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Abstracts from the 11th American Conference on Pharmacometrics ACoP11 ISSN 2688-3953 ACoP11, November 9 – 13, 2020 Individual abstracts will be posted online post meeting. For citation purposes please use the following Citation: Author names, Abstract title, ACoP11, ISSN:2688-3953, 2020, Vol 2 TUE- 001 Updated Review of Vancomycin Population Pharmacokinetic Analyses in Adults Abdullah Aljutayli1, Amélie Marsot2,3, and Fahima Nekka1,4,5 1 Faculty of Pharmacy, Université de Montréal, Montréal, Canada 2Laboratoire de suivi thérapeutique pharmacologique et pharmacocinétique, Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada. 3Centre de recherche, CHU Sainte-Justine, Montréal, Québec, Canada 4 Laboratoire de Pharmacométrie, Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada. 5Centre de recherches mathématiques, Université de Montréal, Montréal, Québec, Canada. Background: Vancomycin is a drug of choice in the management of methicillin-resistant Staphylococcus aureus (MRSA) infections. Nonetheless, vancomycin optimal dosage regimens have, long, been controversial owing to the large between- and within-subject variability in its population pharmacokinetic (PopPK) profile. Objectives: Our primary aim was to better inform vancomycin dosing by providing a comprehensive synthesis of PopPK analyses of vancomycin to determine the most reported models, including the various sources of variability. Methods: Systematic search for vancomycin PopPK studies was conducted on PubMed and EMBASE with a time limit from January of 2011 to May of 2019. In addition, we inspected all relevant lists of references. Results: Thirty analyses met the research criteria and were included in this review. One-compartment and two- compartment models best-described vancomycin PopPK in thirteen and fourteen studies, respectively. Further, three- compartment models were implemented in three studies to account for an additional cite of administration, i.e. in cerebrospinal fluids. Common reported covariates were creatinine clearance and bodyweight (Table 1). Estimated clearance (CL) and total volume of distribution (Vd) varied widely between the studies, ranging from 0.334 to 8.75 L/h (0.0054 to 0.1279 L/h/kg) and from 7.12 to 501.8 L (0.097-6.97 L/kg), respectively. An exponential interindividual variability model was used in almost all the studies, and the highest inter-individual variability on CL and Vd were 99.2% and 101%, respectively. Conclusion: We outlined the wide range of vancomycin parameter estimates and the covariates retained in thirty different PopPK models developed in adults. This information might help guide the clinical dosing of vancomycin in different subpopulations. Table 1. Summary of recurrent and significant covariates including their frequencies on CL and Vd Covariate PK Parameter 1 1 CL Vd Creatinine clearance 19 None Bodyweight 3 12 Age 3 5 Hemodialysis 3 None Fat free mass None 1 1Frequency TUE-002 Pharmacokinetic Modeling and Simulation to Inform Dosing Regimen Selection for BIO 300 After Subcutaneous Administration in Irradiated and Non-Irradiated C57BL/6J Mice Ahmed M. Salem1, Isabel L. Jackson2, Michael D. Kaytor 3, Artur A. Serebrenik3, Zeljko Vujaskovic2, Jogarao Gobburu1, Mathangi Gopalakrishnan1 1Center for Translational Medicine, Department of Pharmacy Practice, University of Maryland School of Pharmacy, Baltimore, Maryland 2Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland 3Humanetics Corporation, Edina, Minnesota OBJECTIVES: BIO 300, a nanosuspension of genistein, is being developed in accordance to the FDA animal rule for the prevention and treatment of the delayed effects of acute radiation exposure (DEARE). A likely mechanism for radioprotection by BIO 300 is the activation of estrogen receptor beta (ERβ). Previous research indicated that activation of ERβ requires an EC50 at least 24 ng/ml. The analysis objectives were to: (i) develop a pharmacokinetic (PK) model describing the disposition of BIO 300 in C57BL/6J mice following subcutaneous administration, (ii) perform PK simulations of multiple dosing to identify dose levels that are safe, therapeutic and do not cause significant drug accumulation. An optimistic EC50 threshold of 24 ng/ml and a conservative EC50 threshold of 240 ng/ml were explored as steady state Ctrough targets. METHODS: The PK analysis included 162 genistein serum concentrations from 162 sex-matched C57BL/6J mice following single subcutaneous administration of 100 or 200 mg/kg in non-irradiated mice or 200 mg/kg in 14.5 Gy total body irradiated mice with 2.5% bone marrow sparing. The data from irradiated and non-irradiated mice were pooled together as the radiation effect on PK was minimal