Large Volume Of Distribution Research Articles

Pharmacokinetics of macrolactin A and 7-O-succinyl macrolactin A in mice

1. As promising anti-macular degeneration and/or anti-tumour agents, a better understanding of the pharmacokinetics of macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA) is essential. Thus, we evaluated the pharmacokinetics of MA and SMA after intravenous, oral, or intraperitoneal administration of each drug to mice.2. Both hepatic and extra-hepatic extractions of MA were expected based on the rapid total body clearance (CL) of MA. MA also showed a large steady-state volume of distribution (Vss) in mice. A relatively slower CL (by 54.1%) and smaller Vss (by 85.8%) were observed for SMA than for MA. In accordance with the larger Vss values of MA than of SMA, the mouse tissues studied had good affinity to MA but less affinity to SMA.3. Both MA and SMA had an extremely low oral extent of absolute bioavailability (F). This could have been a result of the instability of MA and SMA in the gastrointestinal tract, supported by their unstable property in acidic buffer. Gastrointestinal and/or hepatic first-pass extraction of MA and SMA may be other reasons.4. The pharmacokinetic profiles of both MA and SMA were much improved (greater AUC and F values) following intraperitoneal administration than following oral administration due to avoidance of acidic degradation and/or gastrointestinal first-pass extraction.

Phase I Pharmacokinetic and Pharmacodynamic Study of the First-in-Class Spliceosome Inhibitor E7107 in Patients with Advanced Solid Tumors

To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m(2) were explored. Forty patients [24M/16F, median age 61 years (45-79)] were enrolled. At 4.5 mg/m(2), dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m(2), DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m(2), one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m(2). No complete or partial responses during treatment were observed; one patient at 4.0 mg/m(2) had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. The MTD for E7107 using this schedule is 4.0 mg/m(2). Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107.

Influence of neuropathology on convection-enhanced delivery in the rat hippocampus.

Local drug delivery techniques, such as convention-enhanced delivery (CED), are promising novel strategies for delivering therapeutic agents otherwise limited by systemic toxicity and blood-brain-barrier restrictions. CED uses positive pressure to deliver infusate homogeneously into interstitial space, but its distribution is dependent upon appropriate tissue targeting and underlying neuroarchitecture. To investigate effects of local tissue pathology and associated edema on infusate distribution, CED was applied to the hippocampi of rats that underwent electrically-induced, self-sustaining status epilepticus (SE), a prolonged seizure. Infusion occurred 24 hours post-SE, using a macromolecular tracer, the magnetic resonance (MR) contrast agent gadolinium chelated with diethylene triamine penta-acetic acid and covalently attached to albumin (Gd-albumin). High-resolution T1- and T2-relaxation-weighted MR images were acquired at 11.1 Tesla in vivo prior to infusion to generate baseline contrast enhancement images and visualize morphological changes, respectively. T1-weighted imaging was repeated post-infusion to visualize final contrast-agent distribution profiles. Histological analysis was performed following imaging to characterize injury. Infusions of Gd-albumin into injured hippocampi resulted in larger distribution volumes that correlated with increased injury severity, as measured by hyperintense regions seen in T2-weighted images and corresponding histological assessments of neuronal degeneration, myelin degradation, astrocytosis, and microglial activation. Edematous regions included the CA3 hippocampal subfield, ventral subiculum, piriform and entorhinal cortex, amygdalar nuclei, middle and laterodorsal/lateroposterior thalamic nuclei. This study demonstrates MR-visualized injury processes are reflective of cellular alterations that influence local distribution volume, and provides a quantitative basis for the planning of local therapeutic delivery strategies in pathological brain regions.

Evaluating the Roles of Autophagy and Lysosomal Trafficking Defects in Intracellular Distribution-Based Drug-Drug Interactions Involving Lysosomes

Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs.

