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Woodburn K.W.,Affymax Inc. | Woodburn K.W.,Aerospace Dap Therapeutics LLC | Fong K.-L.,Accellient Partners LLC | Wilson S.D.,Aclairo Pharmaceutical Development Group Inc. | And 6 more authors.
Drug Metabolism and Disposition | Year: 2013

Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Aungst B.J.,QPS LLC
AAPS Journal | Year: 2012

Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability. While at least one product utilizing an absorption enhancer for transdermal use has reached the market, quite a few more appear to be at the threshold of becoming products, and these include oral and transmucosal applications. This paper will review some of the most advanced absorption enhancers currently in development and the formulation technologies employed that have led to their success. In addition, a more basic review of the barriers to absorption and the mechanisms by which those barriers can be surmounted is presented. Factors influencing the success of absorption-enhancing formulations are discussed. If ultimately successful, the products now in development should offer non-injection alternatives for several peptide or protein drugs currently only administered by injection. The introduction of new absorption enhancers as accepted pharmaceutical excipients, and the development of formulation technologies that afford the greatest benefit/risk ratio for their use, may create opportunities to apply these enabling technologies more broadly to existing drugs with non-optimal delivery properties. © 2011 American Association of Pharmaceutical Scientists.


Solon E.G.,QPS LLC
Chemical Research in Toxicology | Year: 2012

Radioactivity has been used in drug discovery and development for several decades because it offers researchers a highly sensitive way to quantitatively assess the absorption, distribution, metabolism, and/or excretion (ADME) of chemical entities by incorporating a radioactive isotope into the structure of the drug molecule. Regulatory agencies around the world require drug makers to characterize the ADME properties of prospective new drugs as one way to help ensure that patients are not exposed to dangerous drug and/or drug metabolite levels before they can be approved for human use. Radiolabeled compounds have consistently proved to be the most efficient tool for determining that information, even though attempts have been made to use nonradioactive techniques. The techniques of quantitative whole-body autoradiography (QWBA) and microautoradiography (MARG), which rely on the use of radiolabeled drugs, are two techniques that are routinely used to examine tissue distribution of drugs in discovery and development. These techniques provide drug researchers with quantitative tissue concentration data and a visual location of those concentrations in intact organs, tissues, and cells of laboratory animals. It is important for readers to realize that these techniques visualize total radioactivity, which can include the parent molecule along with its metabolites, and/or degradation products or impurities. This requires investigators to treat the quantitative data with caution unless the identity of the radioactivity is determined using some type of other bioanalytical techniques, such as mass spectroscopy and/or radio-HPLC, which can be easily performed on the tissue obtained from the animals used for QWBA and/or MARG. Nevertheless, these data are used in drug discovery and development to answer questions related to tissue penetration, fetal/placental transfer, tissue retention, routes of elimination, drug-drug interactions, enzyme induction/inhibition, formulation comparisons, in vivo compound solubility, differential metabolite distribution, interspecies comparisons, and to predict human exposure to parent drugs, metabolites, and radiation during clinical studies. This review will consider the strategic use of WBA, QWBA, and MARG in the pharmaceutical industry. Case studies and anecdotal information will also be presented; however, readers should realize that these are general examples and that some details have been omitted for brevity and/or because the data is proprietary and could not be presented at this time. Nevertheless, the images and discussions are provided to demonstrate how the techniques can and have been used to examine in situ tissue distribution of therapeutic compounds. © 2012 American Chemical Society.


Lacy S.,Exelixis | Hsu B.,Exelixis | Miles D.,Genentech | Aftab D.,Exelixis | And 2 more authors.
Drug Metabolism and Disposition | Year: 2015

Metabolism and excretion of cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg cabozantinib L-malate containing 14C-cabozantinib (100 μCi/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N-oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 (Kiapp = 4.6 and 1.1 μM, respectively). In an in vitro drug transporter panel, cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 μM, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 μM, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both cabozantinib and EXEL-1644 may represent potential for drugdrug interactions. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.


Xue Y.-J.,Celgene | Gao H.,Vertex Pharmaceuticals | Ji Q.C.,Bristol Myers Squibb | Lam Z.,QPS LLC | And 5 more authors.
Bioanalysis | Year: 2012

Distribution of drugs into tissues is an important determinant of the overall PK and PD profile. Thus, bioanalysis of drugs and their metabolites in tissues can play an important role in understanding the pharmacological and toxicological properties of new drug candidates. Unlike liquid matrices, bioanalysis in tissues offers unique challenges such as proper tissue sampling, appropriate tissue sample preparation, efficient extraction of the analytes from the tissue homogenates, and demonstration of stability and recovery of analytes in intact tissues. This article provides a systematic review of tissue sample analysis for small molecules using LC-MS/MS. The authors provide rationale for tissue sample analysis, and discuss strategies for method development, method qualification or validation, and sample analysis. Unique aspects of method development and qualification/validation are highlighted based on authors' direct experiences and literature summary. Analysis using intact tissue samples such as MALDI imaging is also briefly discussed. © 2012 Future Science Ltd.