to none from prior non-compartmental analysis (NCA). Each animal contributed to one of the PK sampling times between 0.5 to 72 hours’ post-dose with triplicate measurements per time point. Hence, the naïve-pooled approach was used to estimate the mean PK parameters. The final PK model and the estimated mean parameters were used to simulate the following dosing scenarios: 25 mg/kg to 200 mg/kg every 12, 24, 48 or 72 hours at steady state. The analysis was performed using Pumas v0.10.0 (www.pumas.ai). RESULTS: A two compartment PK model with first-order absorption and linear elimination adequately described the mean concentration time-profile of BIO 300. The maximum concentration occurred at 0.5 hours. The mean apparent volume of central and peripheral compartments was 40227 ml/kg and 107030 ml/kg, respectively indicating extensive distribution of genistein due to high lipophilicity. Consistent with a previous NCA, the mean value of apparent systemic clearance was 3873 ml/hr/kg. All the simulated dosing scenarios maintained steady state Ctrough levels above the EC50 target of 24 ng/ml. However, only the regimens of 200 mg/kg dose, twice daily and daily regimens of 50 mg/kg - 100 mg/kg were able to meet the Ctrough levels above the EC50 target of 240 ng/ml. CONCLUSIONS: Assuming a conservative EC50 target of 240 ng/ml and adequate safety, 50 mg/kg to 200 mg/kg daily subcutaneous doses would meet efficacy targets and avoid excessive fluctuation in concentrations. Given a possibility of dose disproportionality at 200 mg/kg or higher, possible dose levels that could effectively activate ERβ and be administered consecutively for several weeks are 50 mg/kg – 150 mg/kg administered daily subcutaneously. TUE-003 Stimulation of erythropoiesis with ESA or blood donation: QSP model. Alexander Stepanov1, Galina Lebedeva2 1InSysBio, Moscow, Russia; 2InSysBio UK Ltd, Edinburgh, UK Objectives: Erythropoiesis-stimulating agents (ESAs) enhance the red blood cells (RBC) formation by bone marrow. They are used to manage anemic states caused by chemotherapy, bleeding, bone marrow’s malfunctions etc. To predict the effect of pharmacological intervention on hematopoiesis-related clinical endpoints we propose the QSP model of erythropoiesis. Methods: Multi-compartment ODE model of erythropoiesis was constructed to comprehensively describe cell dynamics from hematopoietic stem cell to circulating red cells. The model includes variables corresponding to specific stages of cell development distinguished based on morphology and surface markers expression. Model processes are cell self-renewal, differentiation, proliferation, migration from bone marrow into circulation and cell death. Binding of erythropoietin (EPO) and stem cell factor (SCF) to cell-surface receptors regulates cell dynamics with feedback on the receptor expression modulated by interleukine-3 (IL-3). Regulation effects of EPO were implemented via explicit description of EPO binding to its receptor followed by internalization leading to acceleration of cell proliferation and differentiation, and inhibition of apoptosis. Hypoxia-Inducible Factor (HIF) stabilizers (Roxadustat, Desidustat, Daprodustat and Molidustat) included in the model prevent the degradation of HIF, thereby inducing synthesis of EPO mRNA. Upregulation of EPO contributes to a negative feedback on HIF degradation through increased hemoglobin production. The model was calibrated across published in vitro/in vivo data including cell expansion under growth factors exposure in vitro, flow cytometry cell counting of bone marrow aspirates and clinical data of ESAs’ administration such as epoetins and HIF stabilizers. The QSP model was implemented in Heta language https://hetalang.github.io. Modeling files were transformed to SBML, DBSolveOptimum and Simbiology format using Heta-compiler [1]. Results: Data-driven model satisfactorily describes baseline levels of various cell precursors of erythroid branch in bone marrow and RBC in circulation of healthy subjects. The response of clinical outcomes such as reticulocytes count, erythropoietin and hemoglobin levels to administration of growth factors (epoetins, SCF and IL-3) as well as HIF stabilizers (Roxadustat, Desidustat, Daprodustat and Molidustat) were also well described by the model. The model was validated on the data for erythropoiesis recovery after blood donation. Conclusions: The proposed comprehensive human erythropoiesis QSP model describes clinical data and could be seen as predictive tool for investigation of potential pharmacological interventions including epoetins and HIF stabilizers, and explanation of observed phenomena. The model is regarded as a branch of developing a general platform of human hematopoiesis. [1]