RESUMEN
PURPOSE: This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives. METHODS: Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis. RESULTS: Thirty-six patients (n = 18 each arm) were enrolled and received at least 1 dose of study drug. In the drug-drug interaction analysis (n = 15 each arm), the geometric mean ratio (GMR) of maximum concentration (Cmax) with and without rucaparib was 1.29 for rosuvastatin, 1.09 for ethinylestradiol, and 1.19 for levonorgestrel. GMR of area under the concentration-time curve from time zero to last quantifiable measurement (AUC0-last) was 1.34 for rosuvastatin, 1.43 for ethinylestradiol, and 1.56 for levonorgestrel. There was no increase in frequency of treatment-emergent adverse events (TEAEs) when rucaparib was given with either of the probe drugs. In both arms, most TEAEs were mild in severity and considered unrelated to study treatment. CONCLUSION: Rucaparib 600 mg BID weakly increased the plasma exposure to rosuvastatin or oral contraceptives. Rucaparib safety profile when coadministered with rosuvastatin or oral contraceptives was consistent with that of rucaparib monotherapy. Dose adjustments of rosuvastatin and oral contraceptives are not necessary when coadministered with rucaparib. ClinicalTrials.gov NCT03954366; Date of registration May 17, 2019.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Anticonceptivos Orales/farmacocinética , Neoplasias/tratamiento farmacológico , Rosuvastatina Cálcica/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticonceptivos Orales/administración & dosificación , Interacciones Farmacológicas , Etinilestradiol/farmacocinética , Femenino , Humanos , Indoles/administración & dosificación , Levonorgestrel/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Rosuvastatina Cálcica/administración & dosificaciónRESUMEN
AIM: The aim of the study was to review the current diagnostic approach, based on the experience of one center performed during a 4-year period, according to WHO criteria of GEP - NET. MATERIAL AND METHODS: The study group comprised case records of 134 patients with confirmed GEP-NET carcinomas (WHO groups 2-4). All patients were subjected to clinical, biochemical and imaging examinations performed as routine clinical work-up. The imaging techniques consisted of anatomical (CT, EUS) and functional approaches (SRS, mIBG and FDG PET). RESULTS: The clinical classification considered the primary origin of the tumor as follows: 49% - foregut tumors, 44% - midgut, and 7% of tumors of unknown origin. Group of patients with WHO 2 consisted of 98 (73%) subjects. Considering those with foregut tumors EUS followed by CT and SRS were used in each case. SRS and CT imaging was used to assess the extent of the tumor. Patients with midgut tumors had CT and SRS as routine diagnostic imaging examinations. Considering the above-mentioned patients, CT and SRS were used to localize the primary tumor, and assess tumor extent. Overall sensitivity of CT considering the active disease amounted to 96%, while specificity - 75%. Sensitivity of SRS was 97%, while specificity- 85%. WHO 3-29 patients, 17 foregut and 9 midgut tumors, and 3 of unknown origin. Diagnostic imaging examinations consisted of CT. Standard SRS (sst2) was negative in most cases. The aggressive behaviour of this type of tumors was detected by means of FDG-PET. Sensitivity of CT amounted to 100%, and that of SRS - 44%. Specificity of CT amounted to 67% and that of SRS - 100%. WHO 4-7 patients, including 4 foregut and 3 midgut neoplasms. The imaging approach consisted of CT/MR and in 5 cases FDG-PET. Sensitivity of CT amounted to 100%. Only one patient presented with a SRS positive study. FDG-PET sensitivity amounted to 100%. CONCLUSION: Diagnostic imaging of GEP-NET, consider anatomical and functional techniques, which should be read together. The diagnostic value of CT and SRS were similar in case of WHO 2, while in case of WHO 3 CT had a higher diagnostic accuracy. FDG-PET seems to be a very attractive imaging functional modality in case of patients with WHO 3 and WHO 4.
