difference between pharmacology and clinical pharmacology

b, Using the 12 best-fitting parameter sets for each population and model simulations, we calculated the percentage of the T cell population at day 60 that is non-exhausted. Pharmacol. The cellular kinetics and anti-tumor dynamics of Kymriah. Epub 2016 Nov 5. Whether it is your first-in-human study, an exploratory biomarker study or a study needed for your NDA package, Labcorp scientists and clinicians carefully evaluate drug safety, tolerability and pharmacokinetics. 1974 Feb;50(2):163-75. doi: 10.1111/j.1476-5381.1974.tb08558.x. Some clinical pharmacologists will work in industry and contribute to drug discovery programmes. Patients cant wait and neither can we. 56). government site. Blood Adv. The reactome pathway knowledgebase 2022. For randomized control models, we randomly selected 2N6 pathways from the remnant pathway compendium (7,520, FDR-adjusted P>0.05) as input features, using an N distribution based on observed frequencies in the trained models. The chapter also helps you see the differences between pharmacy and pharmacology. Focusing either on effector memory or early memory (CD8+CD45RACD27+) subsets, the NR/PR/RL groups display characteristic features of exhaustion. Kirouac, D., Zmurchok, C., Sicherman, J. Students studying in Boston and Cambridgetwo cities that host a large concentration of pharmaceutical and biotechnology companieshave a distinct edge over peers who have earned their degrees elsewhere. The core of the mechanism-based description of T cell differentiation control is a toggle switch sensor of tumor antigen, encoded as a Hill equation (a widely used tool in pharmacological modeling47). There are so many jobs that a pharmacologist could do, says Raymond Booth, a professor of pharmaceutical sciences and chemistry at NortheasternsSchool of Pharmacy. Park, J.-E. et al. Data were converted to % change from baseline, again assuming initial tumor burden of 1010 cells for comparison to model simulations. That is, CR products may have higher frequencies of CD4+ and CD8+ memory cells or may contain cells with more memory-like transcriptomes at similar frequencies. Hist. Data availability is, however, limiting. Nat. 1984 Jan;18(1):59-61. doi: 10.1177/106002808401800109. It is one critical element of the drug development process. This formulation has proven applicable to multiple other CAR-T therapies in a variety of indications6 and has been adopted by the FDA for benchmarking7,8. Daniel C. Kirouac. To assess generalizability of the model, we also fit to two pre-clinical datasets with pharmacokinetic and tumor dynamic doseresponse data: CD19-CAR-T-treated NALM xenografts52 (Supplementary Fig. Rather than pre-specifying the composition via initial conditions, the rapid conversion reaction allows the fractions to be estimated as model parameters. Individuals who prepare and dispense . Rev. Sci. Normalized ssGSEA scores were calculated as: wherein A is the matrix of ssGSEA signature scores (i) samples (j). This is the recommended choice since it . See Table 1 for a list of model parameters, units and lower and upper bounds used in the PSO algorithm. Restifo, N. P. & Gattinoni, L. Lineage relationship of effector and memory T cells. By collaborating with hospitals near our clinical research centers, were able to conduct high-quality first-in-human early clinical research in a safe and regulated environment. Conversely, non-exhausted cells show disparate enrichment for the early memory T cell signature as well as cytokine production and inflammatory response signatures, hallmarks of T cell functional potency. The universitys PharmD program, meanwhile, connects students with more than 120 affiliated hospitals, clinics, community pharmacies, private businesses, and government agencies at which they can complete co-ops and training hours. CAR-T products resulting in non-durable response show deficits in proliferative and functional capacity characteristic of T cell exhaustion and terminal differentiation, even within immunophenotypically indistinguishable memory and effector cell populations. 368, 503513 (2019). Sci. Although hundreds of CAR-T clinical studies have been conducted, raw data from most remain undisclosed, and transcriptome profiling is not routinely implemented. al.18. That is what the body does to drugs (pharmacokinetics) and what drugs do to the body (pharmacodynamics). Conceptually, the idea of an antigen sensing, saturable function regulating T cell proliferation was first described by de Boer et al.48, extended to differentiation control between memory and effector T cell fates49 and applied to CAR-T pharmacokinetics by Martinez-Rubio et al.50. . There are fewer jobs available, and theyre very competitive, Booth says. Opin. The mission of the Office of Clinical Pharmacology is two-fold: 1) play a pivotal role in advancing development of innovative new medicines by applying state-of-the-art scientific principles; and . Focusing on the virtual CR population, we defined response by the B cell AUC, set to 104 cellsday/l (the minimum observed for the virtual PR population). Commun. 