derivatives, bile acid sequestrants, probucol, fish oils and orlistat are also used in solid organ transplant recipients. Most of them do not interact with cyclosporin, but there are reports indicating that both probucol and orlistat may reduce cyclosporin bioavailablility to a clinically relevant degree. There is no information on possible interaction effects of cyclosporin on the pharmacokinetics of lipid-lowering drugs other than statins, but it is not likely that any clinical relevant interference exists with fish oil, orlistat, probucol or bile acid sequestrants.

The effect of food on the bioavailability of oral gemifloxacin in healthy volunteers

The effect of food on the bioavailability of gemifloxacin was investigated at two doses (320 and 640 mg) in healthy male and female volunteers. A total of 21 subjects entered the open label, four-period crossover study. Each subject received single oral doses of 320 and 640 mg in the fasted state and after a high fat meal, on separate dosing occasions in a randomised fashion. There was on average, a 3% (95% CI (0.88,1.07)) and 12% (95% CI (0.79,0.97)) reduction in AUC and a 12% (95% CI (0.76, 1.02) and 14% (0.75, 1.00) reduction in C max after the 320- and 640-mg doses, respectively. The results indicate a minor effect of food on bioavailability of gemifloxacin (320 and 640 mg). Such a reduction in systemic exposure would be considered to be not clinically relevant. T max data were inconclusive but indicated a possible slight delay in T max of, on average, 0.75 and 0.21 h after the 320- and 640-mg doses, respectively. Delays of this magnitude in reaching maximum concentrations are unlikely to be of clinical importance for an antibiotic drug. Both 320 and 640 mg gemifloxacin were well tolerated in fed and fasted states by healthy volunteers. It can be concluded therefore, that gemifloxacin can be taken with and without food.