title: Balancing Blood Sample Volume with 3Rs: Implementation and Best Practices for Small Molecule Toxicokinetic Assessments in Rats.
abstract: 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.
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Harstad
authors.affiliation: 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.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Andaya
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Couch
authors.affiliation: 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.
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.affiliation: 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.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Messick
authors.affiliation: 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.
authors.forename: Trung
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: 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.
authors.forename: Michelle
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: 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.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tarrant
authors.affiliation: 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.
authors.forename: Shelly
authors.initials: S
authors.lastname: Zhong
authors.affiliation: 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.
authors.forename: Brian
authors.initials: B
authors.lastname: Dean
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001800:Blood Specimen Collection / Q000295:instrumentation / Q000379:methods*; D051381:Rats; D066007:Toxicokinetics
chemical_list: D015415:Biomarkers
keywords: GLP; bioanalysis; microsampling; plasma; rats; satellite; toxicokinetics