Publications by authors named "Michelle Schweiger"

14 Publications

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Complex formation of anti-VEGF-C with VEGF-C released during blood coagulation resulted in an artifact in its serum pharmacokinetics.

Pharmacol Res Perspect 2020 04;8(2):e00573

Preclinical and Translational Pharmacokinetics and Pharmacodynamics Department, Genentech, Inc., South San Francisco, CA, USA.

A phage-derived human monoclonal antibody against VEGF-C was developed as a potential anti-tumor therapeutic and exhibited fast clearance in preclinical species, with notably faster clearance in serum than in plasma. The purpose of this work was to understand the factors contributing to its fast clearance. In vitro incubations in animal and human blood, plasma, and serum were conducted with radiolabeled anti-VEGF-C to determine potential protein and cell-based interactions with the antibody as well as any matrix-dependent recovery dependent upon the matrix. A tissue distribution study was conducted in mice with and without heparin infusion in order to identify a tissue sink and determine whether heparin could affect antibody recovery from serum and/or plasma. Incubation of radiolabeled anti-VEGF-C in human and animal blood, plasma, or serum revealed that the antibody formed a complex with an endogenous protein, likely VEGF-C. This complex was trapped within the blood clot during serum preparation from blood, but not within the blood cell pellet during plasma preparation. Low level heparin infusion in mice slowed down clot formation during serum preparation and allowed for better recovery of the radiolabeled antibody in serum. No tissue sink was found in mice. Thus, during this characterization, we determined that the blood sampling matrix greatly impacted the amount of antibody recovered in the samples, therefore, altering its derived pharmacokinetic parameters. Target biology should be considered when selecting appropriate sampling matrices for PK analysis.
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http://dx.doi.org/10.1002/prp2.573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053556PMC
April 2020

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology.

AAPS J 2018 10 8;20(6):107. Epub 2018 Oct 8.

Preclinical and Translational Pharmacokinetics, Genentech Research and Early Development, South San Francisco, California, 94080, USA.

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (V), interstitial volumes (V), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. In addition, whole-body blood volumes (BV) were determined across species. The results demonstrate that V, V, and Q, measured using our methods scale approximately by body weight across mouse, rat, and monkey in the tissues considered here, where allometric analysis allowed extrapolation to human parameters. Significant differences were observed between the values determined in this study and those reported in the literature, including V in muscle, brain, and skin and Q in muscle, adipose, heart, thymus, and spleen. The impact of these differences for selected tissues was evaluated via sensitivity analysis using a physiologically based pharmacokinetic model. The blood-brain barrier in monkeys was shown to be more impervious to an infused radioactive tracer, indium-111-pentetate, than in mice or rats. The body weight-normalized total BV measured in monkey agreed well with previously measured value in rats but was lower than that in mice. These findings have important implications for the common practice of scaling physiological parameters from rodents to primates in translational pharmacology.
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http://dx.doi.org/10.1208/s12248-018-0264-zDOI Listing
October 2018

Balancing Blood Sample Volume with 3Rs: Implementation and Best Practices for Small Molecule Toxicokinetic Assessments in Rats.

ILAR J 2016 12;57(2):157-165

Eric Harstad, PhD, DABT, and Jessica Couch, PhD, DABT, are senior scientists and therapeutic area leaders in the Department of Safety Assessment, Genentech, Inc. in South San Francisco, CA. Roxanne Andaya, BS, is a toxicology analyst in the Department of Safety Assessment, Genentech, Inc. Xiao Ding, PhD, Xiaorong Liang, PhD, and Bianca Liederer, PhD, are senior scientists in the Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc. Kirsten Messick, BS, and Trung Nguyen, BS, are scientific managers in the Department of Safety Assessment, Genentech, Inc. Michelle Schweiger, BS, LATG, is a group leader in the Department of Safety Assessment, Genentech, Inc. Jacqueline Tarrant, BVSc, PhD, DACVP, is a senior scientist in the Department of Safety Assessment, Genentech, Inc. Shelly Zhong, BS, is a senior study monitor in the Department of Safety Assessment, Genentech, Inc. Brian Dean, PhD, is a Director of Bioanalytical Sciences in the Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc.

