David Z D'Argenio

University of Southern California, Los Angeles, CA, United States

Are you David Z D'Argenio?

Claim your profile

Publications (34)108.6 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: FLT3(ITD) subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of action of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3(ITD) and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML.
    Journal of Pharmacokinetics and Pharmacodynamics 10/2014; · 1.81 Impact Factor
  • Alyssa Zhou, Giovanni Pacini, Bo Ahrén, David Z D'Argenio
    [Show abstract] [Hide abstract]
    ABSTRACT: Given the importance of glucagon in the development of type 2 diabetes and as a potential therapeutic agent, the aim of this study was to characterise glucagon kinetics in mice and its regulation by the nutritional state. Anaesthetised C57BL/6 mice fed normal or high-fat diets, or fasted, were injected intravenously with glucagon (0.1, 0.3, 1.0, 10.0 or 20 μg/kg); blood samples were withdrawn before injection and 1, 3, 5, 10, 20 min thereafter for glucagon assay by RIA. Glucagon kinetics were described by two-compartment models using a population analysis. The population mean and between-animal SD of glucagon clearance in the fed mice was 6.03 ± 2.58 ml/min, with a rapid elimination half-life of 2.92 ± 1.21 min. Fasted mice showed a slower glucagon clearance. The kinetics of glucagon in the fed and fasted group was linear across this large dose range. The mice fed a high-fat diet, however, showed non-linear kinetics with a faster terminal clearance of 20.4 ± 5.45 ml/min (p < 0.001) and a shorter elimination half-life of 1.59 ± 0.606 (p < 0.001) min relative to normal mice. This first systematic dose-ranging study of glucagon kinetics produced several findings: (1) a linear two-compartment model describes glucagon in normal C57BL/6 mice; (2) fasting reduces the clearance of glucagon and (3) high-fat diet enhances the clearance of glucagon. These results may direct future studies on glucagon physiology and indicate that there are other mechanisms, not included in the current model, needed to fully explain glucagon's kinetics.
    Diabetologia 12/2013; · 6.49 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI)-based regimen to treat HIV-infection. As with all PIs, the trough concentration (C trough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters. Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry. The LPVt typical value of clearance ([Formula: see text]) was 4.73 L/h and the distribution volume ([Formula: see text]) was 55.7 L. The clearance ([Formula: see text]) and distribution volume (V f/F) for LPVf were 596 L/h and 6,370 L, respectively. The virion clearance rate was 0.0350 h(-1). The simulated [Formula: see text] C trough values at 90 % (EC90) and 95 % (EC95) of the maximum response were 316 and 726 ng/mL, respectively. The pharmacokinetic-pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modelling and simulation approach could be used as a surrogate assessment of antiretroviral (ARV) activity where adequate early-phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.
    Clinical Pharmacokinetics 12/2013; · 5.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed.
    The AAPS Journal 02/2013; · 4.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Modeling studies of the insulin-glucose relationship have mainly utilized parametric models, most notably the minimal model (MM) of glucose disappearance. This article presents results from the comparative analysis of the parametric MM and a nonparametric Laguerre based Volterra Model (LVM) applied to the analysis of insulin modified (IM) intravenous glucose tolerance test (IVGTT) data from a clinical study of gestational diabetes mellitus (GDM). An IM IVGTT study was performed 8 to 10 weeks postpartum in 125 women who were diagnosed with GDM during their pregnancy [population at risk of developing diabetes (PRD)] and in 39 control women with normal pregnancies (control subjects). The measured plasma glucose and insulin from the IM IVGTT in each group were analyzed via a population analysis approach to estimate the insulin sensitivity parameter of the parametric MM. In the nonparametric LVM analysis, the glucose and insulin data were used to calculate the first-order kernel, from which a diagnostic scalar index representing the integrated effect of insulin on glucose was derived. Both the parametric MM and nonparametric LVM describe the glucose concentration data in each group with good fidelity, with an improved measured versus predicted r2 value for the LVM of 0.99 versus 0.97 for the MM analysis in the PRD. However, application of the respective diagnostic indices of the two methods does result in a different classification of 20% of the individuals in the PRD. It was found that the data based nonparametric LVM revealed additional insights about the manner in which infused insulin affects blood glucose concentration.
