Rada Savic, PhD

Associate Professor

Department of Bioengineering and Therapeutic Sciences

[email protected]

Phone: +1 415 502-0640

1700 4th St, Rm 503C

UCSF Box 2552

San Francisco, CA 94158

United States

Links

Savic Lab

UCSF Profiles

Division of Clinical Pharmacology & Experimental Therapeutics

Educational programs

Pharmaceutical Sciences and Pharmacogenomics Graduate Program (PSPG)

What I do

I investigate the causes of variations in clinical outcomes, using computational methods. My goal is to determine the optimal dosage, timing, and duration of therapeutic regimens. Ultimately, I want to develop precise, personalized treatments.

Departmental research area

drug development and regulatory sciences

computational biology and systems pharmacology

My research expertise

pharmacometrics, precision dosing, clinical pharmacology, systems pharmacology, precision medicine, pharmacogenetics, translational sciences, nonlinear mixed effects models, infectious diseases, tuberculosis, malaria, HIV cure, developmental pharmacology, disease progression models, drug development, NONMEM, modeling and simulations, clinical trial design, pediatrics, pharmacokinetics, pharmacodynamics, data science

Degrees

PhD, Pharmacometrics, Uppsala University, Uppsala, Sweden, 2008

MS, Biomedical Sciences, Uppsala University, Uppsala, Sweden, 2004

BSc, Pharmacy, University of Belgrade, Serbia, 2003

Biography

My research uses computational methods to study the dynamic interplay between disease progression, drug and biomarker response across relevant scales (molecule, cell, tissue, organ & whole body) in order to determine causal links underlying variability in (safety and efficacy) clinical outcomes. By integrating multi-scale, and multi-level clinical data, we aim to determine the right dose, right schedule and right treatment duration of various therapies, potentially bringing novel, precise and personalized treatment options to patients with unmet need more quickly.

Research keywords

Multiple sclerosis, Pharmacometrics, Infectious diseases, quantitative pharmacology, Nonlinear mixed effects models, Disease progression models, Rifampin, Tuberculosis, Meningeal, Metformin, pharmacokinetics, Antibiotics, Antitubercular

News

Publications

Dooley KE, Hanna D, Mave V, Eisenach K, Savic RM. Advancing the development of new tuberculosis treatment regimens: The essential role of translational and clinical pharmacology and microbiology. PLoS Med. 2019 Jul; 16(7):e1002842.

Sarathy J, Blanc L, Alvarez-Cabrera N, O'Brien P, Dias-Freedman I, Mina M, Zimmerman M, Kaya F, Ho Liang HP, Prideaux B, Dietzold J, Salgame P, Savic RM, Linderman J, Kirschner D, Pienaar E, Dartois V. Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations. Antimicrob Agents Chemother. 2019 May; 63(5).

Strydom N, Gupta SV, Fox WS, Via LE, Bang H, Lee M, Eum S, Shim T, Barry CE, Zimmerman M, Dartois V, Savic RM. Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization. PLoS Med. 2019 Apr; 16(4):e1002773.

Lee SA, Elliott JH, McMahon J, Hartogenesis W, Bumpus NN, Lifson JD, Gorelick RJ, Bacchetti P, Deeks SG, Lewin SR, Savic RM. Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial. Clin Pharmacol Ther. 2019 Mar; 105(3):692-702.

Blanc L, Sarathy JP, Alvarez Cabrera N, O'Brien P, Dias-Freedman I, Mina M, Sacchettini J, Savic RM, Gengenbacher M, Podell BK, Prideaux B, Ioerger T, Dick T, Dartois V. Impact of immunopathology on the antituberculous activity of pyrazinamide. J Exp Med. 2018 Aug 06; 215(8):1975-1986.

Rifat D, Prideaux B, Savic RM, Urbanowski ME, Parsons TL, Luna B, Marzinke MA, Ordonez AA, DeMarco VP, Jain SK, Dartois V, Bishai WR, Dooley KE. Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data. Sci Transl Med. 2018 Apr 04; 10(435).

Wallender E, Vucicevic K, Jagannathan P, Huang L, Natureeba P, Kakuru A, Muhindo M, Nakalembe M, Havlir D, Kamya M, Aweeka F, Dorsey G, Rosenthal PJ, Savic RM. Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz. J Infect Dis. 2018 Mar 05; 217(6):964-972.

Guiastrennec B, Ramachandran G, Karlsson MO, Kumar AKH, Bhavani PK, Gangadevi NP, Swaminathan S, Gupta A, Dooley KE, Savic RM. Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications. Clin Pharmacol Ther. 2018 Oct; 104(4):733-741.

Savic RM, Novakovic AM, Ekblom M, Munafo A, Karlsson MO. Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis. Clin Pharmacokinet. 2017 10; 56(10):1245-1253.