Solon E.G.,QPS LLC | Schweitzer A.,Novartis | Stoeckli M.,Novartis | Prideaux B.,Novartis
AAPS Journal | Year: 2010

Whole-body autoradiography ((WBA) or quantitative WBA (QWBA)), microautoradiography (MARG), matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI), and secondary ion mass spectrometric imaging (SIMS-MSI) are high-resolution, molecular imaging techniques used to study the tissue distribution of radiolabeled and nonlabeled compounds in ex vivo, in situ biological samples. WBA, which is the imaging of the whole-body of lab animals, and/or their organ systems; and MARG, which provides information on the localization of radioactivity in histological preparations and at the cellular level, are used to support drug discovery and development efforts. These studies enable the conduct of human radiolabeled metabolite studies and have provided pharmaceutical scientists with a high resolution and quantitative method of accessing tissue distribution. MALDI-MSI is a mass spectrometric imaging technique capable of label-free and simultaneous determination of the identity and distribution of xenobiotics and their metabolites as well as endogenous substances in biological samples. This makes it an interesting extension to WBA and MARG, eliminating the need for radiochemistry and providing molecular specific information. SIMS-MSI offers a complementary method to MALDI-MSI for the acquisition of images with higher spatial resolution directly from biological specimens. Although traditionally used for the analysis of surface films and polymers, SIMS has been used successfully for the study of biological tissues and cell types, thus enabling the acquisition of images at submicrometer resolution with a minimum of samples preparation. © 2009 American Association of Pharmaceutical Scientists.


1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions. 2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [ 14C]GTx-024 derived radioactivity was observed. [14C]GTx- 024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5mL/h/kg) and mean elimination half-life of 0.6h and 16.4h in male and female rats, respectively. 3. Fecal excretion was the predominant route of elimination, with ∼70% of total radioactivity recovered in feces and 21-25% in urine within 48h. Feces of intact rats contained primarily unchanged [ 14C]GTx-024 (49.3-64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8-12%) and the cyanophenol ring (M4, 1.3-1.5%), and glucuronidation of [14C]GTx-024 at the tertiary alcohol (M6, 3.5-3.7%). There was no quantifiable metabolite in plasma. 4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug. © 2013 Informa UK Ltd.


Solon E.G.,QPS LLC
Cell and Tissue Research | Year: 2015

The use of radiolabeled drug compounds offers the most efficient way to quantify the amount of drug and/or drug-derived metabolites in biological samples. Autoradiography is a technique using X- ray film, phosphor imaging plates, beta imaging systems, or photo-nuclear emulsion to visualize molecules or fragments of molecules that have been radioactively labeled, and it has been used to quantify and localize drugs in tissues and cells for decades. Quantitative whole-body autoradiography or autoradioluminography (QWBA) using phosphor imaging technology has revolutionized the conduct of drug distribution studies by providing high resolution images of the spatial distribution and matching tissue concentrations of drug-related radioactivity throughout the body of laboratory animals. This provides tissue-specific pharmacokinetic (PK) compartmental analysis which has been useful in toxicology, pharmacology, and drug disposition/patterns, and to predict human exposure to drugs and metabolites, and also radioactivity, when a human radiolabeled drug study is necessary. Microautoradiography (MARG) is another autoradiographic technique that qualitatively resolves the localization of radiolabeled compounds to the cellular level in a histological preparation. There are several examples in the literature of investigators attempting to obtain drug concentration data from MARG samples; however, there are technical issues which make that problematic. These issues will be discussed. This review will present a synopsis of both techniques and examples of how they have been used for drug research in recent years. © 2015, Springer-Verlag Berlin Heidelberg.


Human 14C-and 3H-radiolabeled drug studies are performed as part of drug development to determine human metabolism. Sponsors conducting the study must assure that human volunteers will not be subjected to dangerous radiation exposure from the radiolabeled drug. Several different mathematical methods to determine human dosimetry have been developed and are used by different pharmaceutical companies. Most often these studies have utilized organ homogenate data from animal studies. However, rodent quantitative whole-body autoradiography (QWBA) data, which provides true tissue concentrations, is now being used for dosimetry predictions. Anecdotal evidence suggested that different dosimetry methods provide different estimates. This study tested that hypothesis. Methods: rat tissue distribution data obtained from a QWBA 14C-drug study was utilized to estimate human 14C dosimetry using 3 different equations suggested by the FDA and the International Commission on Radiological Protection (ICRP)]. The results of the study showed that each method produced different dosimetry predictions. Moreover it demonstrated a need to revise the methods to utilize tissue concentration data, which is more precise than organ homogenate data. The benefits of a proper rodent study design and using tissue distribution data provided by QWBA vs. organ homogenate assays will also be discussed. Copyright © 2010 John Wiley & Sons, Ltd.


Historically, percutaneous absorption permeation parameters have been derived from in vitro infinite dose studies, yet there is uncertainty in their accuracy if the applied vehicle saturates or damages the stratum corneum, or when the permeation parameters are inappropriately derived from cumulative absorption data. An approach is provided for determining penetration parameters from in vitro finite dose data. Key variables, and equations for their derivation, are identified from the literature and provide permeation parameters that use only Tmax, AUC, and AUMC from finite dose data. The equations are tested with computer-generated model data and to actual study data. Derived permeation parameters obtained from the computer model data match those used in generating the simulated finite dose data. Parameters obtained from actual study data reasonably and acceptably model the penetration profile kinetics of the study data. From in vitro finite dose absorption data, three parameters can be obtained: the diffusion transit time (td), which characterizes the diffusion coefficient, the partition volume (VmP), which characterizes the partition coefficient, and the permeation coefficient (Kp). These parameters can be obtained from finite dose data without having to know the length of the diffusion pathway through the membrane. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

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