In Vitro Kinetic Characterization of Axitinib Metabolism

Abstract

, respectively. Using a CYP3A4-specific inhibitor (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the axitinib intrinsic clearance was attributable to CYP3A4 and 15% to CYP3A5. Axitinib N-glucuronidation was primarily catalyzed by UDPglucuronosyltransferase (UGT) UGT1A1, which was verified by chemical inhibitors and UGT1A1 null expressers, with lesser contributions from UGTs 1A3, 1A9, and 1A4. The K m and V max values describing the formation of the N-glucuronide in HLM or rUGT1A1 were 2.7 mM or 0.75 mM and 8.9 or 8.3 pmol·min 21 ·mg 21 , respectively. In summary, CYP3A4 is the major enzyme involved in axitinib clearance with lesser contributions from CYP3A5, CYP2C19, CYP1A2, and UGT1A1.

Use of Physiologically Based Pharmacokinetic Modeling to Identify Physiological and Molecular Characteristics Driving Variability in Axitinib Exposure: A Fresh Approach to Precision Dosing in Oncology

“…Intestinal permeability was predicted based on in vitro kinetic data generated using untransfected Caco‐2 cells . Metabolism and elimination parameters were calculated by scaling reported intersystem extrapolation factor–adjusted in vitro CYP and uridine 5′‐diphospho‐glucuronosyltransferase data and in vivo data based on the impact of clinical index inhibitors (Figure ). As passive diffusion is the dominant mechanism for axitinib compartmental distribution, transporter kinetics were not incorporated into the model.…”

“…At neutral pH (ie, 7.4) the solubility of axitinib is <1 μM, although evidence suggests that the impact of pH on axitinib absorption is not clinically relevant under normal dosing conditions . Axitinib is primarily cleared by cytochrome P450 (CYP) 3A4, with minor contributions from CYP1A2 and 2C19, and the uridine 5′‐diphospho‐glucuronosyltransferases 1A1, 1A3 and 1A9 . Axitinib has high passive permeability (in vitro P app > 6 × 10 −6 cm/s) and is minimally transported by efflux or uptake transporters .…”

“…The mean (90% confidence interval [CI]) elimination half‐life for axitinib in cancer patients following a single oral dose is 4.8 hours (3.4‐6.2 hours) . Axitinib half‐life is not affected by steady‐state dosing; steady‐state half‐life is 4.1 hours (1.2‐7.0 hours), indicating that axitinib does not induce or inhibit its own metabolism …”

“…3 Axitinib is primarily cleared by cytochrome P450 (CYP) 3A4, with minor contributions from CYP1A2 and 2C19, and the uridine 5 -diphospho-glucuronosyltransferases 1A1, 1A3 and 1A9. 4 Axitinib has high passive permeability (in vitro P app > 6 × 10 −6 cm/s) and is minimally transported by efflux or uptake transporters. 2 The mean (90% confidence interval [CI]) elimination half-life for axitinib in cancer patients following a single oral dose is 4.8 hours (3.4-6.2 hours).…”

“…5 Axitinib half-life is not affected by steady-state dosing; steady-state half-life is 4.1 hours (1.2-7.0 hours), indicating that axitinib does not induce or inhibit its own metabolism. 4 A pooled population pharmacokinetic analysis of the steady-state exposure-response relationship for axitinib in renal cell carcinoma patients (n = 168) demonstrated that a 24-hour (2 dose) axitinib steady-state area under the plasma concentration-time curve (AUC SS ) of >300 ng/mL/hr is associated with superior progressionfree survival and overall survival. 6 In contrast, the relationship between steady-state axitinib trough concentration (C trough ) and therapeutic outcomes has not been established.…”