Bartelink IH, Prideaux B, Krings G, Wilmes L, Lee PRE, Bo P, Hann B, Coppé JP, Heditsian D, Swigart-Brown L, Jones EF, Magnitsky S, Keizer RJ, de Vries N, Rosing H, Pawlowska N, Thomas S, Dhawan M, Aggarwal R, Munster PN, Esserman LJ, Ruan W, Wu AHB, Yee D, Dartois V, Savic RM, Wolf DM, van 't Veer L. Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors. Breast Cancer Res. 2017 Sep 11; 19(1):107.

Bartelink IH, Zhang N, Keizer RJ, Strydom N, Converse PJ, Dooley KE, Nuermberger EL, Savic RM. New Paradigm for Translational Modeling to Predict Long-term Tuberculosis Treatment Response. Clin Transl Sci. 2017 Sep; 10(5):366-379.

Savic RM, Weiner M, MacKenzie WR, Engle M, Whitworth WC, Johnson JL, Nsubuga P, Nahid P, Nguyen NV, Peloquin CA, Dooley KE, Dorman SE. Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials. Clin Pharmacol Ther. 2017 Aug; 102(2):321-331.

Nguyen TH, Mouksassi MS, Holford N, Al-Huniti N, Freedman I, Hooker AC, John J, Karlsson MO, Mould DR, Pérez Ruixo JJ, Plan EL, Savic R, van Hasselt JG, Weber B, Zhou C, Comets E, Mentré F. Model Evaluation of Continuous Data Pharmacometric Models: Metrics and Graphics. CPT Pharmacometrics Syst Pharmacol. 2017 02; 6(2):87-109.

Rizk ML, Zou L, Savic RM, Dooley KE. Importance of Drug Pharmacokinetics at the Site of Action. Clin Transl Sci. 2017 05; 10(3):133-142.

Jayakumar A, Savic RM, Everett CK, Benator D, Alland D, Heilig CM, Weiner M, Friedrich SO, Martinson NA, Kerrigan A, Zamudio C, Goldberg SV, Whitworth WC, Davis JL, Nahid P. Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure. J Clin Microbiol. 2016 12; 54(12):3028-3033.

Goswami S, Yee SW, Xu F, Sridhar SB, Mosley JD, Takahashi A, Kubo M, Maeda S, Davis RL, Roden DM, Hedderson MM, Giacomini KM, Savic RM. A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin. Clin Pharmacol Ther. 2016 Nov; 100(5):537-547.

Hibma JE, Zur AA, Castro RA, Wittwer MB, Keizer RJ, Yee SW, Goswami S, Stocker SL, Zhang X, Huang Y, Brett CM, Savic RM, Giacomini KM. The Effect of Famotidine, a MATE1-Selective Inhibitor, on the Pharmacokinetics and Pharmacodynamics of Metformin. Clin Pharmacokinet. 2016 06; 55(6):711-21.

Conde MB, Mello FC, Duarte RS, Cavalcante SC, Rolla V, Dalcolmo M, Loredo C, Durovni B, Armstrong DT, Efron A, Barnes GL, Marzinke MA, Savic RM, Dooley KE, Cohn S, Moulton LH, Chaisson RE, Dorman SE. A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis. PLoS One. 2016; 11(5):e0154778.

Bahr NC, Marais S, Caws M, van Crevel R, Wilkinson RJ, Tyagi JS, Thwaites GE, Boulware DR. GeneXpert MTB/Rif to Diagnose Tuberculous Meningitis: Perhaps the First Test but not the Last. Clin Infect Dis. 2016 May 01; 62(9):1133-5.

Gupta A, Mathad JS, Abdel-Rahman SM, Albano JD, Botgros R, Brown V, Browning RS, Dawson L, Dooley KE, Gnanashanmugam D, Grinsztejn B, Hernandez-Diaz S, Jean-Philippe P, Kim P, Lyerly AD, Mirochnick M, Mofenson LM, Montepiedra G, Piper J, Sahin L, Savic R, Smith B, Spiegel H, Swaminathan S, Watts DH, White A. Toward Earlier Inclusion of Pregnant and Postpartum Women in Tuberculosis Drug Trials: Consensus Statements From an International Expert Panel. Clin Infect Dis. 2016 Mar 15; 62(6):761-769.

Savic RM, Ruslami R, Hibma JE, Hesseling A, Ramachandran G, Ganiem AR, Swaminathan S, McIlleron H, Gupta A, Thakur K, van Crevel R, Aarnoutse R, Dooley KE. Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children. Clin Pharmacol Ther. 2015 Dec; 98(6):622-9.

Sundell K, Jagannathan P, Huang L, Bigira V, Kapisi J, Kakuru MM, Savic R, Kamya MR, Dorsey G, Aweeka F. Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children. Malar J. 2015 Sep 24; 14:368.