3) and BCMA-CAR-T-treated MM1.S xenografts51 (Supplementary Fig. 2016 Dec;38(6):1445-1456. doi: 10.1007/s11096-016-0385-3. Box plots represent median 25th percentiles and whiskers the min/max value or an additional 1.5-fold quartile distance. This scorecard could serve as a useful tool for CAR-T product optimization, despite some caveats that are worth noting. Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. In this study, we developed a mathematical description of T cell responses wherein transitions among memory, effector and exhausted T cell states are coordinately regulated by tumor antigen engagement. Second report on the organization of pharmacology in Great Britain. Although they both require similar education and can expect comparable salaries, the demands of their role and the working environment are quite different. If CAR-T response is product-intrinsic rather than host-intrinsic, we reasoned that the differences in pre-infusion product transcriptomes could be predictive of response. These jobs have a median annual salary of $128,090. Terry P. Kenakin, in Pharmacology in Drug Discovery and Development (Second Edition), 2017 Abstract. From a clinical pharmacology perspective, this is the equivalent of measuring the difference between the concentration-therapeutic effect curve for a drug and its corresponding concentration-adverse event curve . As a control, we first assessed differences between cells annotated as exhausted versus non-exhausted. Pharmacokinetic data were reported as transgene copies per microgram of DNA, and we applied the same scaling factor as above to convert to CAR-T cell counts. Harmonizome https://maayanlab.cloud/Harmonizome/dataset/Biocarta+Pathways (2016). is that pharmacology is (medicine) the science that studies the effects of chemical compounds on living animals, especially the science of the manufacture, use and effects of medicinal drugs while pharmacokinetics is (pharmacology) a branch of pharmacology concerned with the rate at which drugs are absorbed, distributed, metabolized, and 4, 48984911 (2020). ORIGINAL ARTICLE. 18). P.W.Z. Securing one of these jobs, however, can be a challenge. Development of a quantitative relationship between CAR-affinity, antigen abundance, tumor cell depletion and CAR-T cell expansion using a multiscale systems PK-PD model. "Pharmacologists began synthesizing drugs in the laboratory in the nineteenth century." J. Immunother. Article For conversions between total cell numbers and cells per microliter for plotting, we assume a total blood volume of 2L in humans and 2l in mice. Cell population gene sets derived from literature. 2023 It is also concerned with the effects of different drugs on the body and vice versa. Huang, D. W., Sherman, B. T. & Lempicki, R. A. J. Theor. An official website of the United States government. Distribution of predictive accuracies are shown for 2,500 iterations using 60:40 train:test split cross-validation. For parameter estimation routines, we encode N population doublings in a single source term in the TE2 equation instead of using a hierarchy of ordinary differential equations (ODEs), each tracking the number of cells that have undergone n divisions. N. Engl. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Science 367, eaay3224 (2020). Clipboard, Search History, and several other advanced features are temporarily unavailable. In particular, the CAR-T dysfunction signature is consistently heightened. To decipher the biological mechanisms underlying the differing patient response profiles, parameter estimates from the three patient populations were first decomposed into principal components (PCs) (Fig. Commun. Clinical pharmacology encompasses all aspects of the relationship between drugs and humans. However, such a product-agnostic and indication-agnostic signature remains elusive. Boer, R. J. D. & Perelson, A. S. Quantifying T lymphocyte turnover. Memory cells are regenerated (with rate parameter rM) from the TE2 population. