Laboratory-Clinic InterfaceVariability in bioavailability of small molecular tyrosine kinase inhibitors
Introduction
The development of anticancer drugs is a very quickly expanding area in which two trends are clearly present. In the first place new agents are designed fulfilling the requirements for personalized medicine. The advancement of techniques such as (cell-based) high throughput screening and the diverse possibilities in molecular modeling have lead to a therapeutic target-based drug discovery regime [1], [2]. Along with the evolution of synthetical methods, compounds are found that are highly specific and demonstrate great affinity for molecular targets [3], [4], [5], [6]. Individual tumors, and their specific targets, can be genetically characterized and a suitable ‘personalized’ chemotherapy can be appointed depending on the neoplasm’s genotype [7]. The second movement is also referred to as ‘the intravenous to oral switch’. The last decade has shown an increasing number of anticancer drugs that are administered orally [8], [9]. Currently, most of the anticancer drugs that are in development or recently approved are destined for oral ingestion. Unlike previous conventions, oral therapy in cancer has proven efficient and less costly [10]. On top of that comes the preference of the patient, especially since oral ingestion can take place in the home setting and is highly convenient compared to intravenous administration [8].
In the middle of these trends stands a promising and growing group of drugs; the tyrosine kinase inhibitors (TKIs). In the past ten years, the size of this group has doubled [11], [12], [13]. The TKIs target specific parts of tyrosine kinase receptor proteins that play an important role in the intracellular signaling pathways in tumor cells. Their interference leads to a deregulation of essential cell functions such as proliferation and differentiation [14]. One of the two types of TKIs, the small molecular TKIs (smTKIs) with an intracellular activity, are without exception administered orally. Currently, twenty of these small molecular compounds are approved by both the EMA and the FDA. General information on the drugs is found in Table 1 [11], [12]. This review will focus on these particular compounds. The other type of TKI is a group of monoclonal antibodies, which possess a larger molecular structure and interfere with signal transduction by binding extracellularly and are administrated intravenously. The small molecular inhibitors have proven useful in the therapy of certain types and lines of cancer [6], [11], [12], [15]. Additionally, smTKIs may be prescribed as alternatives when other therapeutic options have failed or are not appropriate. Although the development of personalized oral chemotherapy is very promising, the nature of the selection process leads to drugs, however, that are hindered by a low and variable bioavailability (F). This aspect and its causes are underexposed subjects in literature. Indeed, smTKIs may be very potent and suitable for certain tumor types. When they are unable to reach their target in sufficient quantities, the therapy will be suboptimal or even failing. This review will address the bioavailability-determining factors for the smTKIs and presents prerequisites in both the marketed formulations and chemotherapeutical practice to minimize the reduction and variation in oral F. It is important to be aware of and understand the various factors that determine F and its variability of the smTKIs. This will allow for the betterment of their use in chemotherapy.
The fraction of the total ingested drug that reaches the systemic circulation unchanged, and is transported to its therapeutic target, is defined and termed (absolutely) bioavailable (F) [16]. Fig. 1 schematically presents the different processes that govern the extent of F. F is the product of the drug fraction that is absorbed (FF), the dose that reaches the hepatic portal vein unchanged (FG) and the fraction of the dose that is not metabolized by enzymes in the liver (FH), as presented in Eq. (1) [16], [17],
In each of the before mentioned steps, an amount of drug might be lost. Whatever the cause, a low F is associated with an increased intra- and interpatient variability in drug plasma concentration [18]. Registration texts and other studies, as far as could be accessed, show significant inter-individual variation in important pharmacokinetic parameters of all smTKIs [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. This may result in possibly dangerous situations for patients that experience extensively low, or high, exposure to the substances. Many anticancer drugs are known to exhibit a small therapeutic window, where the minimum therapeutic dose and the maximum tolerated dose (MTD) are close to each other [38]. The same is true for the smTKIs, with a possible exception of Dabrafenib, Imatinib, Gefitinib and Pazopanib [13], [19], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52]. As a consequence of pharmacokinetic variation, inter-individual differences in therapeutic dose and MTD should be taken into account. Under- and overdosing are thus potential hazards of oral chemotherapy. Thus, careful dose titration and adjustments are required to assure an adequate therapy, in both effect and tolerance. Hence, therapeutic drug monitoring (TDM) is upcoming for smTKIs [38].
