The Role of Lymphatic Transport on the Systemic Bioavailability of the Bcl-2 Protein Family Inhibitors Navitoclax (ABT-263) and ABT-199

Abstract

Navitoclax (ABT-263), a Bcl-2 family inhibitor and ABT-199, a Bcl-2 selective inhibitor, are high molecular weight, high logP molecules that show low solubility in aqueous media. While these properties are associated with low oral bioavailability (F), both navitoclax and ABT-199 showed moderate F in preclinical species. The objective of the described study was to determine if lymphatic transport contributes to the systemic availability of navitoclax and ABT-199 in dogs. The intravenous pharmacokinetics of navitoclax and ABT-199 were determined in intact (noncannulated) dogs. In oral studies, tablets (100 mg) of navitoclax and ABT-199 were administered to both intact and thoracic lymph duct-cannulated (TDC) dogs. The clearance of navitoclax and ABT-199 was low; 0.673 and 0.779 ml/min per kilogram, respectively. The volume of distribution of both compounds was low (0.5-0.7 l/kg). The half-lives of navitoclax and ABT-199 were 22.2 and 12.9 hours, respectively. The F of navitoclax and ABT-199 were 56.5 and 38.8%, respectively, in fed intact dogs. In fed TDC dogs, 13.5 and 4.67% of the total navitoclax and ABT-199 doses were observed in lymph with the % F of navitoclax and ABT-199 of 21.7 and 20.2%, respectively. The lower lymphatic transport of ABT-199 corresponds to the lower overall % F of ABT-199 versus navitoclax despite similar systemic availability via the portal vein (similar % F in TDC animals). This is consistent with the higher long chain triglyceride solubility of navitoclax (9.2 mg/ml) versus ABT-199 (2.2 mg/ml). In fasted TDC animals, lymph transport of navitoclax and ABT-199 decreased by 1.8-fold and 10-fold, respectively.

BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer

“…We modelled concentrations that resulted in an effective tissue concentration of 0 to 5 μM of ABT-199 over 12 hours in the presence of 5FU/ oxaliplatin-based chemotherapy. This concentration of ABT-199 is in line with measured levels in plasma in dogs, where the plasma concentration is a maximum of 5 μM after oral administration with ∼10 mg/kg body weight [28]. The stress dose required for MOMP dropped in all patients with increasing ABT-199 doses (Fig.…”

Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin Lymphoma

“…The effect of food on venetoclax pharmacokinetics could be attributed to stimulation of the formation of triglyceride‐rich lipoprotein in enterocytes by food lipids. This has the potential to enhance venetoclax intestinal lymphatic transport and hence increase the absorbed fraction of venetoclax dose and to bypass the hepatic first‐pass effect …”

A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia

“…Navitoclax plasma PK samples were obtained coincident with the week 1, lead-in day 5 dose: pre-dose and at 2, 4, 6 and 8 h post-dose; and on week 8, day 1: pre-dose and at 2, 4, 6, 8 and 24 h post-dose in arm B and arm C. Pre-infusion and post-infusion rituximab samples were obtained on day 1 at weeks 2, 4 and 8, and rituximab concentrations were subsequently followed at weeks 12, 16, 20 and 24. Navitoclax concentrations in plasma were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) method [22]. Rituximab concentrations in serum were analyzed using a validated immunoassay [23].…”