Failure to recognize important features of a drug’s pharmacokinetic characteristics is a key cause of inappropriate dose and schedule selection, and can lead to reduced efficacy and increased rate of adverse drug reactions requiring medical intervention. As oral chemotherapeutic agents, tyrosine kinase inhibitors (TKIs) are particularly prone to cause drug-drug interactions as many drugs in this class are known or suspected to potently inhibit the hepatic uptake transporters OATP1B1 and OATP1B3. In this article, we provide a comprehensive overview of the published literature and publicly-available regulatory documents in this rapidly emerging field. Our findings indicate that, while many TKIs can potentially inhibit the function of OATP1B1 and/or OATP1B3 and cause clinically-relevant drug-drug interactions, there are many inconsistencies between regulatory documents and the published literature. Potential explanations for these discrepant observations are provided in order to assist prescribing clinicians in designing safe and effective polypharmacy regimens, and to provide researchers with insights into refining experimental strategies to further predict and define the translational significance of TKI-mediated drug-drug interactions.

Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations, common in pediatric acute myeloid leukemia (AML), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT3-ITD+ AML. Using RNA sequencing and a next-generation targeted gene panel, we broadly characterize the co-occurring genomic alterations in pediatric cytogenetically normal (CN) FLT3-ITD+ AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL11B. At diagnosis, the median number of mutations other than FLT3 per patient was 1 (range 0-3), which involved 8 gene pathways; WT1 and NPM1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency (VAF) mutants, which included WT1, NPM1, SMARCA2, RAD21, and TYK2, were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAFs were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT3-ITD+ AML and could help stratify future targeted treatment strategies.Pediatric acute myeloid leukemia (AML) is a rare heterogeneous disease that accounts for 30% of all childhood leukemia. 1,2 It is distinct from the adult counterpart in both their genomic alterations and therapeutic response. 3 However, in both settings, pediatric and adult AML have relatively low somatic mutation burden compared with other tumor types. 4,5 Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations are among the most common

Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment–mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3 -ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL -PTD, ASXL1 , SRSF2 , and WT1 , which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.

Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized that antifungal drugs may increase venetoclax exposure through inhibition of both CYP3A-mediated metabolism and OATP1B-mediated transport. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms, or OATP1B2 that received venetoclax alone or in combination with ketoconazole or micafungin. In mice lacking all CYP3A isoforms, venetoclax AUC was increased by 1.8-fold, and pretreatment with the antifungal ketoconazole further increased venetoclax exposure by 1.6-fold, despite the absence of CYP3A. Ensuing experiments demonstrated that the deficiency of OATP1B-type transporters is also associated with increases in venetoclax exposure, and that many antifungal drugs, including micafungin, posaconazole, and isavuconazole, are inhibitors of this transport mechanism both in vitro and in vivo. These studies have identified OATP1B-mediated transport as a previously unrecognized contributor to the elimination of venetoclax that is sensitive to inhibition by various clinically-relevant antifungal drugs. Additional consideration is warranted when venetoclax is administered together with agents that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport.

Organic cation transporter 1 (OCT1) is a transporter that regulates the hepatic uptake and subsequent elimination of diverse cationic compounds. Although OCT1 has been involved in drug-drug interactions and causes pharmacokinetic variability of many prescription drugs, details of the molecular mechanisms that regulate the activity of OCT1 remain incompletely understood. Based on an unbiased phospho-proteomics screen, we identified OCT1 as a tyrosine-phosphorylated transporter, and functional validation studies using genetic and pharmacological approaches revealed that OCT1 is highly sensitive to small molecules that target the protein kinase YES1, such as dasatinib. In addition, we found that dasatinib can inhibit hepatic OCT1 function in mice as evidenced from its ability to modulate levels of isobutyryl L-carnitine, a hepatic OCT1 biomarker identified from a targeted metabolomics analysis. These findings provide novel insight into the post-translational regulation of OCT1 and suggest that caution is warranted with polypharmacy regimes involving the combined use of OCT1 substrates and kinase inhibitors that target YES1.