Abstract 5040: The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates

Abstract

Abstract Background: Pegylated liposomal doxorubicin (PLD) exhibits altered plasma pharmacokinetics (PK) compared to doxorubicin, with a longer half-life (55 hours), large area under the concentration-time curve (AUC), lower rate of clearance, and markedly smaller volume of distribution. The cerebrospinal fluid (CSF) PK of PLD are unknown. We evaluated the plasma and CSF PK of PLD in a non-human primate (NHP) model. Methods: PLD was given as single dose (1 mg/kg = low adult recommended dose of 20 mg/m2) intravenously over 60 minutes to 3 NHP with indwelling central venous catheters and central nervous system ventricular reservoirs or lumbar ports. Serial blood and CSF samples were obtained for 96 hours after completion of the infusion. The total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUCCSF:AUCplasma. Results: PLD was well tolerated. Total doxorubicin plasma concentration time curves were characterized by sustained PLD exposure, comparable to the exposure observed in humans at a similar dose. The terminal elimination phase was not captured. In CSF, doxorubicin was measurable and still present at the last time point in all animals, but the CSF penetration was limited (Table). Conclusions: Using a sensitive assay, we could quantify doxorubicin in CSF. However, the CSF penetration is limited in NHP with intact blood brain barrier. Our assay analyzed the total doxorubicin concentration in plasma. It is unknown if PLD can penetrate into the CSF, therefore we could not determine if the CSF penetration represents total versus free. Plasma and CSF PK of pegylated liposomal doxorubicin in NHPAnimalCmax Plasma(ng/mL)Tmax Plasma(h)AUC0-96h Plasma(ng*h/mL)Cmax CSF (ng/mL)Tmax CSF (h)AUC0-96h CSF (ng*h/mL)CSF Penetration (%)19396487.24E+051.84524.210.3323044901.76E+060.71618.750.113374670.081.91E+063.251036.410.2Mean25770161.46E+061.93726.460.21 Citation Format: Christine Higham, Robert Murphy, Cynthia McCully, Katherine Warren, Brigitte Widemann. The plasma and cerebrospinal fluid pharmacokinetics of pegylated liposomal doxorubicin after intravenous administration in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5040. doi:10.1158/1538-7445.AM2017-5040