Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma

Rini, Brian I.; Melichar, Bohuslav; Fishman, Mayer; Oya, Mototsugu; Pithavala, Yazdi K.; Chen, Y.; Bair, Angel H.; Grünwald, Viktor

doi:10.1093/annonc/mdv103

Cited by 71 publications

(66 citation statements)

References 9 publications

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“…However, given that prospective studies using dBP are already available, an integrated approach using both PK and dBP to guide dosing may be the most appropriate strategy to optimize treatment, as has been advocated previously 46. Although more evidence is available to support the AUC target, the more practical C min target of >5 ng/mL could also be considered (as it requires only a single plasma sample) 45…”

Section: Practical Recommendations For Tdm Of Kis In Oncologymentioning

confidence: 99%

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Verheijen

Schellens

et al. 2017

Clin Pharma and Therapeutics

227

287

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Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs.

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Section: Practical Recommendations For Tdm Of Kis In Oncologymentioning

confidence: 99%

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Verheijen

Schellens

et al. 2017

Clin Pharma and Therapeutics

227

287

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“…These results demonstrate significant associations between exposure and clinical response for axitinib (i.e., patients with lower exposure are likely to receive less benefit than patients with higher exposure). Furthermore, as shown in Figure 2F, even after dose optimization, patients who achieve a higher axitinib exposure seem to have a better clinical outcome; these positive associations were further confirmed using data from the Phase II 1046 study [8]. Treatment-naïve patients with mRCC received axitinib 5 mg b.i.d.…”

Section: Interpatient Variability In Drug Exposure Translates Into Vamentioning

confidence: 65%

“…In a retrospective analysis of pooled data [8] (two Phase II studies in which axitinib was evaluated in cytokinerefractory mRCC [n = 116] [28,29] and one Phase II study in which axitinib was evaluated in sorafenib-refractory mRCC [n = 62] [30]), variability in axitinib exposure (as measured by the area under the plasma concentrationtime curve [AUC]) was demonstrated in patients after they each received the same standard dose of 5 mg b.i.d. ; Figure 2A shows the extent to which variations occurred between patients.…”

Section: Interpatient Variability In Axitinib Exposurementioning

confidence: 99%

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Individualized Dosing with Axitinib: Rationale and Practical Guidance

et al. 2017

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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.

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“…ВБП оказалась достоверно выше. Исследователи ре-зюмировали, что индивидуализация режима дозиро-вания акситиниба в настоящее время на основании использования фармакокинетических данных и пока-зателей АД не долж на использоваться в качестве единственного прогностического фактора [29].…”

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