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Background: Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future., Methods: After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode., Results: The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 ± 4.55% (mean ± SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib., Conclusions: A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens., Methods: This was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1-14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase., Results: The galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes., Conclusion: Galunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach., Trial Registration Number: ClinicalTrials.gov identifier: NCT02734160., Competing Interests: Competing interests: DM has received research funding from Celgene, Incyte, and Shire, and has a consulting role with Baxter, Eli Lilly and Company, Incyte, and Shire. D-YO has received research funding from Array, AstraZeneca, Eli Lilly and Company, and Novartis, and has a consulting/advisory role with ASLAN, AstraZeneca, Bayer, Celgene, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho, and Zymeworks. AH has received travel and accommodation expenses from Eli Lilly and Company. EC has received research funding from AbbVie, Amcure, Amgen, AstraZeneca, BeiGene, BMS, Boehringer-Ingelheim, CytomX, Eli Lilly and Company, H3, Incyte, Kura, LOXO, Macrogenics, Menarini, Merck, Merck Serono, Merus, Millennium Pharmaceuticals, Nanobiotix Janssen, Nektar, Novartis, Pfizer, PharmaMar, Principia Bayer, PsiOxus Therapeutics, PUMA, Rigontec, Roche/Genentech, Sanofi, Tahio, Tesaro; has a consulting/advisory role with AbbVie, Amcure, AstraZeneca, Boehringer-Ingelheim, Celgene, Cerulean Pharma, EUSA, GLG, Guidepoint Global, Janssen-Cilag, Nanobiotix Janssen, Novartis, Pfizer, Pierre Pharma, PsiOxus Therapeutics, Roche/Genentech, Seattle Genetics, Servier; is employed by HM Hospitals Group and START; has shares in HM Hospitals Group, International Cancer Consultants, Oncoart Associated, and START; and is president and founder of NPO Foundation Intheos (Investigational Therapeutics in Oncological Sciences). AMV has participated in clinical trials funded by Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Silenseed, and Verastem. EB has received honoraria for consultancy from Corcept Therapeutics and Invitae, is on the speaker bureau for Ipsen, and his institution has received research funding from Biontech, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Helix, Mabvax, Merck, Minneamrita Therapeutics, Pharmacyclics, and Samumed. TM has received honoraria for consultancy from Baxalta, Baxter, Celgene, Genzyme, Roche, Sanofi, Shire Pharmaceuticals, Tesaro, and QED Therapeutics, and has received travel/accommodation compensation from Bayer, H3 Biomedicine, Merck, and Sanofi. VM and CZ have no conflicts of interest to disclose. YZ, IG, MM, LG, STE, and EA are employees and stock holders of Eli Lilly and Company. KAB was an employee of Eli Lilly and Company at the time this research was conducted and is a stock holder of Eli Lilly and Company and a current employee of Taiho Oncology. MCL is a current employee and stock holder of AstraZeneca. SCG was an employee of Eli Lilly and Company at the time this research was conducted and is a stock holder of Eli Lilly and Company. RG-C declares having provided scientific advice and/or received honoraria from AAA, Advanz Pharma, Amgen, Bayer, BMS, Eli Lilly and Company, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Roche, and Sanofi, and has received research support from Pfizer and BMS. Work in the unit of DM was partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) Investigator Grant n°23719 and 5x1000 Grant n°12182, by the Italian Ministry of Health Ricerca Finalizzata 2016 GR-2016- 02361134 grant, and by the patients associations 'Nastro Viola' and 'Voglio il Massimo' donations., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lenvatinib (Lenvima™) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial-derived growth factor receptors 1, 2 and 3, fibroblast growth factor receptors 1, 2, 3 and 4, platelet-derived growth factor receptor α, RET and KIT. In addition to their role in normal cellular function, these kinases have been implicated in pathogenic angiogenesis, tumour growth and cancer progression. Lenvatinib is being developed by Eisai Co. Ltd for the treatment of solid tumours, primarily for differentiated thyroid cancer, and other malignancies. A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Lenvatinib is in pre-registration for this indication in the EU, Australia, Brazil, Canada, Japan, South Korea, Russia, Singapore and Switzerland, and is in phase 3 development in Argentina, Chile and Thailand. Lenvatinib has orphan designation in the EU and Japan for use in differentiated thyroid cancer. In addition, an ongoing global, phase 3 trial is evaluating the use of lenvatinib as first-line treatment in unresectable hepatocellular carcinoma. This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer.

Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians', and increasingly patients and families' preference, patients' comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.

Objectives: Pitavastatin, a statin recently approved in the United States, has a potential benefit of reduced risk of cytochrome P450 (CYP)-mediated drug-drug interaction due to minimal metabolism by the CYP system. The primary objective was to investigate pharmacokinetic (PK) effects of lopinavir/ritonavir 400 mg/100 mg twice daily on pitavastatin 4 mg when coadministered., Design: This was an open-label one-arm study., Method: Pitavastatin 4 mg was administered once daily (days 1-5 and days 20-24). Lopinavir/ritonavir 400 mg/100 mg was administered twice daily (days 9-24). Plasma samples for PK assessments were collected on days 5, 19, and 24. Plasma concentrations of analytes were determined by liquid chromatography with tandem mass spectrometric detection methods., Results: PK data were available for 23 of 24 subjects enrolled. For pitavastatin, area under the concentration time curve (AUC0-τ) and maximum concentration (C(max)) were 136.8 ± 52.9 ng·h(-1)·mL(-1) and 58.6 ± 30.4 ng/mL, respectively, when given alone, versus 113.9 ± 53.8 ng·h(-1)·mL(-1) and 58.2 ± 32.7 ng/mL when combined with lopinavir/ritonavir. The geometric mean ratio for AUC(0-τ) for pitavastatin with lopinavir/ritonavir versus pitavastatin alone was 80.0 (90% confidence interval: 73.4 to 87.3) and C(max) was 96.1 (90% confidence interval: 83.6 to 110.4). Median T(max) of pitavastatin was approximately 0.5 hours for both treatments. The PK effect of pitavastatin on lopinavir/ritonavir was minimal. No significant safety issues were reported., Conclusions: The effect on exposures when pitavastatin and lopinavir/ritonavir are coadministered was minimal. Concomitant use of pitavastatin and lopinavir/ritonavir was safe and well tolerated in healthy adult volunteers.