Evaluation of Novel Strategies to Address the Challenges of Precision Dosing for Small Molecule Kinase Inhibitors

Author: Madelé van Dyk

van Dyk, Madelé, 2018 Evaluation of Novel Strategies to Address the Challenges of Precision Dosing for Small Molecule Kinase Inhibitors, Flinders University, College of Medicine and Public Health

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Small molecule protein kinase inhibitors (KIs) are a key class of oral antineoplastic drugs that are effective at treating numerous malignancies, including previously difficult to treat forms of cancers. However, variability in KI absorption and disposition causes variability in KI exposure that is inadequately addressed by the standard fixed-dose schedule of administration. Accordingly, it is proposed that the optimisation of KI dosing has great potential to maximise therapeutic response, minimise adverse drug reactions (ADRs), and improve cost-effectiveness of these expensive drugs. To facilitate this, a more comprehensive understanding of the sources of variability in KI exposure is required.

Results presented in Chapters II and III elucidate sources of variability in KI exposure using physiologically based pharmacokinetic (PBPK) modelling and a healthy volunteer study. Specifically, in Chapter II, robust mechanistic models with the capacity to describe epidermal growth factor receptor (EGFR) KI exposure and the impact of covariates on exposure are developed and verified. These models may be applied to inform the impact of different dosing regimens on EGFR KI exposure, the potential impact of poor compliance on EGFR KI efficacy, the need to perform bridging studies when introducing EGFR KIs to new international markets, and the potential impact of DDIs on EFGR KI exposure. In Chapter III inter-racial variability in midazolam exposure was assessed in a cohort of healthy males with Caucasian and South Asian ancestries. This study demonstrated significantly higher midazolam clearance in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.

Given the limitations in terms of evidence generation, novel and practical strategies are required to facilitate the clinical application of dose optimisation. Such strategies may facilitate earlier dose optimisation and identify patients for whom TDM is most critical. In this regard, pathway phenotyping (PP) involves monitoring the blood for a rapidly cleared surrogate probe, or cocktail of probes (typically exogenous), that are substrates for pathways involved in the disposition of the drug of interest. Chapter IV describes the development of a novel phenotyping approach based on dietary markers of CYP3A4 activity to optimise KI dosing from a limited number of blood samples without a requirement to administer prescription drugs

Studies have demonstrated the benefit of using therapeutic drug monitoring (TDM) to individualise KI dosing on the basis of plasma-KI concentration, and therapeutic concentration ranges have been established for dasatinib, erlotinib, gefitinib, imatinib, nilotinib, pazopanib and sunitinib. However, the broader clinical uptake of TDM is hindered by the requirement to: (i) establish and validate separate analytical methods for each KI as they enter clinical practice, and (ii) generate sufficiently powered evidence to support the clinical validity of the benefit of concentration guided dosing. Chapter V describes the development and verification of a panel based approach to facilitate the efficient assessment of KI plasma concentrations. This approach was developed, validated and reported in accordance with the 2015 version of the FDA guidance for industry on ‘analytical procedures and methods validation for drugs and biologics’ facilitating direct application as a clinical trials platform.

Keywords: Pharmacology, Pharmacokinetics, Tyrosine Kinase Inhibitors, Therapeutic Drug Monitoring, Cancer

Subject: Clinical Pharmacology thesis

Thesis type: Doctor of Philosophy
Completed: 2018
School: College of Medicine and Public Health
Supervisor: Dr Andrew Rowland