Karthick Vishwanathan's research while affiliated with University of Massachusetts Boston and other places

... Recent examples indicate the emerging value of circulating tumor DNA (ctDNA). 20,21 The translational utility of ctDNA, cancer cell DNA found in the bloodstream, is manifold, including detecting and diagnosing cancer, guiding tumor-specific treatment, and monitoring treatment and remission. In the context of dose optimization, characterizing the underlying exposure-response relationship for on-treatment ctDNA dynamics to inform the definition of a clinically active dose range represents an untapped opportunity. ...

... The mean C max and AUC values of acalabrutinib increased 1.37 (1.14-1.64) and 1. [89]. No dose adjustment of acalabrutinib is required in combination with moderate CYP3A inhibitors [87]. ...

... Plasma concentrations of acalabrutinib and ACP-5862 were determined using previously developed and validated methods based on liquid chromatography with tandem mass spectrometry. 18 The nominal ranges of quantitation were 1-1000 ng/mL for plasma acalabrutinib and 5-5000 ng/mL for plasma ACP-5862. ...

... According to earlier research [16][17][18][19], the ACB showed a moderate metabolism rate, which led to a favorable in vivo bioavailability and a moderate duration of action. The small extraction ratio of ACB was discovered to be in line with the frequently advised regular dosage of ACB (100 mg), which should be given twice daily to patients diagnosed with B-cell malignancies [20]. The suggested theory for in silico metabolic stability, which matched the outcomes of the in vitro metabolic stability, was supported by screening for structural alarms inside the ACB chemical structure using DEREK software. ...

... Isavuconazole and fluconazole are less likely to be associated with midazolam interactions. 60 Diazepam has only a weak interaction (∼15%) with voriconazole and itraconazole. Although not extensively studied, voriconazole likely increases the plasma concentrations of other benzodiazepines metabolized by CYP3A4, leading to a prolonged sedative effect. ...

... 20, 52,47 On the basis of a defined exposure-response relationship, it is suggested that PopPK models be developed to support dose individualization. Up to now, studies on PopPK have been conducted for a variety of antineoplastic drugs, including atezolizumab, 53 brentuximab vedotin, 54 busulfan, 9,11,55 dasatinib, 56 methotrexate, 7,57,58 sunitinib, 59 and vincristine 60,61 in pediatric patients and acalabrutinib, 62 afatinib, 63 atezolizumab, 53 brentuximab vedotin, 54 dostarlimab, 64 erlotinib, 65 necitumumab, 66 nivolumab, 67 pembrolizumab, 68 savolitinib plus osimertinib, 69 siltuximab, 70 and trastuzumab 71 in adults. Based on heterogeneous data, the quantification, and identification of variability and simulations, PopPK is an essential tool to individualize drug doses to reduce toxicity and improve patients' outcomes. ...

... It has been used to justify a biowaiver for a selected BCS 2 compounds [124] and determine the impact of different formulation factors such as solubility, particle size, size distribution, and food on the absorption of drugs [125][126][127][128][129][130][131]. The ADAM model is also available commercially, Symcyp®, and is used to predict the effect of drug release rate on the absorption [120,[132][133][134], to allow the optimization of paediatric drug [135,136], and to investigate drug-drug interactions [137]. Additional compartmental models are reviewed in Huang et al. [4]. ...

... 23 Previous human PBPK models have been published for vincristine with incorporation of tubulin as a key driver of drug disposition. 24,25 These previous models, however, utilized a relative tubulin expression value for all relevant tissues. To our knowledge, the presented model is the first PBPK model of VBL, and the first vinca alkaloid model to incorporate variability in organ tubulin expression and provide an interspecies scaled model from mouse to canine and human. ...

... Te pharmacokinetic (PK) profle of selumetinib, along with its active metabolite N-desmethyl selumetinib (3-5 times more potent than selumetinib, circulating at about 7% of selumetinib concentration in plasma, consequently about 20-30% contribution to the selumetinib activity), has been well characterized in several population pharmacokinetic (PopPK) analyses [15][16][17][18]. Te PK profles of selumetinib and N-desmethyl selumetinib are comparable among healthy subjects, adult patients with various tumors, and pediatric patients with NF1 and PN. ...

... Median PFS was not reached with a follow-up time of 11 months. Consistent with the high rates of CNS response rates, molecular imaging with 11C-labelled osimertinib in a phase I study (ODIN-BM) showed excellent blood-brain-barrier penetration (48). ...