Pharmacokinetics and Metabolism of 4‐O‐Methylhonokiol in Rats

The purpose of this study was to characterize the pharmacokinetics and metabolism of 4-O-methylhonokiol in rats. The absorption and disposition of 4-O-methylhonokiol were investigated in male Sprague-Dawley rats following a single intravenous (2 mg/kg) or oral (10 mg/kg) dose. Its metabolism was studied in vitro using rat liver microsomes and cytosol. 4-O-Methylhonokiol exhibited a high systemic plasma clearance and a large volume of distribution. The oral dose gave a peak plasma concentration of 24.1±3.3 ng/mL at 2.9±1.9 h and a low estimated bioavailability. 4-O-Methylhonokiol was rapidly metabolized and converted at least in part to honokiol in a concentration-dependent manner by cytochrome P450 in rat liver microsomes, predicting a high systemic clearance consistent with the pharmacokinetic results. It was also shown to be metabolized by glucuronidation and sulfation in rat liver microsomes and cytosol, respectively. 4-O-Methylhonokiol showed a moderate permeability with no apparent vectorial transport across Caco-2 cells, suggesting that intestinal permeation process is not likely to limit its oral absorption. Taken together, these results suggest that the rapid hepatic metabolism of 4-O-methylhonokiol could be the major reason for its high systemic clearance and low oral bioavailability.

Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury

Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury

Pharmacokinetics of gamithromycin after intravenous and subcutaneous administration in broiler chickens

Gamithromycin is a new macrolide antibiotic that is only registered for use in cattle to treat respiratory disorders such as bovine respiratory disease. The aim of this study was to determine the pharmacokinetics of gamithromycin in broiler chickens. Gamithromycin (6 mg/kg of BW) was injected intravenously (IV) or subcutaneously (SC) to six 4-wk-old chickens in a parallel study design, and blood was collected at different time points postadministration. Quantification of gamithromycin in plasma was performed using an in-house validated liquid chromatography-tandem mass spectrometry method and the pharmacokinetics analyzed according to a 2-compartmental model. Following IV administration, the mean area under the plasma concentration-time curve (AUC0→∞), and α and β half-life of elimination (t1/2el α and t1/2el β) were 3,998 h•ng/mL, 0.90 h, and 14.12 h, respectively. Similar values were obtained after a SC bolus injection, i.e., 4,095 h•ng/mL, 0.34 h, and 11.63 h, for AUC0→∞, t1/2el α, and t1/2el β, respectively. The mean maximum plasma concentration (889.46 ng/mL) appeared at 0.13 h. Gamithromycin showed a large volume of distribution after IV as well as SC administration, 27.08 and 20.89 L/kg, respectively, and a total body clearance of 1.61 and 1.77 L/h•kg, respectively. The absolute bioavailability was 102.4%, showing that there is a complete absorption of gamithromycin after a SC bolus injection of 6 mg/kg of BW.

Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumors.

