Beyond intravenous delivery: choosing better administration routes for oncologic drugs
By Karthik Chellappan
Intravenous delivery remains the dominant paradigm in oncology, but even with precision medicine few drugs pass late stage clinical trials. Karthik Chellappan proposes that early exploration of better administration routes could make all the difference.
Over the last decade, the shift towards “precision” medicine has led to increasing use of biomarkers and, more recently, next-generation sequencing to guide therapy selection. Here we argue that there is another, underexplored dimension to “precision” oncology: the adoption of targeted alternatives to intravenous infusion, such as intratumoral delivery, delivery via locoregional vasculature and lymphatic delivery.
The approach we propose broadens opportunities in drug design and can enhance the effects of existing targeting approaches employed in the pharmaceutical industry. First, by avoiding systemic toxicity, targeted administration via alternative routes may enlarge the design space for oncologic drugs, thus leading to drug candidates with improved efficacy. Second, targeted administration also has the potential to enhance the effects of other, formulation-based targeting technologies by helping drug entities overcome the physiological barriers that hinder drug transport and retention.
However, as we explain below, early preclinical assessment of different targeted routes is essential to increase the likelihood of successful therapeutic outcomes. Moreover, the effectiveness of a targeted administration route is heavily influenced by the device-specific delivery parameters, such as fluid pressures and flow rates, and therefore requires multidisciplinary understanding of tissue biomechanics and anatomic and fluidic principles to complement medical device design and development.
Constraints imposed by intravenous delivery
Currently, the most widely accepted route of delivery for oncologic drugs is intravenous administration. Most monoclonal antibodies and chemotherapies, regardless of their indications, are delivered through this route. The maturity of intravenous delivery can feel reassuring amongst the many uncertainties during the early phases of drug discovery. However, due to the systemic nature of intravenous delivery, the design space for suitable drug candidates is constrained by the conflicting requirements of efficacy, toxicity and drug physicochemical characteristics.
Sustained efforts to improve the lead optimisation process have been effective at reducing the severity of adverse events in clinical trials, but efficacy in late stage clinical trials remains very low, with the lowest approval rates observed in oncology. Only 7% of all oncology drugs that entered phase 2 trials between 2000 and 2015, eventually achieved approval, making the current approach to drug development economically unsustainable . The use of novel biomarkers in clinical trials to stratify patients and as indicators for toxicity or efficacy has improved the drug approval rate to 11%, suggesting that other complementary solutions are still required to address this challenge.
What is ‘targeted’ delivery?
Targeted delivery typically refers to formulation-based nanotechnologies that enhance shielding of intravenously delivered drugs to prevent non-specific binding and improve circulation times, while actively targeting diseased tissue. Formulation-based targeted technologies often increase the physical dimensions of the therapeutic entity, however. This can significantly influence drug transport, with larger entities typically showing poorer ability to cross tumour vasculature and subsequently diffuse into tumour tissue. The ‘targeted’ delivery approach we propose is to select targeted administration routes and delivery parameters that overcome the physiological barriers to drug transport and retention. This approach is compatible with formulation-based nanotechnologies and may enhance the consistency of delivery despite interpersonal variations.
Why consider targeted delivery?
Targeted delivery modalities have the potential to reduce systemic toxicity whilst simultaneously increasing the dose concentration at the target location, and thus provide an effective lever during lead optimisation and to ensure safety and efficacy in subsequent clinical trials. These considerations are becoming increasingly relevant with the widespread use of new biologic mechanisms that treat haematological malignancies or act as immune checkpoint inhibitors. In addition, targeted delivery remains particularly desirable for some emerging drug mechanisms such as siRNA and gene-based therapies. However, despite these benefits, the adoption of targeted delivery routes has been slow, presumably because it shifts the technical constraints in the therapy development process from pharma-centric skills in drug lead optimisation to the design of novel medical device technologies that enable consistent, minimally invasive delivery to specific compartments within the body.
In silico time-stepped modelling of drug penetration and dispersion through a tumour following intravenous infusion .
The current landscape of ‘targeted’ delivery devices
For a number of treatments, FDA-approved ‘targeted’ solutions already exist that aim to circumvent or modulate the physiological barriers encountered when treating solid tumours. For example, intraparenchymal catheters are used to circumvent the blood brain barrier for delivery to glioblastomas, hyaluronidase is used to enhance permeability and transport of drugs within subcutaneous tissue, and tumour debulking/ablation strategies are used in conjunction with chemotherapy to enhance drug concentrations in liver, kidney and pancreatic tumours.
And next-generation medical devices are now exploring new solutions. For example, devices are under development to infuse into multiple intratumor locations through a single procedure, to isolate sections of hollow organs for chemotherapy delivery, to overcome flow stagnation and functional shunts in tumour vasculature and to deliver to the lymphatic system for more effective targeting of tumour metastasis and other haematological malignancies.
Developing a ‘targeted’ delivery device
Effective integration of novel solutions requires a thorough understanding of medical device development and the interaction of the drug with the pathophysiological fluidic and mechanical phenomena encountered along the administration route. These considerations are crucial for clinical trial outcomes and hence must be investigated early to inform the specification for any medical device development. Investigations should employ a combination of in-silico, in-vitro and traditional in-vivo approaches during pre-clinical development to robustly assess the sensitivities of key delivery parameters. These approaches help to avoid unnecessary device complexity while building confidence in the targeted delivery modality by matching physiology-driven needs to device requirements. Lastly, the delivery device parameters for targeted administration also need to consider the binding kinetics of the drug, which determines the duration of retention required at the target site for sufficient target engagement and therapeutic effect.
The advent of novel immuno-oncologic drugs and the desire to improve the therapeutic efficacy of established chemotherapeutics creates a pressing need within oncology to look beyond the most common options of intravenous and subcutaneous administration to device-based targeted administration modalities.
The current situation of low clinical trial success rates and high costs in oncology mean that even small improvements in efficacy through this approach could create significant clinical and economic benefits. Devices that exploit targeted administration routes can significantly limit adverse effects while improving exposure at the target location.
Safety profiles for targeted administration routes should therefore be evaluated alongside intravenous options in the early phases of clinical trials. This will reduce the barriers to subsequent comparative assessment of the efficacy of targeted delivery modalities in later stages of clinical trials.
However, the proposed paradigm of successfully exploiting targeted delivery modalities requires a multidisciplinary approach to product development that integrates traditional approaches to product design with a strong focus on strategies that aim to consistently overcome the physiological barriers presented by the administration route.
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02. Image used. “Interstitial Fluid Flow and Drug Delivery in Vascularized Tumors: A Computational Model”, Michael Welter, Heiko Rieger, August 2013