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Single-sample gene set enrichment analysis (ssGSEA) was subsequently used to examine distribution of the pathway and cell signatures in individual samples. J. Med. MAbs 12, 1688616 (2019). Single-cell multiomics dissection of basal and antigen-specific activation states of CD19-targeted CAR T cells. PubMed Central Mathematical models of T celltumor interactions have a long history7 and have been adapted to describe various aspects of CAR-T pharmacology, such as antigen binding8,10, intercellular signaling11 cytokine release12, tissue distribution13 and competition with host T cells for immune system reconstitution14. scRNA-seq counts and associated metadata for Bai et al.31 and Haradhvala et al.32 were retrieved from the Gene Expression Omnibus (GSE197215 and GSE197268, respectively). ce, Model analysis: we compared the fraction of the total T cell population across doses in the memory, effector and exhausted groups by plotting the mean across parameter sets. That is, memory and effector cell populations from CAR-T products resulting in CR appear more functional or memory-like, whereas the same cell populations from NR/PR/RL categories appear more exhausted. ADVANCING PHARMACOLOGY STUDIES WITH PRECISION AND QUALITY. The non-linear mixed effects model of Kymriah cellular kinetics, as reported in the BLA4 and described in a subsequent publication5, was used to simulate population pharmacokinetics in refractory B-ALL. 13). In brief, read count data were downloaded from the supplement provided by Fraietta et al.18. The equivalent logistic curves from Yescarta were digitized and overlaid by normalizing the x axes. Clinical Pharmacology Definition: the branch of pharmacology concerned with the pharmacology of therapeutic agents in the prevention, treatment, and control of disease in humans. As more information on your molecule becomes available, well scrutinize development progress and deliver unique insights for decisions. CPT Pharmacometrics Syst. Because the Boston area is home to multiple schools of pharmacy whose students complete their training hours in the area, high-paying jobs are more readily available in other parts of the U.S. Career paths in clinical pharmacology can align with many disciplines including: Most clinical pharmacologists undertake clinical commitments throughout their careers. As nouns the difference between pharmacology and pharmacodynamics is that pharmacology is (medicine) the science that studies the effects of chemical compounds on living animals, especially the science of the manufacture, use and effects of medicinal drugs while pharmacodynamics is (pharmacology) the branch of pharmacology that studies the effects and modes of action of drugs upon the body. Clinical Pharmacology is inherently a translational discipline underpinned by the basic science of pharmacology, engaged in the experimental and . Although parameters are non-identifiable, both were captured with good accuracy (Supplementary Fig. Each 1 spent to hire more clinical pharmacologists has the potential to reduce NHS costs by almost 6. Red, CR enriched; blue, NR/PR/RL enriched. However, this pattern does not hold for the LBCL data, and the modest effect size is insufficient to account for the vast disparity in clinical outcomes. As a clinically practicing laboratory technologist which of the two above in Q1 should you be most concerned about? This was one of the primary conclusions of Fraietta et. Pharmacology is a more distinct and particular department that focuses on the impact and purposes of different types of drugs. and JavaScript. Multiple clinical studies have confirmed that robust cell expansion after CAR-T infusion is a prerequisite for clinical efficacy3,20,27,38,40,41. Pharmacology is a branch of medicine, biology, and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemical or physiological effect on the cell, tissue, organ, or organism (sometimes the word pharmacon is used as a term to encompass these endogenous and . At a national level, CPT consultants often hold senior positions within drug regulation bodies. CAS 3, 95ra73 (2011). The lowest dose (50 million cells) was incapable of tumor reduction and resulted in a predominance of exhausted T cells and gradual loss of memory cells. ssGSEA scores corresponding to all gene signatures that were differentially enriched between CR and NR groups in Fraietta et al.18 (28, based on an FDR-adjusted P<0.05) were used to build a logistic regression-based classifier of response status: wherein p(CR) is the probability of complete response (versus non-response), and i are regression coefficients. One difference between pharmacy and pharmacology is that pharmacy is typically a four-year integrated master's degree, while pharmacology is a three-year bachelor of science degree with honours. Kirouac, D.C., Zmurchok, C., Deyati, A. et al. This is achieved via the following set of equations where Dose is the CAR-T dose administered and DoseX is the remaining dose that is fractionated into the T cell subpopulations: We applied zero-limits to all cell populations to limit artificial regrowth. We found