2521 Background: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases (Plk). Volasertib and afatinib, an irreversible ErbB family blocker, have shown single agent anti-tumor activity and manageable safety profiles in patients (pts) with advanced solid tumors. This dose escalation study was designed to determine the maximum tolerated dose (MTD) of two combination schedules of volasertib and afatinib in pts with advanced solid tumors refractory to or not amenable to standard therapy. Methods: In a 3 + 3 design, cohorts of 3–6 pts received volasertib 150–300 mg IV d1 Q3W + afatinib 30–50 mg PO QD d2–21 Q3W (Schedule A) or afatinib 50–90 mg d2–6 Q3W (Schedule B). Up to 12 additional pts were enrolled at the MTD. Primary endpoint was the MTD per schedule. Secondary endpoints included pharmacokinetics (PK), safety and efficacy (RECIST). Results: 57 pts (median 58 yr; ECOG PS 0/1/2: 35%/60%/5%) were treated (n=29, Schedule A; n=28, Schedule B). MTD was volasertib 300 mg/afatinib 30 mg (Schedule A) and volasertib 300 mg/afatinib 70 mg (Schedule B). Cycle 1 dose limiting toxicities (DLTs) were experienced by 5 (Schedule A) and 7 (Schedule B) pts. Most common DLTs were diarrhea (n=5), neutropenia (n=3), fatigue (n=2) and decreased ejection fraction (n=2) in Schedule A, and thrombocytopenia (n=6), neutropenia (n=5), diarrhea (n=4) and febrile neutropenia (n=3) in Schedule B. Most common grade 3/4 adverse events were neutropenia (n=8), thrombocytopenia (n=6), diarrhea (n=3) and febrile neutropenia (n=3). Volasertib exhibited multi-exponential PK behavior with a long half-life (130 hr), moderate clearance (900 mL/min) and large volume of distribution (Vss >6000 L). Co-administration of volasertib and afatinib had no effect on the PK profile of either drug. Two pts in Schedule A (volasertib 300 mg/afatinib 30 mg) achieved partial responses (tumor types: NSCLC, head and neck). Conclusions: MTD of volasertib was 300 mg Q3W combined with afatinib 30 mg d2-21 (Schedule A) or afatinib 70 mg d2-6 (Schedule B). Both agents could be combined at previously shown active single agent doses. At the MTD, treatment was manageable and showed preliminary anti-tumor activity. Clinical trial information: NCT01206816.

Pharmacokinetics, urinary excretion and plasma protein binding of ofloxacin in water buffalo calves (<i>Bubalus bubalis</i>)

Pharmacokinetics and urinary excretion of an intravenous dose of 5 mg.kg-1 ofloxacin were investigated in water buffalo calves. Plasma concentrations of ofloxacin were determined by high-performance liquid chromatography. Ofloxacin was rapidly distributed from the central to the peripheral compartment as evidenced by a short distribution half-life (0.09 h ± 0.003 h) and high K12 (4.7 h(-1) ± 0.1 h(-1)), and was detected in plasma for 8 h. The large volume of distribution (2.48 L.kg(-1) ± 0.18 L.kg(-1)) obtained in this study indicated high distribution of ofloxacin in water buffalo calves. The elimination half-life, the area under the plasma drug concentration-time curve and total body clearance were 2.11 h ± 0.13 h, 6.20 µg.mL(-1) ± 0.23 µg.mL(-1).h and 0.81 mL.kg(-1).h(-1) ± 0.03 mL.kg(-1).h(-1), respectively. About 18.7% of administered drug was bound to plasma proteins and approximately 32.5% of the administered dose was recovered in urine within 48 h. The results of the study indicated a favourable pharmacokinetic profile of ofloxacin in water buffalo calves, which suggests that ofloxacin may be effective against urinary pathogens in this species.

Telaprevir: Clinical Pharmacokinetics, Pharmacodynamics, and Drug–Drug Interactions

This article provides an unbiased review of the pharmacokinetic, pharmacodynamic, and drug-drug interaction data of telaprevir, an NS3/4A protease inhibitor. Telaprevir is well absorbed with fatty food, moderately protein bound (59-76%) with a large volume of distribution (~252L), primarily metabolized by cytochrome P450 (CYP) 3A4 and P-glycoprotein, and is largely excreted into feces. Pharmacokinetic and pharmacodynamic parameters are well described in healthy subjects and individuals infected with hepatitis C virus (HCV), although only limited data are available in specific patient subpopulations. Telaprevir is recommended to be given at 750mg by mouth every 8h for 12weeks, in combination with peginterferon and ribavirin (the standard care). The addition of telaprevir to the standard care regimen results in increased sustained virological response in treatment-naïve patients (30%) and treatment-experienced patients (up to 50%), and works synergistically to lower viral resistance. Telaprevir is a substrate and/or inhibitor of CYP3A4 and P-glycoprotein, and drug-drug interaction studies in humans have focused on these pathways. Based on our analysis, a few reported drug-drug interactions may be classified as clinically significant, but more experiments under dosing conditions that resemble those given in the clinic are needed to understand the relevance of some of the reported interactions. Future studies should focus on the pharmacokinetics/pharmacodynamics of telaprevir in special populations or patients with concomitant conditions that will likely co-exist with HCV infection, with an emphasis on establishing pharmacokinetic-pharmacodynamic relationships. In vitro characterization of other phase 1-3 metabolic pathways could assist in elucidating the mechanisms of the drug-drug interactions observed in humans.

