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Aims: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open-label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations., Methods: Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m 2 orally twice daily on days 1-5 and 8-12 of each 28-day cycle., Results: Twenty-four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve., Conclusions: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment., (© 2019 The British Pharmacological Society.)

Objective: To review literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of lasofoxifene (CP-336156), a selective estrogen receptor modulator (SERM) that is not approved for use in the US., Data Sources: Literature was accessed through the MEDLINE and EMBASE databases (1985-June 2010) using the terms lasofoxifene and selective estrogen receptor modulators. Reference lists from retrieved articles were also manually reviewed. The Food and Drug Administration and Pfizer provided additional information., Study Selection and Data Extraction: All clinical trials evaluating lasofoxifene were included in this review. In addition, all articles evaluating the pharmacology, pharmacokinetics, and safety of lasofoxifene in humans were reviewed., Data Synthesis: Lasofoxifene is a third-generation SERM with markedly higher in vitro and in vivo potency and oral bioavailability than other SERMs. The drug has produced significant improvements in bone density and biochemical markers of bone turnover in preclinical studies and in Phase 2 and 3 clinical trials. In these trials, lasofoxifene has shown a favorable safety profile, with adverse events including hot flushes, leg cramps, and increased vaginal moisture. One 2-year major comparative study in postmenopausal women determined that lasofoxifene and raloxifene were equally effective at increasing total hip bone mineral density (BMD), while lasofoxifene had a significantly greater effect on lumbar spine BMD., Conclusions: Osteoporosis is a significant health problem. While the results of further clinical trials are needed to define the risks and benefits of treatment, particularly relating to fractures, lasofoxifene may prove to be an effective and well-tolerated therapeutic option for the prevention of bone loss in postmenopausal women.

MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.