    Journal of diabetes science and technology 01/2013; 7(4):952-62.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dulanermin (rhApo2L/TRAIL) and conatumumab bind to transmembrane death receptors and trigger the extrinsic cellular apoptotic pathway through a caspase-signaling cascade resulting in cell death. Tumor size time series data from rodent tumor xenograft (COLO205) studies following administration of either of these two pro-apoptotic receptor agonists (PARAs) were combined to develop a intracellular-signaling tumor-regression model that includes two levels of signaling: upstream signals unique to each compound (representing initiator caspases), and a common downstream apoptosis signal (representing executioner caspases) shared by the two agents. Pharmacokinetic (PK) models for each drug were developed based on plasma concentration data following intravenous and/or intraperitoneal administration of the compounds and were used in the subsequent intracellular-signaling tumor-regression modeling. A model relating the PK of the two PARAs to their respective and common downstream signals, and to the resulting tumor burden was developed using mouse xenograft tumor size measurements from 448 experiments that included a wide range of dose sizes and dosing schedules. Incorporation of a pro-survival signal-consistent with the hypothesis that PARAs may also result in the upregulation of pro-survival factors that can lead to a reduction in effectiveness of PARAs with treatment-resulted in improved predictions of tumor volume data, especially for data from the long-term dosing experiments.
    Journal of Pharmacokinetics and Biopharmaceutics 08/2012; 39(5):577-90. · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The vitamin D(3) catabolizing enzyme, CYP24, is frequently over-expressed in tumors, where it may support proliferation by eliminating the growth suppressive effects of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). However, the impact of CYP24 expression in tumors or consequence of CYP24 inhibition on tumor levels of 1,25(OH)(2)D(3)in vivo has not been studied due to the lack of a suitable quantitative method. To address this need, an LC-MS/MS assay that permits absolute quantitation of 1,25(OH)(2)D(3) in plasma and tumor was developed. We applied this assay to the H292 lung tumor xenograft model: H292 cells eliminate 1,25(OH)(2)D(3) by a CYP24-dependent process in vitro, and 1,25(OH)(2)D(3) rapidly induces CYP24 expression in H292 cells in vivo. In tumor-bearing mice, plasma and tumor concentrations of 1,25(OH)(2)D(3) reached a maximum of 21.6 and 1.70ng/mL, respectively, following intraperitoneal dosing (20μg/kg 1,25(OH)(2)D(3)). When co-administered with the CYP24 selective inhibitor CTA091 (250μg/kg), 1,25(OH)(2)D(3) plasma levels increased 1.6-fold, and tumor levels increased 2.6-fold. The tumor/plasma ratio of 1,25(OH)(2)D(3) AUC was increased 1.7-fold by CTA091, suggesting that the inhibitor increased the tumor concentrations of 1,25(OH)(2)D(3) independent of its effects on plasma disposition. Compartmental modeling of 1,25(OH)(2)D(3) concentration versus time data confirmed that: 1,25(OH)(2)D(3) was eliminated from plasma and tumor; CTA091 reduced the elimination from both compartments; and that the effect of CTA091 on tumor exposure was greater than its effect on plasma. These results provide evidence that CYP24-expressing lung tumors eliminate 1,25(OH)(2)D(3) by a CYP24-dependent process in vivo and that CTA091 administration represents a feasible approach to increase tumor exposure to 1,25(OH)(2)D(3).
    Steroids 01/2012; 77(5):477-83. · 2.80 Impact Factor
  • Source
    Journal of Pharmacokinetics and Biopharmaceutics 01/2012; 39(1):3. · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (C(max)) and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg. C(max) and time to maximum concentration of drug in serum (T(max)) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [K(a)], 0.414 h(-1); lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effects in vivo and should be evaluated in clinical trials.
    Antimicrobial Agents and Chemotherapy 01/2012; 56(1):70-4. · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AIMS: There are limited data on isoniazid (INH) pharmacokinetics in infants and young children and, therefore, uncertainty on appropriate dosing. METHODS: Pharmacokinetic data were obtained from perinatally HIV-exposed South African infants aged 3-24 months receiving INH 10-20 mg.kg.d orally for Mycobacterium tuberculosis prophylaxis. INH pharmacokinetic parameters were characterized using a population pharmacokinetic approach. Dosing simulations were performed to evaluate weight-based INH doses in children based on N-acetyltransferase 2 enzyme (NAT2) genotype, age, maximum concentrations (Cmax) >/=3 mg/L, and area under the curve (AUC0-24) >/=10.52 mg.h/L. RESULTS: In 151 infants (53% female, 48% HIV positive) receiving a mean INH dose of 14.5 mg.kg.d, mean (+/-SD) Cmax at 3, 6, and 23 months of age were 10.0 (3.5), 8.6 (2.6), and 9.3 (3.8) mg/L, respectively, mean (+/-SD) AUC0-24 were 53.6 (26.8), 42 (19.9), and 44 (30.7) mg.h/L, respectively, and mean (+/-SD) half-lives were 2.1 (0.7), 1.9 (0.6), and 1.8 (0.9) hours, respectively. A trimodal apparent oral clearance of INH as a function of the NAT2 genotype was apparent as early as 3 months. INH was well tolerated. At an average INH dose of 14.5 mg.kg.d, 99% of infants aged 3-24 months have an INH Cmax >/=3 mg/L, and 98% have an INH AUC0-24 >/=10.52 mg.h/L. CONCLUSIONS: INH at an average dose of 14.5 mg/kg once daily was well tolerated in infants and achieved INH Cmax values >/=3 mg/L and AUC0-24 values >/=10.52 mg.h/L.