The human oral F of the smTKIs is largely unknown or inaccessible in the public domain and published values are generally low and the exposure is variable [39], [53], [54]. The determination of oral F-values requires a comparison between oral and IV-administration. IV-solutions with smTKIs are often difficult to prepare due to the poor water solubility of the drugs (see Section ‘Dissolution’). Table 1 presents the currently known values. Low values for oral F may be due to one or more of several factors. It is often the consequence of a complex interplay of both physicochemical and physiological processes. Furthermore, it may also be influenced by concomitant administration of other drugs. Additionally, the intake of food or certain habits of life-style may exert an impact on F.
The Biopharmaceutics Classification System (BCS) can aid to clarify possible absorption-related causes of an impaired F. Solubility and permeability of a drug are recognized as fundamental parameters in the absorption process [55]. The BCS combines data on the in vitro solubility in the intestinal tract of the drug substance and data on the extent of total permeation through the gut wall and appoints a class to it [55], [56], [57]. Fig. 2 summarizes the assignment of the classes and presents the classes of the smTKIs [58], [59], [37]. Classifications may be interpreted as signals for formulation design (class II and IV) or physicochemical modifications (class III and IV) [58].
The newer Biopharmaceutics Drug Disposition Classification system (BDDCS) correlates the passive permeability rate of drug with their metabolic elimination [60], [61], [62]. Here, passive permeability is considered ‘good’ when elimination is largely governed by metabolism (>70%) [63]. Fig. 2 presents the BDDCS classification between braces where it differs from the BCS classification. The discrepancies between the BCS and BDDCS classes may be due to the fact that BCS is based on total permeation and BDDCS on the passive permeability rate [64]. The latter does not account for interaction with membrane transporters.
Section snippets
Dissolution
The first step in becoming bioavailable is the dissolution of the drug substance into the gastrointestinal fluids. Since only the solute form of the drug can be absorbed, the release from the oral formulation is an important parameter. In fact, the major cause for the different absorption profiles of drugs from various products is dissolution [16]. The dissolution rate of a drug substance can be described using the Noyes-Whitney equation (Eq. 2) [65], [66]:in which dW/dt is the
Permeability and passive transport
The degree of permeability describes the extent of (intestinal) membrane penetration of a drug [86]. The passing of molecules occurs through passive or facilitated diffusion, (active) carrier mediated or paracellular transport [87], [88]. Lipophile, large and relatively uncharged drugs are moved transcellularly through cell membranes. This passive transport is a or the major route of movement across membranes of many drugs [86], [89]. The same is reported for the smTKIs, although this is not
Elderly
The process of aging involves changes in physiology and the functioning of organ systems. Important hepatic changes when considering drugs are a decrease in liver mass and CYP450 content. Kidneys decrease in mass with age and renal blood flow lessens. Gastric motility slows down and the secretion of gastric juices decreases [126]. Cancer is generally considered to be a disease of the elderly, with 60% of the diagnoses of cancer taking place in patients aged 75 and over [127]. Although
Food
The ingestion of food can cause the F of co-ingested drugs to change. The mechanisms by which this happens are not fully understood, but some clarification may be obtained from physiological changes caused by the presence of food [133], [134]. The pH-values in the gastric environment may rise from 1–3.5 to 3.0–6.0 due to buffering and dilutant effects of food stuffs [135]. The proximal part of the duodenum does experience lower pH values when gastric emptying takes place [136]. Overall,
Discussion
The advances in drug discovery have led to a particularly useful niche of chemotherapeutics, the orally applicable smTKIs as key representatives. Although the development of personalized oral chemotherapy is very promising, the nature of the selection process leads to drugs that are hindered by a low and variable F. This low and variable F does not appear to be a hindrance in the wielding of the drugs, but might prove to be troublesome in further expanding the use of these compounds. High or
Conclusion
The smTKI-group generally suffers from a low and variable F, a problem that is receiving little attention in literature. This review presents the various causes of the low and variable F of the smTKIs and provides possible means to enhance F and to reduce variability. Special attention is directed towards food and pH-dependent interactions, which have consequences for the therapeutic regimen of most of the smTKIs. Physicochemical, physiological and pharmacological data is far from complete.
Funding and conflicts of interest
No sources of funding were used to assist in the preparation of this manuscript. The authors declare no conflict of interest.
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