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Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
The exact CFTR binding site of ivacaftor is still unknown but direct binding to the phosphorylated CFTR protein has been reported (105), with the transmembrane domains (TMDs) being suggested as possible binding site candidates (106). Ivacaftor stabilizes a posthydrolytic open state of CFTR and as a result stimulates decoupling of the gating and ATP hydrolysis cycle, resulting in an increased time period that the CFTR channel stays open (106). It is able to exert its function, as demonstrated in a reconstitution system with purified wild-type and mutant CFTR, via an ATP-independent mechanism (105). Indeed, it was reported that spontaneous opening of CFTR may occur without ATP and is coupled to NBD dimerization (107). In vitro studies, however, suggested that the effect of ivacaftor was due to an ATP-dependent increase of the opening rate and reduction of the closing rate of the channel (108). Clearly, more studies are required to elucidate ivacaftor’s mode of action in more detail, which would be beneficial for future development of novel potentiator compounds.
The respiratory system
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
Ivacaftor is a new drug approved for the treatment of CF in patients with specific mutations. The drug works by increasing activity of the abnormal chloride channels in these patients. Unfortunately, the mutations treated by ivacaftor only occur in approximately 5% of patients with cystic fibrosis. Combinations of new drugs that can be used along with ivacaftor to treat the most common forms of cystic fibrosis are currently underway
Saquinavir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Matthew D. M. Rawlins, Martyn A. French
Saquinavir may increase the exposure of cinacalcet via CYP3A4 inhibition. The patient should be monitored for signs of toxicity. The serum calcium should be monitored. Dapoxetine, a short acting selective serotonin reuptake inhibitor (SSRI) for premature ejaculation, should not be used with saquinavir due to increased exposure of dapoxetine from CYP3A4 inhibition. Increased eplerenone exposure with boosted saquinavir is possible. The combination should be avoided. The combination of ivacaftor should be used with caution; monitor for ivacaftor adverse effects and reduce the dose as necessary. Galantamine exposure may be increased after co-administration with saquinavir; exercise caution and monitor for toxicity In a single dose pharmacokinetic study in healthy volunteers, loperamide 16 mg reduced unboosted saquinavir 600 mg exposure by around 50%, possibly by impaired absorption of saquinavir. There is also an increase in loperamide exposure, which is not thought to be clinically significant. The combination should be avoided (Mikus et al., 2004). Macicentan should not be combined with saquinavir due to the potential for increased macicentan exposure There is the potential for possible increases in methylphenidate levels and increased saquinavir exposure when this combination is used (Tseng and Foisy, 1999). An increase in mifepristone exposure is possible when combined with saquinavir. Patients should be monitored for mifepristone toxicity when receiving this combination. An animal cell model suggested that montelukast reduced MRP2-mediated efflux and increased the intracellular retention time of saquinavir. The authors suggest that montelukast could be used as adjust therapy to suppress saquinavir efflux from MRP2 overexpressing cells (Roy et al., 2009). Unpredictable effects (increases or decreases) on quinine exposure may occur with boosted saquinavir. The combination should be used with extreme caution. Increased salmeterol cardiovascular effects are possible with ritonavir-boosted saquinavir. The combination is contraindicated (US DHHS, 2015b). When vilanterol is combined with saquinavir, clinical effects are likely to be minor; the patient should be monitored for vilanterol adverse effects. The combination of tolvaptan with saquinavir should be used only with extreme caution and the patient monitored for tolvaptan toxicity (Where no other reference has been provided in this section, data were sourced from the product information; refer to updated product information to determine current status of drug interactions).
Current pharmacogenomic recommendations in chronic respiratory diseases: Is there a biomarker ready for clinical implementation?
Published in Expert Review of Respiratory Medicine, 2022
Ingrid Fricke-Galindo, Ramcés Falfán-Valencia
Ivacaftor is a selective small-molecule potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) designed to restore protein function [29]. It is indicated for Cystic Fibrosis (CF) treatment, an autosomal disorder caused by the inheritance of two detrimental copies of one or more variants in the CFTR gene [30]. There are more than 2000 variants identified in CFTR, of which 127 are pathogenic, and they are categorized into five classes based on their effect on CFTR function [31]. Ivacaftor targets class III variants which produce proteins that fold and localize appropriately but cannot be regulated by ATP or phosphorylation as needed for normal gating function [32]. Thus, patients carrying other classes of variants may not present an adequate response to ivacaftor. For instance, patients homozygous for the specific F508del variant showed no improvement with ivacaftor treatment alone [33], and there is available combined therapy of ivacaftor for these cases [34]. In this sense, the CFTR genotype is critical for indicating ivacaftor and its combination. A CPIC guideline is available for ivacaftor therapy in the context of CFTR genotype, which provides therapeutic recommendations for ivacaftor based on preemptive CFTR genotype results [35]. This is the only drug in the respiratory-diseases class with an available CPIC guideline as it will be mentioned above.
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
Ivacaftor which is administered orally twice daily is the first personalized or genomically guided therapy for CF. Only around 5% of the total CF population worldwide is eligible for ivacaftor. However, ivacaftor’s development and approval were a breakthrough for CF treatment since it was the proof-of-concept that pharmacological treatment can improve CFTR function. It was demonstrated that ivacaftor achieves a CFTR activity equivalent to approximately 35%–40% of normal activity [20]. Clinical trials and subsequent studies showed that even in adults with a long history of respiratory disease and abnormal lung function, restoring CFTR function can significantly improve lung function and slow the course of the disease. In very young patients with normal lung function, beginning ivacaftor treatment early in life may well be truly disease-modifying: if the treatment is well tolerated in the long term, it may help preserve lung function and improve expected survival. It should be noted, however, that the aviator is currently a high-cost treatment (around 294,000 $ per year), which is a significant issue for a lifelong therapy. It limits access to the treatment in several lower income countries [21].
Knowledge graphs and their applications in drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Pathology is fascinatingly complex. This complexity is often not well-represented in KGs. Many research projects use publicly accessible KGs which provide a reductive model of disease (with edges such as drug-binds-gene, gene-associates-disease and drug-treats-disease). These graphs fail to represent neither the genetic heterogeneity, nor transient nature of disease. Whilst a drug repurposing link prediction model may successfully predict CFTR-associates-chronic_pancreatitis, ivacaftor-binds-CFTR, and ivacaftor-treats-chronic_pancreatitis, these generalizations do not reflect the complexity of the disease, or the prerequisites of ivacaftor to be an effective treatment. In reality, we want to be able to use a KG to approximate the causal reasoning of a team of researchers: ”chronic pancreatitis is caused by loss of function of the CFTR gene. Mutations in CFTR cause an imbalance of calcium homeostasis, leading to early protease activation, fibrosis, inflammation and abdominal pain. Ivacaftor is used to treat a subset of cystic fibrosis patients via potentiation and correction of mutant CFTR, which restores the calcium homeostasis in endothelial cells. Patients with similar loss-of-function mutations in the CFTR gene could be treated with Ivacaftor. Whilst CFTR remains the main pathomechanism of chronic pancreatitis, other possible treatments include immunosuppressants, antifibrotics, protease inhibitors, and analgesics”. A KG that can deliver this level of granularity would be a fundamental asset in any drug discovery company.