[Factors Associated with the Continuation of Anamorelin in Patients with Cancer-associated Cachexia: A Single-center Retrospective Study].

Cancer-associated cachexia, a multifactorial syndrome involving loss of muscle mass and anorexia, affects the survival of cancer patients. Anamorelin was the first drug approved in Japan for the treatment of cachexia. However, cases in which anamorelin is discontinued within 3 weeks are often observed in clinical practice. This study aimed to explore the factors associated with continued anamorelin dosing. We retrospectively reviewed records of patients with lung, gastric, pancreatic, and colorectal cancer who started anamorelin at Fukuoka University Hospital from April 2021 to November 2022. Patients were divided into two groups based on the duration of anamorelin administration: 15 patients were classified into the <3 weeks group and 22 were classified into the ≥3 weeks group. The primary objective was to explore the potential factors associated with the continuation of anamorelin, and the secondary objectives were to compare survival and nutritional indices. In the univariate analysis, there were significant differences between the two groups in terms of cancer type (p=0.007) and serum albumin level (p=0.026). In the multivariate analysis, gastric cancer and albumin 2.7 g/dL or less were associated with the continuation of anamorelin. Survival was significantly shorter in the <3 weeks group (p=0.019). This study suggests that the continuation of anamorelin may be influenced by specific tumor types and serum albumin levels. Furthermore, the duration of anamorelin administration may affect patient survival.

Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants.

Functional protein-protein interactions between UDP-glucuronosyltransferase (UGT)1A isoforms and cytochrome P450 (CYP)3A4 were studied. To this end, UGT1A-catalyzed glucuronidation was assayed in Sf-9 cells that simultaneously expressed UGT and CYP3A4. In the kinetics of UGT1A6-catalyzed glucuronidation of serotonin, both Michaelis constant (Km) and maximal velocity (Vmax) were increased by CYP3A4. When CYP3A4 was coexpressed with either UGT1A1 or 1A7, the Vmax for the glucuronidation of the irinotecan metabolite (SN-38) was significantly increased. S50 and Km both which are the substrate concentration giving 0.5 Vmax were little affected by simultaneous expression of CYP3A4. This study also examined the catalytic properties of the allelic variants of UGT1A1 and 1A7 and their effects on the interaction with CYP3A4. Although the UGT1A1-catalyzing activity of 4-methylumbelliferone glucuronidation was reduced in its variant, UGT1A1*6, the coexpression of CYP3A4 restored the impaired function to a level comparable with the wild type. Similarly, simultaneous expression of CYP3A4 increased the Vmax of UGT1A7*1 (wild type) and *2 (N129K and R131K), whereas the same was not observed in UGT1A7*3 (N129K, R131K, and W208R). In the kinetics involving different concentrations of UDP-glucuronic acid (UDP-GlcUA), the Km for UDP-GlcUA was significantly higher for UGT1A7*2 and *3 than *1. The Km of UGT1A7*1 and *3 was increased by CYP3A4, whereas *2 did not exhibit any such change. These results suggest that (1) CYP3A4 changes the catalytic function of the UGT1A subfamily in a UGT isoform-specific manner and (2) nonsynonymous mutations in UGT1A7*3 reduce not only the ability of UGT to use UDP-GlcUA but also CYP3A4-mediated enhancement of catalytic activity, whereas CYP3A4 is able to restore the UGT1A1*6 function.