Individualized Dosing with Axitinib: Rationale and Practical Guidance

Abstract

Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety. Rationale for individualized dosingBefore the development of molecular targeted therapy, most available anticancer drugs, with hormone therapies and immunotherapies being notable exceptions, were chemotherapy agents: chemicals aimed at having a cytotoxic effect on cancer cells [1,2]. These drugs were dosed according to a patient's weight or body surface area, based on the observation that patients with a greater body size generally have a greater volume of distribution and require higher doses than smaller patients to reach equal drug concentrations [3]. It was thought this approach would deliver consistent systemic drug exposure, thereby optimizing treatment outcomes. This dosing approach was also chosen based on a lack of a better option at that time. However, it was known that multiple factors beyond patient size (including age, sex, renal function, hepatic function, concomitant medication, disease state and genetics) could have an impact on the actual concentration of a drug in an individual's bloodstream [4]. Consequently, there remains high variability between patients (interpatient variability) in systemic drug concentrations, even when normalized for weight/body surface area [5].When molecular targeted agents were first introduced for use in metastatic renal cell carcinoma (mRCC), these drugs were recommended at a fixed dose, based on an assumption that the maximum tolerated fixed dose would result in the best efficacy and that this same high dose would be appropriate for all patients. However, most tyrosine kinase inhibitors (TKIs) demonstrate high interpatient variability in drug exposure (depending on oral bioavailability and first-pass liver metabolism of drugs); therefore, the subsequent therapeutic effect and toxicity for the same administered dose may vary [6]. As a result, fixed dosing may result in suboptimal efficacy for some patients or excessive toxicity in others [7]. In addition, higher-than-needed doses may be excessive if therapeutic effects are already achieved at lower doses.

NK‐Cell Biofactory as an Off‐the‐Shelf Cell‐based Vector for Targeted In Situ Synthesis of Engineered Proteins

“…The dynamic state of cell-based pathologies and inter-patient variability presents a challenge that, in the context of optimal dosing, requires continuous monitoring of the disease state and individual patient. [1,2] Current standard of care in drug delivery is to administer doses normalized to the body weight and surface area. [3] However, the disease burden is different for similar-sized patients.…”

Lentivirus Manufacturing Process for Primary T‐Cell Biofactory Production

“…Continuous monitoring of the disease state for individual patient is not pragmatic. [1,2] Current standard of care in drug delivery is to administer doses normalized to the body weight and surface area. [3] However, the disease burden, that is different for similar-sized patients, is not accounted for.…”

Exposure-response modeling of cabozantinib in patients with renal cell carcinoma: Implications for patient care

“…To better inform dosing strategies with cabozantinib, popPK and ER models were developed to evaluate the relationship of cabozantinib dose, clearance, and exposure with efficacy, safety, and tolerability during the METEOR study [18][19][20][21]. These analyses support dose modification as the principal strategy to manage tolerability of cabozantinib while maintaining efficacy [22,23]. In this review, we present an overview of previously published pharmacometric analyses of cabozantinib in patients with advanced RCC and discuss the implications of these analyses in terms of patient care and appropriate dose modification.…”