Technetium-99m sulfur colloid (TSC) as a phenotypic probe for the pharmacokinetics (PK) and pharmacodynamics (PD) of pegylated liposomal doxorubicin (PLD) in patients (pts) with recurrent epithelial ovarian cancer (EOC).

Abstract

2582 Background: There is significant inter- and intra-patient variability in the PK and PD (efficacy and toxicity) of PLD in pts with EOC and other malignancies. This has been attributed to age and gender, but more specifically, may be related to the mononuclear phagocyte system (MPS). Clearance (CL) of PLD has been proposed to occur primarily via uptake by monocytes, dendritic cells, and macrophages mainly located in the liver, spleen, and blood. TSC is a radioactive colloid used clinically for diagnostic and functional imaging of the MPS. Our aim is to evaluate TSC as a phenotypic probe of MPS activity, which may predict PLD PK and PD in pts with EOC. Methods: Prior to (day -7 to -1) administration of PLD on cycle 1 day 1 (C1D1), TSC was administered at 10 mCi IV × 1. Dynamic planar and SPECT/CT images of the liver and spleen were acquired using a gamma camera. Blood samples were collected up to 60 min after TSC and analyzed for radioactivity using a gamma counter. On C1D1, PLD was administered at 40 mg/m2 alone or at 30 mg/m2 in combination with carboplatin IV over 1 to 1.5 h. Serial blood samples were collected up to 28 days after PLD. Plasma samples were processed to measure encapsulated (encap) and released doxorubicin via HPLC with fluorescence. Results: Six pts have undergone TSC imaging and blood PK, and PLD plasma PK studies. Mean ± SD encap doxorubicin CL and TSC CL were 25.4 ± 4.1 mL/h and 18.9 ± 5.4 mL/h, respectively. There was a positive linear relationship between TSC CL and encap doxorubicin CL (R2 = 0.58). Mean ± SD of encap doxorubicin area under the concentration versus time curve (AUC) and TSC splenic outflow were 2.4 ± 0.5 mg/mL·h and 0.5 ± 0.1 s-1, respectively. There was a positive linear relationship between TSC splenic outflow and encap doxorubicin AUC (R2 = 0.85). There was no relationship between TSC AUC in the liver and spleen and PLD PK. Conclusions: These results suggest that TSC is a probe for MPS function and PLD PK and may be used to individualize PLD therapy in pts with EOC and other malignancies. Evaluation of the relationship between TSC and PLD PD is undergoing further investigation.