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Publications (4)22.7 Total impact

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    ABSTRACT: We characterized the pharmacokinetics (PK) of onartuzumab (MetMAb) in animals and determined a concentration-effect relationship in tumor-bearing mice to enable estimation of clinical PK and target doses. A tumor growth-inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human PK parameters were projected from PK in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 3-week (Q3W) dosing. Onartuzumab total clearance (CLt) in the linear dose range was 21.1and 12.2 mL/day/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 μg/mL. Projected CLt for humans in the linear dose range was 5.74-9.36 mL/day/kg with scaling exponents of clearance at 0.75-0.9. Monte Carlo simulations projected a Q3W dose of 10-30 mg/kg to achieve Ctrough ss of 15 μg/mL in ≥95% of patients. Onartuzumab PK differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CLt in the linear-dose range. Despite this higher clearance, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 μg/mL as the Ctrough ss target. The projected human efficacious dose of 10-30 mg/kg Q3W should achieve the target TSC of 15 µg/mL. These data demonstrate effective PK/pharmacodynamic modeling to project doses to be tested in the clinic.
    Clinical Cancer Research 07/2013; 19(18). DOI:10.1158/1078-0432.CCR-13-0260 · 8.19 Impact Factor
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    ABSTRACT: PURPOSE: To characterize ranibizumab pharmacokinetics in patients with age-related macular degeneration (AMD). METHODS: A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1-3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered bi-weekly, monthly or quarterly for up to 24 months. RESULTS: 696 concentration-time records from 229 subjects with ≥1 measurable serum ranibizumab concentration were analyzed. The systemic concentration-time data for ranibizumab was best described by a 1-compartment model with first-order absorption into and first-order elimination from the systemic circulation. Vitreous elimination half-life (t(1/2)) was calculated to be 9 days and the intrinsic systemic elimination t(1/2) was calculated to be ∼2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation resulting in an apparent serum t(1/2) of 9 days. Systemic-to-vitreous exposure ratio was estimated to be 1:90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steady-state for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit vascular endothelial growth factor A (VEGF)-induced endothelial cell proliferation in vitro by 50% at all times. CONCLUSIONS: Systemic exposure to ranibizumab after ITV injection was very low due to rapid elimination upon reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure.
    Investigative ophthalmology & visual science 01/2013; 54(3). DOI:10.1167/iovs.12-10260 · 3.66 Impact Factor
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    ABSTRACT: Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.
    Journal of Pharmacokinetics and Biopharmaceutics 06/2010; 37(3):221-42. DOI:10.1007/s10928-010-9156-2 · 1.46 Impact Factor
  • EJC Supplements 11/2006; 4(12):65-65. DOI:10.1016/S1359-6349(06)70213-0 · 9.39 Impact Factor