Hemolytic and pharmacokinetic studies of liposomal and particulate amphotericin B formulations

Amphotericin B (AmB) is a very effective antifungal and antiparasitic drug with a narrow therapeutic window. To improve its efficacy/toxicity balance, new controlled release formulations have been developed based on different encapsulation systems, aggregation states and particle sizes modifications. The kinetics of the hemolytic process was studied not only to characterize the toxicity of different formulations but also as an indicator of drug release. Pharmacokinetic studies in beagle dogs were carried out with those formulations that exhibited the least hemolytic toxicity: liposomal formulation (AmBisome), poly-aggregated AmB and encapsulated particulate AmB formulation. A novel poly-aggregated AmB formulation proved to be comparable in terms of low hemolytic activity with the marketed gold standard formulation: AmBisome. Its pharmacokinetic profile, characterized by a smaller area under the curve and larger volume of distribution, was markedly different from AmBisome, resulting in a cost-effective alternative for the treatment of leishmaniasis which can enhance the AmB passive target by the uptake by the cells of the reticulo-endothelial system. Effects of different variables such as type of formulation, dose, microencapsulation, anesthesia and dog's healthy state on AmB pharmacokinetics were studied.

Nanoparticle-Based Passive Drug Targeting to Tumors: Considerations and Implications for Optimization

There are many potential barriers to the effective delivery of small-molecule drugs to solid tumors. Most small-molecule chemotherapeutic drugs have a large volume of distribution upon intravenous administration, which is often associated with a narrow therapeutic index due to their high level of toxicity in healthy tissues. Nanoparticle-based therapeutics for tumor targeting have emerged as one of the promising approaches to overcome the lack of tissue specificity of conventional chemotherapeutic drugs. Various different concepts have been envisioned for nanoparticle-mediated drug targeting. Among them, the passive drug targeting strategy has been the most widely investigated, and numerous preclinical studies have provided insights into the validity of the strategy. This review article briefly introduces our recent findings related to the passive drug targeting strategy including its application in anti-angiogenic therapy, along with considerations to be taken into account and implications for the rational design of a passive drug targeting strategy.

Pharmacokinetics Alterations of Midazolam Infusion versus Bolus Administration in Mechanically Ventilated Critically Ill Patients.

There is no randomized study carried out in order to compare their pharmacokinetic parameters although midazolam, as a sedative, has been widely administered via continuous infusion as well as intermittent bolus doses in mechanically ventilated critically ill patients. We prospectively investigated the effect of these two principal methods on pharmacokinetic parameters in 23 of mentioned patients (16 males, 7 females) with the mean (± SD) age of 41.22 ± 17.5. All patients received total dose of 72 mg throughout the test days, 9 of whom received 1 mg/h (continuous infusion) and the rest obtained 4 mg / 4 h (intermittent bolus doses). Blood samples were collected at 8 and 4 h prior to the end time of drug administration (zero time), zero time and 4, 8, 12, 20 and 30 h after it. APACHE (Acute Physiology and Chronic Health Evaluation) II required data was recorded daily and the patients' mean score was 16.26 ± 4.38. The mean (± SD) value of pharmacokinetic parameters of Midazolam in continuous infusion and intermittent bolus doses methods were as follows: (t½ = 17.88 ± 14.65 h, Cl = 21.80 ± 14.95 L/h) vs. (t½ = 19.74 ± 12.45 h, Cl = 29.43 ± 19.45 L/h). Volume of distribution (Vd) was measured in continuous infusion group which was 612.58 ± 582.93 L. The calculated clearance and half-life were found not to be significantly different (p < 0.05). The patients might be exposed to similar undesired effects due to the large volumes of distribution following the administration methods studied.