Improved small molecule bioanalytical sensitivity and concomitant decreased sample volume requirements provide an opportunity to reconsider how toxicokinetic (TK) data are collected in rat toxicity studies. Often, satellite groups of rats are designated to separate procedural effects of TK blood collection from the primary toxicity evaluation. Blood microsampling (i.e., ≤50 μL) decreases the blood volume collected such that TK samples can be collected from toxicity groups without impacting toxicity assessment. Small plasma sampling uses slightly higher blood volumes (i.e., 200 μL) with comparable technical feasibility and, importantly, allows multiple analyses with no negative impact on study interpretation. Our "base case" study designs utilize sparse TK sampling from sample toxicity group rats (1-2 samples/rat). Alternate designs with satellite animals may still be warranted based on study objectives (e.g., biomarkers), intolerability, or smaller rat strains; however, we propose these as exceptions rather than standard practice and with a focus to use the fewest animals possible. We review the state of knowledge in bioanalytical and blood sampling techniques and support the paradigm whereby TK sampling of main study animals significantly decreases the overall number of rats required for toxicity assessments and refines study interpretation with additional data options. These efforts maintain a commitment to the 3Rs (replacement, reduction, and refinement) while maintaining high-quality TK evaluations on toxicity studies.
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http://dx.doi.org/10.1093/ilar/ilw023DOI Listing
December 2016

45,X/46,XY Mosaicism and Possible Association With Hypothyroidism in Males.

Clin Pediatr (Phila) 2016 Jun 20;55(6):549-51. Epub 2015 Aug 20.

Cleveland Clinic, Cleveland, OH, USA.

Mosaicism has a wide phenotypic spectrum but frequently manifests as the normal male phenotype. Its association with short stature has been well recognized and appears to respond effectively to growth hormone therapy. We present 2 phenotypically normal males who both initially presented with short stature and were found to have hypothyroidism. They were treated for hypothyroidism but their growth did not improve as expected. Further testing revealed 45,X/46,XY mosaicism in both males. We propose that a potential link exists between 45,X/46,XY mosaicism and hypothyroidism, which has not been previously described in the literature. Furthermore, it may be beneficial to evaluate for other disorders such as 45,X/46,XY mosaicism in young males with short stature and hypothyroidism if their growth does not improve once they become euthyroid.
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http://dx.doi.org/10.1177/0009922815600439DOI Listing
June 2016

Postinjection Muscle Fibrosis from Lupron.

Case Rep Pediatr 2015 25;2015:938264. Epub 2015 May 25.

Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA ; Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.

We describe the case of a 6.5-year-old girl with central precocious puberty (CPP), which signifies the onset of secondary sexual characteristics before the age of eight in females and the age of nine in males as a result of stimulation of the hypothalamic-pituitary-gonadal axis. Her case is likely related to her adoption, as children who are adopted internationally have much higher rates of CPP. She had left breast development at Tanner Stage 2, adult body odor, and mildly advanced bone age. In order to halt puberty and maximize adult height, she was prescribed a gonadotropin releasing hormone analog, the first line treatment for CPP. She was administered Lupron (leuprolide acetate) Depot-Ped (3 months) intramuscularly. After her second injection, she developed swelling and muscle pain at the injection site on her right thigh. She also reported an impaired ability to walk. She was diagnosed with muscle fibrosis. This is the first reported case of muscle fibrosis resulting from Lupron injection.
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http://dx.doi.org/10.1155/2015/938264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458552PMC
June 2015

A Case of Primary and Secondary Adrenal Insufficiency in Children.

Clin Pediatr (Phila) 2016 Mar 19;55(3):304-7. Epub 2015 Jun 19.

Cleveland Clinic Children's, Cleveland, OH, USA

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http://dx.doi.org/10.1177/0009922815591895DOI Listing
March 2016

Comparative physiology of mice and rats: radiometric measurement of vascular parameters in rodent tissues.

Mol Pharm 2014 May 21;11(5):1591-8. Epub 2014 Apr 21.

Genentech Research and Early Development , South San Francisco 94080, United States.

A solid understanding of physiology is beneficial in optimizing drug delivery and in the development of clinically predictive models of drug disposition kinetics. Although an abundance of data exists in the literature, it is often confounded by the use of various experimental methods and a lack of consensus in values from different sources. To help address this deficiency, we sought to directly compare three important vascular parameters at the tissue level using the same experimental approach in both mice and rats. Interstitial volume, vascular volume, and blood flow were radiometrically measured in selected harvested tissues of both species by extracellular marker infusion, red blood cell labeling, and rubidium chloride bolus distribution, respectively. The latter two parameters were further compared by whole-body autoradiographic imaging. An overall good interspecies agreement was observed for interstitial volume and blood flow on a weight-normalized basis in most tissues. In contrast, the measured vascular volumes of most rat tissues were higher than for mouse. Mice and rats, the two most commonly utilized rodent species in translational drug development, should not be considered as interchangeable in terms of vascular volume per gram of tissue. This will be particularly critical in biodistribution studies of drugs, as the amount of drug in the residual blood of tissues is often not negligible, especially for biologic drugs (e.g., antibodies) having long circulation half-lives. Physiologically based models of drug pharmacokinetics and/or pharmacodynamics also rely on accurate knowledge of biological parameters in tissues. For tissue parameters with poor interspecies agreement, the significance and possible drivers are discussed.
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http://dx.doi.org/10.1021/mp400748tDOI Listing
May 2014

Solvent-based formulations for intravenous mouse pharmacokinetic studies: tolerability and recommended solvent dose limits.