    Therapeutic drug monitoring. 01/2012; 34(4):446-51.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The vast array of in silico resources and data of high throughput profiling currently available in life sciences research offer the possibility of aiding cancer gene and drug discovery process. Here we propose to take advantage of these resources to develop a tool, TARGETgene, for efficiently identifying mutation drivers, possible therapeutic targets, and drug candidates in cancer. The simple graphical user interface enables rapid, intuitive mapping and analysis at the systems level. Users can find, select, and explore identified target genes and compounds of interest (e.g., novel cancer genes and their enriched biological processes), and validate predictions using user-defined benchmark genes (e.g., target genes detected in RNAi screens) and curated cancer genes via TARGETgene. The high-level capabilities of TARGETgene are also demonstrated through two applications in this paper. The predictions in these two applications were then satisfactorily validated by several ways, including known cancer genes, results of RNAi screens, gene function annotations, and target genes of drugs that have been used or in clinical trial in cancer treatments. TARGETgene is freely available from the Biomedical Simulations Resource web site (http://bmsr.usc.edu/Software/TARGET/TARGET.html).
    PLoS ONE 01/2012; 7(8):e43305. · 3.53 Impact Factor
  • IEEE transactions on bio-medical engineering 12/2011; 58(12):3434-9. · 2.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The roles of the NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics were investigated in South African infants with perinatal HIV exposure enrolled in a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10 to 20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis along with NAT2 genotype, body weight, age, and sex. The results showed a different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight-normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age, respectively, with no significant change in the apparent clearance of the slow group during this period. A hypothesis is proposed to explain the genotype-dependent enzyme maturation processes for the NAT2 enzyme.
    The Journal of Clinical Pharmacology 05/2011; 52(4):511-9. · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The increase in insulin secretion caused by glucagon-like peptide-1 (GLP-1) and GLP-1 mimetics observed during an intravenous glucose test (IVGTT) has been reported in both normal and disease animal models, as well as in humans. In this study, a hierarchical population modeling approach is used, together with a previously reported model relating glucose to insulin appearance, to determine quantitative in vivo dose-response relationships between GLP-1 dose level and both first- and second-phase insulin release. Parameters of the insulin kinetic model were estimated from the complete set of glucose and insulin data collected in 219 anesthetized nonfasted NMR-imaged mice after intravenous injection of glucose (1 g/kg) alone or with GLP-1 (0.03-100 nmol/kg). The resulting dose-response curves indicate a difference in GLP-1 effect on the two release phases, as is also evident from the different ED(50) parameter values (0.107 vs. 6.65 nmol/kg for phase 1 vs. phase 2 insulin release parameters). The first phase of insulin release is gradually augmented with increasing GLP-1 dose, reaching saturation at a dose of ~1 nmol/kg, while the second-phase release changes more abruptly at GLP-1 doses between 3 and 10 nmol/kg and shows a more pronounced 100-fold increase between control and the high GLP-1 dose of 100 nmol/kg Moreover, separate disposition indices calculated for phase 1 and 2 insulin release, show a different pattern of increase with increasing GLP-1 dose.
    AJP Regulatory Integrative and Comparative Physiology 02/2011; 300(5):R1126-33. · 3.28 Impact Factor
  • Marc Pfister, David Z D'Argenio
    The Journal of Clinical Pharmacology 09/2010; 50(9 Suppl):6S. · 2.84 Impact Factor
  • The Journal of Clinical Pharmacology 09/2010; 50(9 Suppl):158S. · 2.84 Impact Factor
  • The Journal of Clinical Pharmacology 09/2010; 50(9 Suppl):7S-8S. · 2.84 Impact Factor
  • Source
    David Z D'Argenio, Donald E Mager
    The Journal of Clinical Pharmacology 09/2010; 50(9 Suppl):56S-57S. · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU). Mice were dosed with 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally. taTHU did not inhibit CD. THU, after 150 mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1 μg/mL, the concentration shown to inhibit CD, for 10 h. Renal excretion accounted for 40-55% of the i.v. taTHU dose, 6-12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150 mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10 μg/mL from 0.5-2 h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU. The availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU.
    Cancer Chemotherapy and Pharmacology 05/2010; 67(2):421-30. · 2.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Three major problems confront the construction of a human genetic network from heterogeneous genomics data using kernel-based approaches: definition of a robust gold-standard negative set, large-scale learning and massive missing data values. The proposed graph-based approach generates a robust GSN for the training process of genetic network construction. The RVM-based ensemble model that combines AdaBoost and reduced-feature yields improved performance on large-scale learning problems with massive missing values in comparison to Naïve Bayes. dargenio@bmsr.usc.edu Supplementary material is available at Bioinformatics online.
    Bioinformatics 03/2010; 26(6):807-13. · 5.47 Impact Factor

Publication Stats

212 Citations
108.60 Total Impact Points

Institutions

  • 2006–2013
    • University of Southern California
      • • Department of Biomedical Engineering
      • • School of Pharmacy
      Los Angeles, CA, United States
  • 2005–2010
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States