[Show abstract][Hide abstract] 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 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To characterize ranibizumab pharmacokinetics in patients with AMD.
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 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months.
A TOTAL OF 696 CONCENTRATION-TIME RECORDS FROM 229 SUBJECTS WITH ONE OR MORE MEASURABLE TOTAL SERUM RANIBIZUMAB CONCENTRATIONS WERE ANALYZED. THE SYSTEMIC CONCENTRATION-TIME DATA FOR RANIBIZUMAB WERE BEST DESCRIBED BY A ONE-COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION INTO AND FIRST-ORDER ELIMINATION FROM THE SYSTEMIC CIRCULATION. VITREOUS ELIMINATION HALF-LIFE (T1/2) WAS CALCULATED TO BE 9 DAYS AND THE INTRINSIC SYSTEMIC ELIMINATION T1/2 WAS CALCULATED TO BE APPROXIMATELY 2 HOURS. FOLLOWING ITV ADMINISTRATION, RANIBIZUMAB EGRESSES SLOWLY INTO THE SYSTEMIC CIRCULATION, RESULTING IN AN APPARENT SERUM T1/2 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 VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times.
Systemic exposure to ranibizumab after ITV injection was very low due to elimination on 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. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.).
[Show abstract][Hide abstract] 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 · 1.86 Impact Factor