Via LE, Savic R, Weiner DM, Zimmerman MD, Prideaux B, Irwin SM, Lyon E, O'Brien P, Gopal P, Eum S, Lee M, Lanoix JP, Dutta NK, Shim T, Cho JS, Kim W, Karakousis PC, Lenaerts A, Nuermberger E, Barry CE, Dartois V. Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives. ACS Infect Dis. 2015 May 08; 1(5):203-214.

Long-Boyle JR, Savic R, Yan S, Bartelink I, Musick L, French D, Law J, Horn B, Cowan MJ, Dvorak CC. Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use. Ther Drug Monit. 2015 Apr; 37(2):236-45.

Dooley KE, Savic RM, Park JG, Cramer Y, Hafner R, Hogg E, Janik J, Marzinke MA, Patterson K, Benson CA, Hovind L, Dorman SE, Haas DW. Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers. Antimicrob Agents Chemother. 2015; 59(6):3399-405.

Bartelink IH, Savic RM, Dorsey G, Ruel T, Gingrich D, Scherpbier HJ, Capparelli E, Jullien V, Young SL, Achan J, Plenty A, Charlebois E, Kamya M, Havlir D, Aweeka F. The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. Pediatr Infect Dis J. 2015 Mar; 34(3):e63-70.

Dorman SE, Savic RM, Goldberg S, Stout JE, Schluger N, Muzanyi G, Johnson JL, Nahid P, Hecker EJ, Heilig CM, Bozeman L, Feng PJ, Moro RN, MacKenzie W, Dooley KE, Nuermberger EL, Vernon A, Weiner M. Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care Med. 2015 Feb 01; 191(3):333-43.

Sheffield JS, Siegel D, Mirochnick M, Heine RP, Nguyen C, Bergman KL, Savic RM, Long J, Dooley KE, Nesin M. Designing drug trials: considerations for pregnant women. Clin Infect Dis. 2014 Dec 15; 59 Suppl 7:S437-44.

Vreeman RC, Nyandiko WM, Liechty EA, Busakhala N, Bartelink IH, Savic RM, Scanlon ML, Ayaya SO, Blaschke TF. Impact of adherence and anthropometric characteristics on nevirapine pharmacokinetics and exposure among HIV-infected Kenyan children. J Acquir Immune Defic Syndr. 2014 Nov 01; 67(3):277-86.

Dooley KE, Luetkemeyer AF, Park JG, Allen R, Cramer Y, Murray S, Sutherland D, Aweeka F, Koletar SL, Marzan F, Bao J, Savic R, Haas DW. Phase I safety, pharmacokinetics, and pharmacogenetics study of the antituberculosis drug PA-824 with concomitant lopinavir-ritonavir, efavirenz, or rifampin. Antimicrob Agents Chemother. 2014 Sep; 58(9):5245-52.

Goswami S, Yee SW, Stocker S, Mosley JD, Kubo M, Castro R, Mefford JA, Wen C, Liang X, Witte J, Brett C, Maeda S, Simpson MD, Hedderson MM, Davis RL, Roden DM, Giacomini KM, Savic RM. Genetic variants in transcription factors are associated with the pharmacokinetics and pharmacodynamics of metformin. Clin Pharmacol Ther. 2014 Sep; 96(3):370-9.

Savic RM, Lu Y, Bliven-Sizemore E, Weiner M, Nuermberger E, Burman W, Dorman SE, Dooley KE. Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability. Antimicrob Agents Chemother. 2014 Jun; 58(6):3035-42.

Weiner M, Savic RM, Kenzie WR, Wing D, Peloquin CA, Engle M, Bliven E, Prihoda TJ, Gelfond JA, Scott NA, Abdel-Rahman SM, Kearns GL, Burman WJ, Sterling TR, Villarino ME. Rifapentine Pharmacokinetics and Tolerability in Children and Adults Treated Once Weekly With Rifapentine and Isoniazid for Latent Tuberculosis Infection. J Pediatric Infect Dis Soc. 2014 Jun; 3(2):132-45.

Bartelink IH, Savic RM, Mwesigwa J, Achan J, Clark T, Plenty A, Charlebois E, Kamya M, Young SL, Gandhi M, Havlir D, Cohan D, Aweeka F. Pharmacokinetics of lopinavir/ritonavir and efavirenz in food insecure HIV-infected pregnant and breastfeeding women in Tororo, Uganda. J Clin Pharmacol. 2014 Feb; 54(2):121-32.

Savic RM, Cowan MJ, Dvorak CC, Pai SY, Pereira L, Bartelink IH, Boelens JJ, Bredius RG, Wynn RF, Cuvelier GD, Shaw PJ, Slatter MA, Long-Boyle J. Effect of weight and maturation on busulfan clearance in infants and small children undergoing hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Nov; 19(11):1608-14.

