Brittney R Starling1, Parag Kumar1,2, Andrew T Lucas1, David Barrow3, Laura Farnan4, Laura Hendrix4, Hugh Giovinazzo1,5, Gina Song1,6, Paola Gehrig7, Jeannette T Bensen4,8, William C Zamboni9,10,11. 1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA. 2. Clinical Pharmacology, Otsuka Pharmaceutical Companies, Rockville, MD, 20850, USA. 3. UNC Cytokine and Biomarker Core Facility, UNC School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. 4. UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA. 5. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 6. ScitoVation LLC, Research Triangle Park, NC, 27709, USA. 7. Department of Gynecologic Oncology, UNC School of Medicine, University of North Carolina Medical Center, Chapel Hill, NC, 27514, USA. 8. Department of Epidemiology, UNC Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. 9. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Suite 1013, CB 7361, Chapel Hill, NC, 27599-7361, USA. zamboni@email.unc.edu. 10. UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA. zamboni@email.unc.edu. 11. Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. zamboni@email.unc.edu.
Abstract
PURPOSE: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. METHODS: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. RESULTS: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67-28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = - 0.75 and - 0.76, respectively, p = 0.02 for both). CONCLUSIONS: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.
PURPOSE:Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. METHODS: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancerpatients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancerpatients. RESULTS: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67-28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = - 0.75 and - 0.76, respectively, p = 0.02 for both). CONCLUSIONS: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obesepatients with cancer. PK simulations suggest higher doses of PLD are required in obesepatients to achieve similar exposures as standard dosing in normal weight patients.
Authors: Ninh M La-Beck; Beth A Zamboni; Alberto Gabizon; Hilary Schmeeda; Michael Amantea; Paola A Gehrig; William C Zamboni Journal: Cancer Chemother Pharmacol Date: 2011-05-18 Impact factor: 3.333
Authors: William C Zamboni; Sandra Strychor; Erin Joseph; Dustin R Walsh; Beth A Zamboni; Robert A Parise; Margaret E Tonda; Ning Y Yu; Charles Engbers; Julie L Eiseman Journal: Clin Cancer Res Date: 2007-12-01 Impact factor: 12.531
Authors: Gina Song; Teresa K Tarrant; Taylor F White; David A Barrow; Charlene M Santos; Roman G Timoshchenko; Suzan K Hanna; Ramesh K Ramanathan; Craig R Lee; Victoria L Bae-Jump; Paola A Gehrig; William C Zamboni Journal: Nanomedicine Date: 2015-06-17 Impact factor: 5.307