Medicinal Potential of Ciprofloxacin and Its Derivatives

Ciprofloxacin (CP) is a fluoroquinolone that is highly active against diverse microorganisms. At concentrations less than 1 µg/ml it is active against a diverse types of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Bacillius subtilius, Escherichia coli and Mycobacterium tuberculosis. In addition, it has shown to be effective against other diseases such as malaria, cancer and AIDS. The extended antimicrobial activity, lack of plasmid-mediated resistance, large volume of distribution and minimal adverse effects of CP are therapeutically advantageous. In the pursuit of increasing their effectiveness against these diseases and prevent unwanted resistance, researchers have begun to synthesize a class of organic, inorganic and organometallic derivatives, which have displayed interesting activities. This review describes the development and recent advances on the evaluation of CP and its derivatives as a new class of drugs with potential for clinical development.

Marqibo® (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine

Vincristine (VCR) is a mainstay of treatment of hematologic malignancies and solid tumors due to its well-defined mechanism of action, demonstrated anticancer activity and its ability to be combined with other agents. VCR is an M-phase cell cycle-specific anticancer drug with activity that is concentration and exposure duration dependent. The pharmacokinetic profile of standard VCR is described by a bi-exponential elimination pattern with a very fast initial distribution half-life followed by a longer elimination half-life. VCR also has a large volume of distribution, suggesting diffuse distribution and tissue binding. These properties may limit optimal drug exposure and delivery to target tissues as well as clinical utility as a single agent or as an effective component of multi-agent regimens. Vincristine sulfate liposome injection (VSLI), Marqibo®, is a sphingomyelin and cholesterol-based nanoparticle formulation of VCR that was designed to overcome the dosing and pharmacokinetic limitations of standard VCR. VSLI was developed to increase the circulation time, optimize delivery to target tissues and facilitate dose intensification without increasing toxicity. In xenograft studies in mice, VSLI had a higher maximum tolerated dose, superior antitumor activity and delivered higher amounts of active drug to target tissues compared to standard VCR. VSLI recently received accelerated FDA approval for use in adults with advanced, relapsed and refractory Philadelphia chromosome-negative ALL and is in development for untreated adult ALL, pediatric ALL and untreated aggressive NHL. Here, we summarize the nonclinical data for VSLI that support its continued clinical development and recent approval for use in adult ALL.

Removal of Dabigatran by Hemodialysis

Dabigatran is a newly available oral direct thrombin inhibitor approved for anticoagulation therapy to prevent strokes in patients with nonvalvular atrial fibrillation. Unlike warfarin, dabigatran's observed therapeutic window and minimal drug-to-drug interaction suggest that invasive laboratory testing and dose adjustment is not necessary. In circumstances of excessive anticoagulation, such as overdoses, decreased kidney function, or instances of significant bleeding, reversing dabigatran's effects may be necessary. Unlike warfarin, no rapid-acting antidote to reverse the effects of dabigatran is known. However, hemodialysis has been suggested as a method of removing dabigatran and thereby reducing its anticoagulant effect. We describe a case in which hemodialysis was used in an attempt to remove dabigatran in a patient with excessive anticoagulation from dabigatran and severe intracranial hemorrhage. Serial dabigatran levels suggested that hemodialysis removed the drug. However, given the large volume of distribution of dabigatran in the terminal phase of elimination, a rebound in drug level was noted. We suggest that a longer duration of therapy or more continuous modality of hemodialysis may be needed in conjunction with the initial hemodialysis treatment of dabigatran coagulopathy.