Yee SW, Nguyen AN, Brown C, Savic RM, Zhang Y, Castro RA, Cropp CD, Choi JH, Singh D, Tahara H, Stocker SL, Huang Y, Brett CM, Giacomini KM. Reduced renal clearance of cefotaxime in asians with a low-frequency polymorphism of OAT3 (SLC22A8). J Pharm Sci. 2013 Sep; 102(9):3451-7.

Savic RM, Barrail-Tran A, Duval X, Nembot G, Panhard X, Descamps D, Verstuyft C, Vrijens B, Taburet AM, Goujard C, Mentré F. Effect of adherence as measured by MEMS, ritonavir boosting, and CYP3A5 genotype on atazanavir pharmacokinetics in treatment-naive HIV-infected patients. Clin Pharmacol Ther. 2012 Nov; 92(5):575-83.

Stocker SL, McLachlan AJ, Savic RM, Kirkpatrick CM, Graham GG, Williams KM, Day RO. The pharmacokinetics of oxypurinol in people with gout. Br J Clin Pharmacol. 2012 Sep; 74(3):477-89.

Crawford KW, Ripin DH, Levin AD, Campbell JR, Flexner C. Optimising the manufacture, formulation, and dose of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement. Lancet Infect Dis. 2012 Jul; 12(7):550-60.

Delattre M, Savic RM, Miller R, Karlsson MO, Lavielle M. Analysis of exposure-response of CI-945 in patients with epilepsy: application of novel mixed hidden Markov modeling methodology. J Pharmacokinet Pharmacodyn. 2012 Jun; 39(3):263-71.

Kang D, Bae KS, Houk BE, Savic RM, Karlsson MO. Standard Error of Empirical Bayes Estimate in NONMEM® VI. Korean J Physiol Pharmacol. 2012 Apr; 16(2):97-106.

Baverel PG, Savic RM, Karlsson MO. Two bootstrapping routines for obtaining imprecision estimates for nonparametric parameter distributions in nonlinear mixed effects models. J Pharmacokinet Pharmacodyn. 2011 Feb; 38(1):63-82.

Savic RM, Mentré F, Lavielle M. Implementation and evaluation of the SAEM algorithm for longitudinal ordered categorical data with an illustration in pharmacokinetics-pharmacodynamics. AAPS J. 2011 Mar; 13(1):44-53.

Savic RM, Karlsson MO. Evaluation of an extended grid method for estimation using nonparametric distributions. AAPS J. 2009 Sep; 11(3):615-27.

Savic R, Lavielle M. Performance in population models for count data, part II: a new SAEM algorithm. J Pharmacokinet Pharmacodyn. 2009 Aug; 36(4):367-79.

Savic RM, Karlsson MO. Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions. AAPS J. 2009 Sep; 11(3):558-69.

Baverel PG, Savic RM, Wilkins JJ, Karlsson MO. Evaluation of the nonparametric estimation method in NONMEM VI: application to real data. J Pharmacokinet Pharmacodyn. 2009 Aug; 36(4):297-315.

Petersson KJ, Hanze E, Savic RM, Karlsson MO. Semiparametric distributions with estimated shape parameters. Pharm Res. 2009 Sep; 26(9):2174-85.

Carlsson KC, Savic RM, Hooker AC, Karlsson MO. Modeling subpopulations with the $MIXTURE subroutine in NONMEM: finding the individual probability of belonging to a subpopulation for the use in model analysis and improved decision making. AAPS J. 2009 Mar; 11(1):148-54.

Savic RM, Kjellsson MC, Karlsson MO. Evaluation of the nonparametric estimation method in NONMEM VI. Eur J Pharm Sci. 2009 Apr 11; 37(1):27-35.

Wilkins JJ, Savic RM, Karlsson MO, Langdon G, McIlleron H, Pillai G, Smith PJ, Simonsson US. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Antimicrob Agents Chemother. 2008 Jun; 52(6):2138-48.

Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007 Oct; 34(5):711-26.

Karlsson MO, Savic RM. Diagnosing model diagnostics. Clin Pharmacol Ther. 2007 Jul; 82(1):17-20.

Hong EU, Savic RM and Yim DS. Population Pharmacokinetic Analysis of the Oral Absorption Process of Tacrolimus in Healthy Volunteers . Kor J Clin Pharmacol Ther. 2007; 15(2):117-126.

Osterberg O, Savic RM, Karlsson MO, Simonsson US, Nørgaard JP, Walle JV, Agersø H. Pharmacokinetics of desmopressin administrated as an oral lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults. J Clin Pharmacol. 2006 Oct; 46(10):1204-11.

Lindemalm S, Savic RM, Karlsson MO, Juliusson G, Liliemark J, Albertioni F. Application of population pharmacokinetics to cladribine. BMC Pharmacol. 2005 Mar 09; 5:4.

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