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We review the general principles and guidelines for using KIs for cancer treatment. This article is not designed for cross trial comparison or to make recommendations for treatment of certain patients, but as a general practice guide. More than five hundred different kinases have been identified in humans.
KIs can target multiple kinases—regorafenib is known to target at least 14 kinases—or have a more limited spectrum of kinase inhibition such as lapatinib, vismodegib, axitinib, and ruxolitinib. Targets inhibited by kinase inhibitors. Data are from each KI package insert; KIs that are not known to inhibit multiple kinases are not listed. Oral medications, while offering convenience and prolonged target inhibition, cannot be as closely monitored as intravenous IV therapies administered in the practitioner's office.
Issues such as non-compliance, miscommunication, and errors in how patients take their medications, as well as interaction with food or other medications, pose challenges to delivering safe and efficacious oral therapy. Such considerations can cause significant differences in the pharmacokinetics PK and drug exposures of KIs. Co-administration of antacids or proton pump inhibitors along with oral kinase inhibitors can also reduce the absorption of KIs, affecting bioavailability.
Most KIs are principally metabolized by the liver and eliminated via the hepatic route except for ruxolitinib, which is excreted via the renal route. During drug metabolism, polar groups are added to lipophilic molecules by oxidation, reduction, or hydrolysis to facilitate water-solubility phase I metabolism ; these reactions are catalyzed predominantly by the cytochrome P superfamily.
Examples of medications that are substrates for CYP enzymes with narrow therapeutic windows. When a drug classified as a CYP substrate is coadministered with a KI, higher substrate plasma concentrations may result Table 5. CYP3A4 inducers reduce plasma concentration of most KIs with the exceptions of vismodegib and ruxolitinib Table 6 , while CYP3A4 inhibitors increase the plasma concentrations of most KIs with the exceptions of sorafenib, vandetanib, and vismodegib Table 6.
For example, imatinib increases the plasma concentration of other CYP3A4 metabolized drugs e. KI interactions with drugs and food are listed. In general, when antacids are used, avoid concurrent intake with KIs to maximize KI absorption.
The presence of food in the stomach can change drug absorption and exposure. Generally, food with a high fat content increases the drug AUC, although there are some exceptions based on drug type. Ten of 19 KIs have no specific food and time requirements see Table 6. Six KIs are required to be taken on an empty stomach, defined in most early clinical trials as at least one hour before or two hours after food consumption unless gastrointestinal GI motility is changed i.
Only regorafenib, bosutinib, and imatinib, are required to be taken with food. To minimize the effect of food on drug absorption, phase 1 clinical evaluation of KIs is usually conducted in fasting subjects. The food-labeling recommendations for recently approved oral oncology drugs are inconsistent with fundamental principles of oral drug delivery.
The marked increase in bioavailability with food has generally led to recommendations to administer non-oncology drugs in a fed state. As noted above, because early-phase oncology trials generally administer drugs to fasting subjects, some approved KIs lack adequate food effect studies with supportive PK data.
Co-administration with food reduces the risk of several adverse events, especially GI side effects. In most cases, food increases drug bioavailability, which results in decreased inter-individual variability of AUC.
Increased drug absorption reduces wasted drug and improves pharmacoeconomic efficiency. Unwarranted food restrictions compromise the practicality of drug administration for patients and can result in decreased adherence. Proton pump inhibitors PPI , H2 blockers, and antacids decrease the solubility of KIs, excluding axitinib and lapatinib. However, the solubility of 11 KIs are not known see Table 6.
If a patient needs antacid treatment, administration of aluminum or magnesium hydroxide is recommended 2 hours prior to or after drug. Recommendations for histamine 2 H2 blockers differ for each KI. Please use consistent nomenclature for abbreviations are not recommended with dasatinib due to reduced absorption.
However, clinical studies to evaluate the effects of PPIs same as above on KI PK are more frequently conducted than for H2 blockers or antacids, and side effects are less well known. Patients with gastrectomy can have decreased KI absorption either due to lack of gastric acid or rapid transit time. P-glycoprotein P-gp is encoded by the multidrug resistance 1 gene and enhances the energydependent cellular efflux of many substrates, such as bilirubin and several medications, and can affect intracellular KI and other drug concentrations.
Most KIs, other than axitinib and ruxolitinib, are P-gp substrates. KIs can increase the concentration of P-gp substrates because of competitive binding to P-gp, or vice versa. For example, vemurafenib is both a substrate and an inhibitor of P-gp.
Systemic exposure of vismodegib may be increased when co-administered with drugs that inhibit P-gp e. Digoxin, fexofenadine, vincristine, and colchicine are examples of other P-gp substrates. Insufficient data are available to assess the risk of concomitant administration of alternative statins and pazopanib.
Because statins are associated with a risk of transaminitis, care should be taken when administering these drugs with KIs known to cause drug-induced liver injury, such as pazopanib.
Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive either low-molecular weight or standard heparin, or INR should be closely monitored to prevent significant drug interactions. INR was increased in patients receiving warfarin and erlotinib or vemurafenib, but there were no significant changes in patients receiving nilotinib or pazopanib. Based on clinical data, the FDA may require the pharmaceutical company to insert a black box warning in the package insert.