Chiral analytical method development and application to pre‐clinical pharmacokinetics of pinocembrin

An analytical method enabling the detection and quantification of the individual enantiomers of racemic (±) pinocembrin is required to fully characterize its pharmacokinetic disposition. Direct resolution of the enantiomers of pinocembrin was achieved using a novel and simple reversed-phase high-performance liquid chromatography method with electrospray ionization and detection by mass spectrometry in rat serum. A Chiralcel® AD-RH column was employed to perform baseline separation with electrospray positive-mode ionization with selected ion monitoring detection. The standard curves were linear from 0.5 to 100 µg/mL for each enantiomer. The limit of quantification was 0.5 µg/mL. The assay was applied successfully to stereoselective serum disposition of pinocembrin enantiomers in rats. Pinocembrin enantiomers were detected in serum. Both enantiomers had a serum half-life of ~15 min in rats. Similar values of volume of distribution between the enantiomers were also observed: 1.76 L/kg for S-pinocembrin and 1.79 L/kg for R-pinocembrin. Total clearance was 5.527 L//h/kg for S-pinocembrin and 5.535 L/h/kg for R-pinocembrin, and the area under the curve was 1.821 µg h/mL for S-pinocembrin and 1.876 µg h/mL for R-pinocembrin. The large volume of distribution coupled with the short serum half-life suggests extensive distribution of pinocembrin into the tissues.

Phase I/II Study of Volasertib (BI 6727), an Intravenous Polo-Like Kinase (Plk) Inhibitor, in Patients with Acute Myeloid Leukemia (AML): Results From the Randomized Phase II Part for Volasertib in Combination with Low-Dose Cytarabine (LDAC) Versus LDAC Monotherapy in Patients with Previously Untreated AML Ineligible for Intensive Treatment