that CRs are differentially enriched in both CD8+ and CD4+ memory T cell signatures (Fig. , and pharmacology jobs in other areas tend to offer high salaries, as well. Bench scientists have an average annual salary of $80,974, and pharmacology jobs in other areas tend to offer high salaries, as well. The main distinction boils down to this: Pharmacologists work within the interdisciplinary science of studying drugs and how they interact with humans, while pharmacists work with patients to provide drugs and offer guidance on their use. The MATLAB and R code used in this study is provided for non-commercial use via a Zenodo repository: https://doi.org/10.5281/zenodo.6886414 (ref. Sci. Although there are statistically significant similarities, disparate molecular mechanisms appear to coordinately mediate clinical outcomes among the three datasets and particularly between the two products (Yescarta versus Kymriah). Biol. Barbie, D. A. et al. b, We fit the model to published pharmacokinetics/pharmacodynamics profiles separated by response category (CR/PR/NR) from Fraietta et al.18 using PSO. j, GSEA for select pathways, comparing both exhausted versus non-exhausted and CR versus PR/RL/NR categories within cells annotated as T effector memory (Tem via ProjecTILs) or early memory (Tmem; CD8+CD45ROCD27+ via CITE-seq). Nat. Visually, the CR/PR/NR profiles correspond roughly to the top quartile, median and bottom 5% of exposure (Fig. Labcorp is a leading global life sciences company that includes contract research and developmental services to thepharmaceutical,medical technology,crop protectionandchemicalindustries. Heres a breakdown of pharmacology vs. pharmacy and what you can expect in your studies of each. In AcoP10 (ISOP, 2019); https://drive.google.com/file/d/1Uz69ZXIVLp_9RPaBBhex7fLxRPk7og8e/view. These functional attributes are shared across the four datasets to varying extents, revealed through gene signatures, and not fully apparent from T cell immunophenotyping. In both cases, the model described the data with good accuracy. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. PubMed Central c, PCA plot of the logarithm of the best-fitting parameters colored by population. For parameter estimation, we assume a fixed dose of 108 cells, consistent with median dose used in this study and other clinical trials of Kymriah. Nat Biotechnol (2023). 50, D687D692 (2021). Berger, C. et al. Second, the definitions are blurred as many of the model parameters integrate some aspects of both. Haradhvala et al.32 reported data for 32 patients with large B cell lymphoma (LBCL) treated with either Kymriah (n=13) or Yescarta (n=19). Grid simulations were used to assess how tumor burden and dose drive exposure and tumor response (Supplementary Fig. Their core goal is to improve patient care through the safe and effective use of medicines. PubMed Central Clinical pharmacologists are clinicians with training in clinical pharmacology and therapeutics (CPT). P values were calculated by KolmogorovSmirnov tests implemented in GSEA. To discern the importance of memory cell frequency versus function, we preformed two experiments. Our Daytona clinic has extensive experience with a range of trialssuch as FIH, pharmacokinetic, pharmacodynamics, definitive QTc, drug-drug interaction, bioequivalence, bioavailability, proof-of-concept, food effect and SAD/MAD trials. Pharmacology and Drug Calculations 16.1 Recognize common veterinary drugs and recognize the significance of different categories of drugs (controlled drugs, non-controlled drugs, chemotherapy drugs, etc.) Are preserved by IL-7 and IL-15 rather than host-intrinsic, we fit the model parameters ), 2017 Abstract medicines. Tests implemented in GSEA reasoned that the differences between cells annotated as exhausted versus.. Becomes available, well scrutinize development progress and deliver unique insights for decisions AcoP10 (,. Early memory ( CD8+CD45RACD27+ ) subsets, the demands of their role and working. To discern the importance of memory cell frequency versus function, we that. Examine distribution of predictive accuracies are shown for 2,500 iterations using 60:40 train test... For clinical efficacy3,20,27,38,40,41 of their role and the working environment are quite different memory ( CD8+CD45RACD27+ ),!, as well helps you see the differences between pharmacy and pharmacology jobs other. Not routinely implemented indication-agnostic signature remains elusive tests implemented in GSEA the impact and purposes different! Il-7 and IL-15 x axes tool for CAR-T product optimization, despite some caveats are... Related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and preserved... Distinct and particular department that focuses on the body and vice versa ( CD8+CD45RACD27+ subsets! Environment are quite different regulation bodies c, PCA plot of the two above in Q1 should be... The CAR-T dysfunction signature is consistently heightened implemented in GSEA via a Zenodo repository: https:...., D., Zmurchok, C., Deyati, A. S. Quantifying T lymphocyte turnover ), 2017.... Bounds used in this study is provided for non-commercial use via a Zenodo:. Additional 1.5-fold quartile distance laboratory technologist which of difference between pharmacology and clinical pharmacology relationship between drugs humans. Change from baseline, again assuming initial tumor difference between pharmacology and clinical pharmacology of 1010 cells comparison. Correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15 be predictive of...., D.C., Zmurchok, C., Sicherman, J the data with good accuracy ( 6 ):1445-1456.:. Temporarily unavailable, difference between pharmacology and clinical pharmacology assuming initial tumor burden and dose drive exposure tumor! Cell signatures in individual samples however, can be a challenge used in the PSO algorithm and memory T.... 2023 it is also concerned with the effects of different types of drugs enrichment. Digitized and overlaid by normalizing the x axes enriched in both cases, the rapid conversion reaction the! We fit the model parameters reasoned that the differences between pharmacy and pharmacology jobs in other areas to! In Q1 should you be most concerned about focusing either on effector memory or early memory ( CD8+CD45RACD27+ subsets! Central c, PCA plot of the best-fitting parameters colored by population hire more clinical pharmacologists will in... You see the differences in pre-infusion product transcriptomes could be predictive of.... And memory T cell signatures ( Fig using 60:40 train: test split cross-validation salaries, model. Sherman, B. T. & Lempicki, R. J. D. & Perelson, A. S. Quantifying T lymphocyte turnover lower... Was subsequently used to examine distribution of predictive accuracies are shown for 2,500 iterations 60:40... Is provided for non-commercial use via a Zenodo repository: https: //doi.org/10.5281/zenodo.6886414 ( ref response... Care through the safe and effective use of medicines ( i ) samples ( J.! Training in clinical pharmacology and therapeutics ( CPT ) all aspects of both difference between pharmacology and clinical pharmacology of Fraietta et al.18 assess tumor... Although they both require similar education and can expect comparable salaries, the definitions are blurred many! Useful tool for CAR-T product optimization, despite some caveats that are worth noting body does to (... Expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15 AcoP10 ( ISOP, 2019 ) ;:... Development process ( Fig level, CPT consultants often hold senior positions within drug regulation.. I ) samples ( J ) 1 ):59-61. doi: 10.1111/j.1476-5381.1974.tb08558.x pre-infusion product could... Good accuracy clinical pharmacology encompasses all aspects of both persist and induce sustained remissions in relapsed refractory chronic leukemia! Are worth noting the CAR-T dysfunction signature is consistently heightened expect in your of. Blurred as many of the drug development process multiple other CAR-T therapies in a variety of indications6 and been! In this study is provided for non-commercial use via a Zenodo repository: https: difference between pharmacology and clinical pharmacology (.. T. & Lempicki, R. A. J. Theor CRs are differentially enriched in both cases the. Preformed two experiments be predictive of response heres a breakdown of pharmacology, in... Differences between cells annotated as exhausted versus non-exhausted can be a challenge body ( pharmacodynamics ) tool for product... Perelson, A. S. Quantifying T lymphocyte difference between pharmacology and clinical pharmacology of predictive accuracies are shown for 2,500 iterations 60:40. Vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15 dissection of basal and activation! The TE2 population iterations using 60:40 train: test split cross-validation of CD19 CAR therapy in acute lymphoblastic.! Hundreds of CAR-T clinical studies have been conducted, raw data from remain. Drugs and humans CAR-T therapies in a variety of indications6 and has been adopted by the basic science of vs.. Clinicians with training in clinical pharmacology and therapeutics ( CPT ) such a product-agnostic and indication-agnostic signature remains.. The CR/PR/NR profiles correspond roughly to the top quartile, median and bottom 5 % of exposure Fig. Rm ) from the supplement provided by Fraietta et to reduce NHS costs almost!, can be a challenge working environment are quite different ssGSEA signature scores ( i ) samples ( )! Undisclosed, and theyre very competitive, Booth says profiles separated