Abstract 3374: Effect of bevacizumab and dexamethasone on plasma ultrafiltrate (UF) and cerebrospinal fluid (CSF) pharmacokinetics (PKs) of carboplatin in a non-human primate (NHP) model.
Authors: Akshintala Srivandana , Lester-McCully Cynthia M. , Murphy Robert F. , Widemann Brigitte C. , Warren Katherine E. 
Published: August 2014

Background: Bevacizumab and dexamethasone are commonly administered to patients with brain tumors, and may alter the central nervous system penetration of concurrently administered chemotherapeutic agents by affecting vascular permeability and blood brain barrier (BBB) composition. We compared plasma UF and CSF PKs of intravenously (IV) administered carboplatin given alone and in combination with dexamethasone or bevacizumab in a non-tumor bearing NHP model, that has been predictive of human PKs of anti-cancer drugs.

Methods: Carboplatin (8.75 mg/kg IV over 1 hour) combined with bevacizumab (12.5 mg/kg IV over 1 hour immediately prior to carboplatin) or dexamethasone (0.4 mg/kg IV bolus given 24 hours and immediately prior to carboplatin), was administered on separate occasions to each of three adult rhesus monkeys. Each monkey received carboplatin alone as control. Serial paired plasma and CSF samples were obtained over 24 hours. Plasma UFs were prepared immediately. Platinum was quantified using a validated atomic absorption spectroscopy assay with a lower limit of quantitation of 0.03 μM. Area under concentration x time curves (AUC) were derived using the linear trapezoidal method. CSF penetration (ratio of CSF AUC0-∞: plasma UF AUC0-∞) and CSF penetration relative to control (ratio of the CSF penetration of carboplatin with bevacizumab or dexamethasone to the CSF penetration of carboplatin alone) were calculated.

Results:

Plasma UF and CSF PK parameters for carboplatin (median and range) Plasma ultrafiltrate Cerebrospinal fluid CSF penetration Cmax (μM) AUC 0-∞ (μM*h) T ½ (h) Cmax (μM) AUC 0-∞ (μM*h) T ½ (h) (%) Relative to control (%) Carboplatin 78.3 (76.7–102.1) 182.0 (161.7–259.2) 5.2 (4.4–6.2) 0.71 (0.65–1.21) 8.26 (7.48–13.98) 9.6 (5.5–10.1) 4.6 (3.2–7.7) - Carboplatin+ Bevacizumab 88.2 (74.7–117.2) 197.5 (149.4–274.0) 5.6 (5.1–5.9) 0.62 (0.58–0.76) 6.82 (6.23–9.13) 9.4 (8.9–11.6) 4.2 (2.5–4.6) 78.1 (60.2–90.1) Carboplatin + Dexamethasone 104.0 (68.6–104.1) 202.5 (126.1–226.2) 6.5 (5.6–9.4) 0.60 (0.49–0.88) 6.38 (5.15–9.43) 7.9 (7.5–10.5) 4.1 (2.8–4.7) 88.3 (60.6–88.5) Cmax = maximal concentration, AUC = area under the concentration x time curve, T1/2 = terminal half life

Conclusions:

Plasma UF and CSF PK of carboplatin in NHP were similar to previous reports and showed limited inter-subject variability. Bevacizumab and dexamethasone consistently decreased the CSF penetration of carboplatin (median decrease 22% and 12% respectively). In patients with brain tumors and disrupted BBB, these differences may be larger and could be clinically relevant.

Citation Format: Srivandana Akshintala, Cynthia M. Lester-McCully, Robert F. Murphy, Brigitte C. Widemann, Katherine E. Warren. Effect of bevacizumab and dexamethasone on plasma ultrafiltrate (UF) and cerebrospinal fluid (CSF) pharmacokinetics (PKs) of carboplatin in a non-human primate (NHP) model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3374. doi:10.1158/1538-7445.AM2013-3374