AbstractAbstract 411 Background:LDAC is an established treatment option for patients (pts) with AML considered ineligible for intensive remission induction treatment. However, the outlook for pts who receive LDAC remains unsatisfactory, and novel therapeutic strategies are needed to improve clinical outcome in these pts.Plk1 plays a key role in mitosis and cell cycle progression and is an attractive target for novel therapeutic approaches in cancer. Volasertib (V) is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plks. The phase I part of this trial determined the maximum tolerated dose of V in combination with LDAC (V + LDAC) to be 350 mg and demonstrated antileukemic activity of V and V + LDAC in pts with relapsed/refractory AML ineligible for intensive therapy (Bug et al, ASH 2010 and 2011). Here we present preliminary phase II data for the randomized comparison of V + LDAC vs LDAC in pts with newly diagnosed AML ineligible for intensive treatment. Methods:In the phase II part of this open-label study, eligible pts were randomized to receive V (350 mg 1-hr intravenously, days 1, 15 Q4W) + LDAC (20 mg bid subcutaneously, days 1–10 Q4W), or LDAC alone until progression/relapse or intolerance. The primary endpoint was objective response (complete remission [CR] or CR with incomplete blood count recovery [CRi]); secondary endpoints included event-free survival (EFS), overall survival (OS), safety and pharmacokinetics (PK). Results:87 pts were treated with V + LDAC (n=42) or LDAC (n=45). Pt characteristics (V + LDAC/LDAC) were largely balanced: median age, 75/76 yrs; secondary AML, 40.5%/64.4%; adverse cytogenetic group, 35.7%/33.3%. At time of analysis (February 22 2012) 15 pts were still on treatment (12 with V + LDAC). Pts received a median (range) of 2 (1–12) cycles of V + LDAC and 2 (1–11) cycles with LDAC.A significantly greater proportion of pts who received V + LDAC achieved a CR or CRi compared with pts who received LDAC (31.0% vs 11.1%; odds ratio 3.59 [95% CI: 1.15, 11.18]; P = 0.0277), with a median (range) time to remission of 71 (29–158) days and 69 (34–125) days, respectively. Remissions with V + LDAC were observed across genetic groups, including pts with adverse cytogenetics.A trend for longer median EFS was observed for pts who received V + LDAC compared with those who received LDAC (HR 0.61 [95% CI: 0.35, 1.05]; P = 0.0725; Figure). Follow-up for OS was ongoing at the time of this analysis. Among pts achieving CR/CRi, only 2 had experienced recurrence or death at the time of analysis (1 in each arm after a remission duration of 57 [V + LDAC] or 67 [LDAC] days). For all other pts ongoing in remission, the remission duration was censored after 53–407 days (LDAC + V) or 32–282 days (LDAC), consistent with prolonged duration of remission in some pts. [Display omitted] The most frequent all grade adverse events (AEs) in the V + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%) and anemia (40.5%). In the LDAC arm, the most common all grade AEs were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), and constipation, asthenia and diarrhea (26.7% each). More pts who received V + LDAC experienced ≥ grade 3 AEs than those who received LDAC (95.2% vs 68.9%), particularly for blood and lymphatic system disorders (81.0% vs 44.4%), gastrointestinal disorders (21.4% vs 6.7%), and infections and infestations (45.2% vs 22.2%). The early death rates (V + LDAC/LDAC) at 30, 60 and 90 days were comparable between the two treatment arms: 30 days, 9.5%/8.9%; 60 days, 21.5%/17.8%; 90 days, 28.9%/33.4% (rates calculated using Kaplan-Meier method).PK analyses demonstrated that V is a moderate clearance drug with multi-compartmental PK behavior, a large volume of distribution and a long terminal half-life. Preliminary data suggest no drug-drug interactions following combination of V with LDAC. Conclusions:These preliminary phase II data demonstrate a significantly improved CR/CRi rate and a trend for EFS benefit with V + LDAC compared with LDAC alone in pts with newly diagnosed AML ineligible for intensive treatment. An increased frequency of AEs was observed with the addition of V, which was expected given its myelosuppressive mechanism of action; available data do not suggest increased early mortality for V + LDAC vs LDAC. A confirmatory phase III trial is needed to determine the clinical benefit of V + LDAC in pts with AML ineligible for intensive treatment. Disclosures:Off Label Use: Volasertib is an investigational agent. Fiedler:Pfizer, Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bug:Boehringer Ingelheim: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Müller-Tidow:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer-Ingelheim: Employment. Döhner:Celgene, Amgen, Ambit, Astellas, Lilly: Consultancy.

Stereospecific analytical method development and preliminary in vivo pharmacokinetic characterization of pinostrobin in the rat

The complete pharmacokinetic disposition of the chiral flavonoid (±) pinostrobin remains unknown without the development of an analytical method of detection and quantitation of its individual enantiomers. Resolution of the enantiomers of pinostrobin was achieved using as simple high-performance liquid chromatographic method. A Chiralpak(®) AD-RH column was employed to perform baseline separation with UV detection at 287 nm. The standard curves were linear ranging from 0.5 to 100 µg/mL for each enantiomer. The limit of quantification was 0.5 µg/mL. Precision and accuracy of the assay was < 15% (RSD) and was with a bias <15% for all points on the calibration curve. The assay was applied successfully to stereoselective serum disposition of pinostrobin enantiomers in rats. Both enantiomers had a serum half-life of ~7 h. They also shared similar values of volume of distribution (V(d) S-pinostrobin, 8.2 L/kg; V(d) R-pinostrobin, 8.9 L/kg), total clearance (S-pinostrobin CL(total), 0.959 L//h/kg; R-pinostrobin CL(total), 1.055 L//h/kg), and area under the curve (S-pinostrobin AUC(inf), 23.16 µg h/mL; R-pinostrobin AUC(inf), 21.296 µg h/mL). The large volume of distribution suggests extensive distribution of pinostrobin into tissues.

Pharmacology of riluzole in acute spinal cord injury

The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI). Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F). The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed. This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.