New pill formulations could fix a hidden problem blocking cancer drug access
Researchers have identified why common cancer drugs fail to work properly in many patients—and found that better pill designs, not complicated dosing tricks, can solve it. The finding matters because patient adherence to cancer medications directly affects survival rates, yet current drugs often require patients to time doses with specific foods or medications, a burden that undermines treatment success.
Originaltitel: Formulation breakthroughs driving broader tyrosine kinase use
Dear editor, Huntjens et al. reported an AI-based model designed and developed to predict the risk of reduced gastrointestinal (GI) absorption and bioavailability (F) for tyrosine kinase inhibitors (TKIs) in patients with altered GI conditions. The authors proposed several strategies to enhance absorption, reduce first-pass extraction and improve bioavailability.1 While their work offers valuable predictive tools for identifying pH-dependent GI absorption challenges associated with conventional TKI formulations, it highlights the urgent need for modern and improved oral dosage forms that eliminate, rather than merely manage, such challenges via patient behavioural modifications. The strategies they presented include dissolving tablets in cola (acidic beverage), implementing precise timing protocols with acid-reducing agents (ARAs), split-dosing regimens, and/or pharmacokinetic (PK) boosting with enzyme inhibitors (CYP3A4).1 While these approaches may improve F, they impose significant behavioural burdens that can compromise long-term adherence. Studies indicate that adherence rates exceeding 90% significantly improve the probability of achieving major molecular response,2-4 yet real-world adherence remains suboptimal.5 Requiring patients to source specific beverages adhere to complex dose-timing intervals or manage additional medications adds complexity that may interfere with other treatments, particularly in patients with multiple comorbidities and in the elderly population. A more rational and sustainable approach to improving TKI therapies involves engineering oral dosage forms that deliver predictable and consistent plasma exposure across variable GI conditions, thereby optimizing long-term efficacy and safety.6 Drugs from Biopharmaceutics Classification System (BCS) classes II (high permeability/low solubility) and IV (low permeability/low solubility) are very sensitive to highly dynamic changes of GI luminal conditions during fasted and fed states, GI comorbidities that cause hypo- and achlorhydria and drug–drug interactions (DDIs) with ARAs.7-12 By eliminating this pH-dependent variability at the formulation level, this approach is expected to maintain simple dosing regimens and to support high adherence rates. Improving GI absorption of lipophilic, basic BCS Class II and IV drugs with low and pH-dependent solubility typically requires an enabling formulation strategy.13, 14 One such strategy is the use of amorphous solid dispersions (ASDs), which improves the luminal solubility and subsequent intestinal absorption of lipophilic, basic TKIs.15-17 A highly variable TKI plasma exposure may compromise therapeutic efficacy and/or increase the risk for adverse effects due to subtherapeutic or excessive drug levels, respectively, depending on the dosing regimen.6 Formulating TKIs as ASDs may mitigate interindividual and intraindividual variability in plasma drug exposure, reduce the risk of DDIs with current and future ARAs and limit food-drug interactions.15, 18, 19 Other formulation strategies include salt selection, exemplified by the use of the maleate salt of acalabrutinib to overcome the limitations of the free base, as well as an oral dosage form of palbociclib incorporating succinic acid to overcome reduced intestinal absorption at elevated gastric pH.20, 21 Together, these examples show that, for most BCS class II TKIs, the dissolution behaviour of the finished dosage form largely dictates GI absorption and the plasma exposure–time profile. A successful formulation may also enable lower doses to be used. Higher oral doses with older products may cause elevated plasma exposure and increase the incidence of adverse events, thereby contributing to treatment discontinuation and suboptimal adherence.6, 22 Therefore, achieving consistent plasma drug exposure at lower doses with novel formulation is crucial to further improve TKI therapy. Nonadherence, often driven by tolerability issues and regimen complexity, remains a key factor influencing treatment success. Studies indicate that adherence rates exceeding 90% significantly improve the probability of achieving major molecular response.2-4 Such high adherence is even more crucial in real-world patients, who are more likely to discontinue TKI therapy because of adverse events than patients enrolled in clinical trials.5 While Huntjens et al. provide valuable predictive tools and describe intervention strategies for managing pH-dependent GI absorption with conventional formulations,1 we believe that the future of achieving optimal TKI therapy lies in pharmaceutical innovation that eliminates the need for complex patient behavioural modifications. Formulation advances such as ASD technology offer a more accessible, scalable and patient-centred solution than strategies that require special beverages, precise dosing intervals and/or pharmacokinetic boosting. Such formulation innovations should be prioritized as first-line approaches, whereas behavioural interventions should be reserved to rescue or critical situations in which pH-independent formulations are not yet available. Looking forward, the future of TKI therapy lies not only in the discovery and development of improved molecules but also in smarter oral drug delivery systems. With the hugely successful effect of TKIs in patients with chronic myeloid leukaemia (CML), virtually normalizing their overall life expectancy,23 the focus of clinical treatment paradigms is now expanded to also include long-term disease control and improved quality of life. In this setting, novel, upgraded formulations of TKIs are anticipated to enhance future outcomes not only in CML but also for patients with a number of other cancer diagnoses. All authors contributed to outline and write this document. Hans Lennernäs reports consultancy for Xspray and equity for Xspray, AstraZeneca, Novo Nordisk, Medivir, Nanologica and Pfizer and research funding from AbbVie. Magnus Brisander reports consultancy and equity for Xspray. Mikael von Euler reports consultancy and equity for Xspray; Board of Director, consultancy and equity for Dicot, Annexin and Spago Nanomedical. Leif Stenke reports consultancy for Xspray. Per Andersson, Claes-Henrik Andersson, Gérald Jesson and Charlotta Liljebris are employees of Xspray and holds equity in Xspray. Data is sharing not applicable to this article as no datasets were generated or analysed during the current study.