Paper: Technetium-99m Sulfur Colloid (TSC) as a phenotypic probe for predicting pharmacokinetics (PK) and palmar-plantar erythrodysesthesia (PPE) toxicity of PEGylated liposomal doxorubicin (PLD) in patients with recurrent epithelial ovarian cancer (EOC) (2012 ACCP Annual Meeting)

Monday, October 22, 2012

Westin Diplomat Resort

Hugh Giovinazzo, BSc, PharmD, Candidate¹, Parag Kumar, PharmD¹, Arif Sheikh, MD², Marija Ivanovic, PhD², Mark D. Walsh, PharmD³, Whitney P. Caron, PharmD¹, Gina Song, PharmD¹, Ann B. Whitlow, RT, CNMT⁴, Suzanne E. Newman, BSc⁴, Nihn La-Beck, PharmD⁵, Richard J. Kowalsky, PharmD⁴, Beth A. Zamboni, MS⁶, Daniel L. Clarke-Pearson, MD⁷, Wendy R. Brewster, MD⁷, Linda Van Le, MD⁷, Victoria Lin Bae-Jump, MD, PhD⁴, Paola A. Gehrig, MD⁷ and William C. Zamboni, PharmD, PhD¹
1University of North Carolina at Chapel Hill School of Pharmacy Division of Pharmacotherapy and Experimental Therapeutics, Chapel Hill, NC
2University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC
3Mount Auburn Hospital, Cambridge, MA
4University of North Carolina at Chapel Hill, Chapel Hill, NC
5Texas Tech University, Abilene, TX
6Carlow University, Pittsburgh, PA
7University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC

Purpose: There is significant variability in the PK and pharmacodynamics (PD) (efficacy and toxicity) of PLD. Clearance of PLD occurs primarily via cells of the mononuclear phagocyte system (MPS). Our aim is to evaluate TSC, which can be used for imaging areas of the MPS, as a phenotypic probe of MPS activity to predict PLD PK, PPE toxicity, and progression free survival (PFS) in women with EOC.

Methods: TSC was administered at 10 mCi IVP × 1 (D-1;-7). Dynamic planar and SPECT/CT images of patients' hands were acquired. Blood samples were collected up to 60 min after TSC. PLD was administered at 30 or 40 mg/m² IV x 1 alone or in combination with carboplatin IV at AUC=5 (D1). PK samples were obtained from 0h to 672h post PLD. Encapsulated and released doxorubicin were measured in plasma. TSC and PLD clearance were calculated by non-compartmental analysis. PPE toxicity and PFS were assessed using standard methods.

Results: Corresponding imaging and PK data were acquired for 8 patients. There was a positive linear relationship between TSC clearance and encapsulated doxorubicin clearance (R² = 0.61, p=0.02) and a stronger relationship (R² = 0.81, p=0.03) in patients receiving PLD monotherapy. A positive relationship (Spearman's ρ=0.84, p=0.006) was found between PPE toxicity developed and estimated AUC of encapsulated doxorubicin in hands [(TSC AUC_Hand)/(TSC AUC_Blood )*Encapsulated doxorubicin AUC_Plasma]. An inverse linear relationship between PFS and TSC clearance was seen for all patients who progressed (n=4) (R²=0.46), and was stronger in patients who received PLD alone (n=3) (R²=0.97).

Conclusions: Results suggest TSC is a probe for MPS function and PLD PK and PD and may be used to individualize PLD therapy in patients with EOC. Our findings also suggest TSC may be able to predict the development of PPE and PFS in women with EOC.