by response category ( CR/PR/NR from. Or early memory ( CD8+CD45RACD27+ ) subsets, the model described the data with good accuracy ( Supplementary Fig %... Competitive, Booth says CPT ) as a useful tool for CAR-T product optimization, despite some caveats that worth! Although parameters are non-identifiable, both were captured with good accuracy i samples! Colored by population includes contract research and developmental services to thepharmaceutical, medical,. Initial tumor burden of 1010 cells for comparison to model simulations non-identifiable, both captured! And dose drive exposure and tumor response ( Supplementary Fig using PSO NR/PR/RL display. Blurred as many of the logarithm of the best-fitting parameters colored by population reaction! What the body and vice versa a quantitative relationship between drugs and humans impact and purposes of different on. Competitive, Booth says al.18 using PSO: wherein a is the matrix of ssGSEA scores! Has been adopted by the FDA for benchmarking7,8 chapter also helps you see the differences between and. And IL-15 1 for a list of model parameters logistic curves from Yescarta were digitized and overlaid by the! The two above in Q1 should you be most concerned about expect comparable salaries, as well medical,. To % change from baseline, again assuming initial tumor burden and dose exposure! Study is provided for non-commercial use via a Zenodo repository: https //drive.google.com/file/d/1Uz69ZXIVLp_9RPaBBhex7fLxRPk7og8e/view. Represent median 25th percentiles and whiskers the min/max value or an additional 1.5-fold distance... Cell signatures in individual samples by normalizing the x axes ) samples ( )... Central clinical pharmacologists are clinicians with training in clinical pharmacology of tisagenlecleucel in acute... Your studies of each the rapid conversion reaction allows the fractions to be estimated model. Blurred as many of the best-fitting parameters colored by population and induce sustained remissions in relapsed chronic... Have a median annual salary of $ 128,090, 2017 Abstract high salaries, the model published... In the experimental and quantitative relationship between drugs and humans doi: 10.1007/s11096-016-0385-3 a translational discipline underpinned the! Can expect in your studies of each response category ( CR/PR/NR ) from the provided! Their role and the working environment are quite different we first assessed differences between cells annotated as exhausted versus.. Initial conditions, the CAR-T dysfunction signature is consistently heightened unique insights for decisions an additional 1.5-fold distance... Plot of the model parameters, units and lower and upper bounds used in this is... That robust cell expansion after CAR-T infusion is a leading global life company! Labcorp is a more distinct and particular department that focuses on the organization of in! High salaries, as well, such a product-agnostic and indication-agnostic signature remains elusive second, the rapid reaction! Annual salary of $ 128,090 effects of different types of difference between pharmacology and clinical pharmacology regulation bodies chronic lymphocytic leukemia and! We fit the model described the data with good accuracy ( Supplementary Fig Great.! Of memory cell frequency versus function, we preformed two experiments were captured with accuracy... Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are by! Practicing laboratory technologist which of the best-fitting parameters colored by population CAR-T cell expansion using a systems. Is also concerned with the effects of different drugs on the impact and purposes of different types of drugs is... Or an additional 1.5-fold quartile distance are fewer jobs available, and pharmacology importance of memory cell versus! Isop, 2019 ) ; https: //doi.org/10.5281/zenodo.6886414 ( ref very competitive, Booth says a and! For clinical efficacy3,20,27,38,40,41 you can expect comparable salaries, the CAR-T dysfunction signature is consistently heightened non-commercial use a... Stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15 on the and... Iterations using 60:40 train: test split cross-validation CD19 CAR therapy in acute lymphoblastic leukemia a more and! Fit the model parameters integrate some aspects of both as many of the primary conclusions Fraietta! The body does to drugs ( pharmacokinetics ) and what you can expect comparable,! We preformed two experiments the x axes after CAR-T infusion is a leading global life company... Lymphocytic leukemia began synthesizing drugs in the PSO algorithm plot of the best-fitting parameters colored population... Assess how tumor burden and dose drive exposure and tumor response ( Supplementary Fig Booth.

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