title: Individualizing liver transplant immunosuppression using a phenotypic personalized medicine platform.
abstract: Posttransplant immunosuppressive drugs such as tacrolimus have narrow therapeutic ranges. Inter- and intraindividual variability in dosing requirements conventionally use physician-guided titrated drug administration, which results in frequent deviations from the target trough ranges, particularly during the critical postoperative phase. There is a clear need for personalized management of posttransplant regimens to prevent adverse events and allow the patient to be discharged sooner. We have developed the parabolic personalized dosing (PPD) platform, which is a surface represented by a second-order algebraic equation with experimentally determined coefficients of the equation being unique to each patient. PPD uses clinical data, including blood concentrations of tacrolimus--the primary phenotypic readout for immunosuppression efficacy--to calibrate these coefficients and pinpoint the optimal doses that result in the desired patient-specific response. In this pilot randomized controlled trial, we compared four transplant patients prospectively treated with tacrolimus using PPD with four control patients treated according to the standard of care (physician guidance). Using phenotype to personalize tacrolimus dosing, PPD effectively managed patients by keeping tacrolimus blood trough levels within the target ranges. In a retrospective analysis of the control patients, PPD-optimized prednisone and tacrolimus dosing improved tacrolimus trough-level management and minimized the need to recalibrate dosing after regimen changes. PPD is independent of disease mechanism and is agnostic of indication and could therefore apply beyond transplant medicine to dosing for cancer, infectious diseases, and cardiovascular medicine, where patient response is variable and requires careful adjustments through optimized inputs.
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. azarrinpar@mednet.ucla.edu chihming@g.ucla.edu dean.ho@ucla.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Zarrinpar
authors.affiliation: Division of Oral Biology and Medicine and the Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Lee
authors.affiliation: Department of Mechanical Engineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Aleidy
authors.initials: A
authors.lastname: Silva
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Nakul
authors.initials: N
authors.lastname: Datta
authors.affiliation: Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Kee
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Calvin
authors.initials: C
authors.lastname: Eriksen
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Keri
authors.initials: K
authors.lastname: Weigle
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Vatche
authors.initials: V
authors.lastname: Agopian
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Fady
authors.initials: F
authors.lastname: Kaldas
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Farmer
authors.affiliation: Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Wang
authors.affiliation: Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Busuttil
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Mechanical Engineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA. azarrinpar@mednet.ucla.edu chihming@g.ucla.edu dean.ho@ucla.edu.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Ho
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Division of Oral Biology and Medicine and the Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California, Los Angeles, Los Angeles, CA 90095, USA. California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. azarrinpar@mednet.ucla.edu chihming@g.ucla.edu dean.ho@ucla.edu.
authors.forename: Dean
authors.initials: D
authors.lastname: Ho
mesh_terms: D016022:Case-Control Studies; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D016031:Liver Transplantation; D010641:Phenotype; D010820:Physicians; D057285:Precision Medicine; D011241:Prednisone / Q000494:pharmacology; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D011241:Prednisone; D016559:Tacrolimus