Black box warnings are the strongest warning required by the FDA, and although uncommon, this designation signifies that a drug carries a specific risk of serious or life-threatening adverse effects. Risk of Torsade de pointes is a black box warning for nilotinib and vandetanib, while risk for perforation, fistula, and hemorrhage are black box warnings for cabozantinib. Major adverse reactions associated with KIs are listed.
Percent may be different from smaller phase 2 studies. It is important to know the plasma half-life of a KI when side effects need to be monitored or when the drug is combined with other CYP interacting agents. Half-life data were obtained primarily from single-dose studies, and thus may differ following chronic dosing.
For example, the estimated elimination half-life of vismodegib is 12 days after a single dose, but shortens to 4 days with continuous, once-daily dosing. Dose modification according to organ dysfunction and metabolism are listed.
Half life is measured in hours for all drugs except vandetanib and vismodegib days. If the potential benefit outweighs the risk of hepatotoxicity, pazopanib can be reintroduced at a dose of no more than mg once daily and LFTs measured weekly for 8 weeks.
Patients with Gilbert's syndrome can have a mild indirect hyperbilirubinemia with pazopanib. Hypothyroidism is reported as a side effect of KIs that target angiogenesis—axitinib, sunitinib, pazopanib, and regorafenib— with an incidence ranging from 4.
Common adverse reactions associated with KIs with anti-angiogenic properties. An expert panel was convened to formulate guidelines for treating patients with sunitinib-induced hypothyroidism. If TSH is elevated, free rather than total T4 should be measured to determine the degree of hypothyroidism. Total T4 can be erroneously low because T4 is primarily bound to serum thyroxine-binding globulin TBG , which can be low in cancer patients.
The level of TSH elevation that warrants treatment has not been established. Overtreatment of hypothyroidism should be avoided because potential benefit of hypothyroidism on cancer growth inhibition has been noted both in preclinical and clinical studies. Also, patients who develop a mmHg increase in diastolic blood pressure over baseline should be treated. Several considerations may influence the choice of antihypertensive therapy.
QT interval is a measure of cardiac muscle cell membrane repolarization. The QT interval on the electrocardiogram is used to identify individuals at risk for ventricular arrhythmias and sudden death, which the FDA has used in the evaluation of new drug applications.
QT interval is dependent upon heart rate; it is shorter at faster heart rates and longer at slower heart rates. Thus, the QT interval needs to be corrected for heart rate QTc. In order to correct the measurement for varying heart rates, different formulas are available for determining the QTc, but the Bazett correction is uniformly accepted, including by the FDA.
Recently, the FDA has focused attention on the use of the Fridericia correction because it corrects for the effects of tachycardia on the QT interval. QT prolongation can occur either due to drugs such as antiarrhythmic agents, phenothiazines, tricyclic antidepressants, and cumulative high-dose anthracycline therapy, conditions such as hypothermia, cerebrovascular disease, ischemic heart disease, or due to a congenital channelopathy prolonged QT syndrome.
A long QT syndrome either acquired or congenital is associated with a potentially life-threatening arrhythmia known as torsade des pointes. QT prolongation may also be a result of delayed repolarization from a metabolic abnormality, such as hypocalcemia or hypomagnesemia. Patients with compromised organ function are rarely enrolled in early-phase clinical trials of KIs unless in separate organ dysfunction studies.
Usual eligibility criteria for early phase trials are listed in Table 8 and can be used for screening patients for KIs. When a patient does not meet eligibility criteria, the KI package insert should be consulted see also Table 9. General eligibility criteria used for early phase trials in drug development are listed.
ECG QTc was not required for every drug development trial. Patients with hepatic dysfunction may need KI dose modification based on the degree of hepatic dysfunction. TB is the most important factor in both classifications. For CPC A liver dysfunction, most KIs can be used without dose reduction, excluding nilotinib, bosutinib, and ruxolitinib, all of which require dose reductions Table 9.
Dose adjustment data for vandetanib, vismodegib, cabozantinib, and crizotinib are unknown or limited in CPC A. For CPC C liver dysfunction, only dasatinib can be used without dose reduction; in these patients, most KIs either require dose reduction, or are prohibited for use.
Most KIs do not need dose adjustments for mild renal dysfunction, but there is no available for dasatinib, vismodegib, lapatinib, and erlotinib see Table 9. Imatinib should not be administered at more than mg to patients with mild renal dysfunction. Three KIs are approved for patients with RCC and severe renal dysfunction, sorafenib, sunitinib, axitinib, and these can be administered without dose adjustments. The specificity of these KIs varies, with axitinib being the most specific. Hypertension occurs mostly within the first or second month.
Axitinib is approved for use in advanced RCC after failure of one prior systemic therapy. The starting dose is 5 mg orally twice daily with water, with or without food. It is available as 1 and 5 mg tablets. In a randomized, open-label, multicenter phase 3 study, patients with advanced RCC whose disease had progressed during or after treatment with one prior systemic therapy, including sunitinib-, bevacizumab-, temsirolimus-, or cytokine- containing regimens were randomized 1: The median progression free survival PFS was significantly increased after axitinib treatment 6.
Pazopanib is approved for patients with advanced RCC and advanced soft tissue sarcoma STS who have received prior chemotherapy.
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