Xenobiotica 2014 Mar 18;44(3):235-41. Epub 2013 Oct 18.

Department of Safety Assessment .

1. Modern high-throughput small molecule drug discovery requires rapid screening of the pharmacokinetic parameters of multiple candidate molecules in parallel. The mouse is often used for such screening, as are solvent-based intravenous formulations. Despite this, the intravenous toxicity of many commonly used solvents is unknown. The purpose of this investigation is to establish recommended no-observed-effect level (NOEL) and maximum tolerated dose (MTD) for several commonly used intravenous solvents in the CD-1 mouse. 2. The acute tolerability of polyethylene glycol 400, N-methylpyrrolidone, dimethyl sulfoxide, ethanol, dimethylacetamide and propylene glycol was established, along with combinations of polyethylene glycol 400 and/or ethanol and DMSO. Based on these data, an acute NOEL and recommended MTD is reported for each solvent or solvent combination. 3. These data can guide the use of these solvents to support single-dose intravenous pharmacokinetic studies in mice. By establishing a defined dose tolerability range for the most commonly used intravenous solvents, undue pain and distress in animals can be avoided while maximizing the generation of critical pharmacokinetic data for project teams.
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http://dx.doi.org/10.3109/00498254.2013.845706DOI Listing
March 2014

Vascular physiology and protein disposition in a preclinical model of neurodegeneration.

Mol Pharm 2013 May 25;10(5):1514-21. Epub 2013 Feb 25.

Preclinical and Translational Pharmacokinetics, Genentech Research and Early Development, South San Francisco, California 94080, United States.

The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration. A transgenic mouse model of amyotrophic lateral sclerosis was selected based on a phenotype resembling clinical symptoms, including loss of motor neurons from the spinal cord and paralysis in one or more limbs, due to expression of a G93A mutant form of human superoxide dismutase (SOD1). The tissue distributions of two proteins, albumin and a representative immunoglobulin G antibody, as well as two blood flow markers, the lipophilic blood flow marker Ceretec (i.e., (99m)Tc-HMPAO) and the polar ionic tracer, rubidium-86 chloride ((86)RbCl), were measured following intravenous injection in SOD1(G93A) and age-matched control mice. The radiopharmaceutical TechneScan PYP was also used to measure the distribution of (99m)Tc-labeled red blood cells as a blood pool marker. Both the antibody and (86)Rb were able to cross the blood-spinal cord barrier in SOD1(G93A) mice to a greater extent than in control mice. Although the biodistribution patterns of antibody, albumin, and RBCs were largely similar, notable differences were detected in muscle and skin. Moreover, vastly different biodistribution patterns were observed for a lipophilic and polar perfusion agent, with SOD1(G93A) mutation resulting in reduced renal filtration rates for the former but not the latter. Overall, the multiprobe strategy provided an opportunity to efficiently collect an abundance of physiological information, including the degree and regional extent of blood-CNS barrier permeability, in a preclinical model of neurodegeneration.
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http://dx.doi.org/10.1021/mp3004786DOI Listing
May 2013

Evaluation of dried blood spot sampling following cassette dosing in drug discovery.

Bioanalysis 2011 Oct;3(20):2291-302

Drug Metabolism & Pharmacokinetics, Genentech Inc., South San Francisco, CA 94080, USA.

Background: Dried blood spot (DBS) sampling has received growing interest mainly in regulatory preclinical and clinical studies while not routinely used in exploratory discovery pharmacokinetic screening. An intravenous bolus cassette dose of six compounds in rats followed by hemolyzed blood sample (HBS) and DBS sampling was evaluated in this study.

Results: A sensitive liquid chromatography tandem mass spectrometry method was developed and qualified for the simultaneous determination of six compounds in rat whole blood using DBS or HBS techniques. The concentrations obtained from DBS samples matched well with those from HBS for each individual compound.

Conclusion: This study demonstrated the applicability of DBS sampling for cassette dosing in discovery pharmacokinetics screening.
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http://dx.doi.org/10.4155/bio.11.205DOI Listing
October 2011

Effects of anti-VEGF on predicted antibody biodistribution: roles of vascular volume, interstitial volume, and blood flow.

PLoS One 2011 Mar 15;6(3):e17874. Epub 2011 Mar 15.

Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Inc., South San Francisco, California, United States of America.

Background: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences.

Methodology/principal Findings: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay. Anti-VEGF had no significant effect (p>0.05) on the fractional vascular volumes of any tissues studied; these findings were further supported by single photon emission computed tomographic imaging. In addition, apart from a borderline significant increase (p = 0.048) in mean hepatic blood flow, no significant anti-VEGF-induced differences were observed (p>0.05) in two additional physiological parameters, interstitial fluid volume and the organ blood flow rate, measured using indium-111-pentetate and rubidium-86 chloride, respectively. Areas under the concentration-time curves generated by a physiologically-based pharmacokinetic model changed substantially (>25%) in several tissues when model parameters describing compartmental volumes and blood flow rates were switched from literature to our experimentally derived values. However, negligible changes in predicted tissue exposure were observed when comparing simulations based on parameters measured in naïve versus anti-VEGF-administered mice.

Conclusions/significance: These observations may foster an enhanced understanding of anti-VEGF effects in murine tissues and, in particular, may be useful in modeling antibody uptake alone or in combination with anti-VEGF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017874PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060062PMC
March 2011

Effect of immune complex formation on the distribution of a novel antibody to the ovarian tumor antigen CA125.

Drug Metab Dispos 2010 Dec 7;38(12):2309-19. Epub 2010 Sep 7.

Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, CA, USA.

3A5 is a novel antibody that binds repeated epitopes within CA125, an ovarian tumor antigen that is shed into the circulation. Binding to shed antigen may limit the effectiveness of therapeutic antibodies because of unproductive immune complex (IC) formation and/or altered antibody distribution. To evaluate this possibility, we characterized the impact of shed CA125 on the in vivo distribution of 3A5. In vitro, 3A5 and CA125 were found to form ICs in a concentration-dependent manner. This phenomenon was then evaluated in vivo using quantitative whole-body autoradiography to assess the tissue distribution of (125)I-3A5 in an orthotopic OVCAR-3 tumor mouse model at different stages of tumor burden. Low doses of 3A5 (75 μg/kg) and pathophysiological levels of shed CA125 led to the formation of ICs in vivo that were rapidly distributed to the liver. Under these conditions, increased clearance of 3A5 from normal tissues was observed in mice bearing CA125-expressing tumors. Of importance, despite IC formation, 3A5 uptake by tumors was sustained over time. At a therapeutically relevant dose of 3A5 (3.5 mg/kg), IC formation was undetectable and distribution to normal tissues followed that of blood. In contrast, increased levels of radioactivity were observed in the tumors. These data demonstrate that CA125 and 3A5 do form ICs in vivo and that the liver is involved in their uptake. However, at therapeutic doses of 3A5 and clinically relevant CA125 levels, IC formation consumes only a minor fraction of 3A5, and tumor targeting seems to be unaffected.
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http://dx.doi.org/10.1124/dmd.110.034330DOI Listing
December 2010

Development and evaluation of a novel method for preclinical measurement of tissue vascular volume.

Mol Pharm 2010 Oct 12;7(5):1848-57. Epub 2010 Aug 12.

Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Research and Early Development, South San Francisco, CA 94080, USA.

Identification of clinically predictive models of disposition kinetics for antibody therapeutics is an ongoing pursuit in drug development. To encourage translation of drug candidates from early research to clinical trials, clinical diagnostic agents may be used to characterize antibody disposition in physiologically relevant preclinical models. TechneScan PYP was employed to measure tissue vascular volumes (V(v)) in healthy mice. Two methods of red blood cell (RBC) labeling were compared: a direct in vivo method that is analogous to a clinical blood pool imaging protocol, and an indirect method in which radiolabeled blood was transfused from donor mice into recipient mice. The indirect method gave higher precision in RBC labeling yields, lower V(v) values in most tissues, and lower (99m)Tc uptake in kidneys and bladder by single photon emission computed tomographic (SPECT) imaging relative to the direct method. Furthermore, the relative influence of each method on the calculated area under the first 7 days of the concentration-time curve (AUC(0-7)) of an IgG in nude mice was assessed using a physiologically based pharmacokinetic model. The model was sensitive to the source of V(v) values, whether obtained from the literature or measured by either method, when used to predict experimental AUC(0-7) values for radiolabeled trastuzumab in healthy murine tissues. In summary, a novel indirect method for preclinical determination of V(v) offered higher precision in RBC labeling efficiency and lower renal uptake of (99m)Tc than the direct method. In addition, these observations emphasize the importance of obtaining accurate physiological parameter values for modeling antibody uptake.
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http://dx.doi.org/10.1021/mp100183kDOI Listing
October 2010
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