PMID- 37515369 OWN - NLM STAT- MEDLINE DCOM- 20231023 LR - 20231023 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 16 IP - 10 DP - 2023 Oct TI - Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study. PG - 1876-1885 LID - 10.1111/cts.13595 [doi] AB - Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (C(min) ) was greater than three times higher than reported; moreover, midostaurin C(min) , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade >/=3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient. CI - (c) 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. FAU - Menna, Pierantonio AU - Menna P AUID- ORCID: 0000-0002-7755-818X AD - University Campus Bio-Medico and, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Marchesi, Francesco AU - Marchesi F AUID- ORCID: 0000-0001-6353-2272 AD - Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy. FAU - Cattaneo, Chiara AU - Cattaneo C AD - Azienda Socio Sanitaria Territoriale and Spedali Civili, Brescia, Italy. FAU - Candoni, Anna AU - Candoni A AD - Azienda Sanitaria Universitaria Integrata, University Hospital, Udine, Italy. FAU - Delia, Mario AU - Delia M AD - Hematology Section, Department of Emergency and Organ Transplant, Univeristy of Bari, Bari, Italy. FAU - Nadali, Gianpaolo AU - Nadali G AD - U.O.C. Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Borgo Roma, Verona, Italy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. FAU - Vatteroni, Alessandra AU - Vatteroni A AD - U.O.C. Ematologia, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Borgo Roma, Verona, Italy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. FAU - Pasciolla, Crescenza AU - Pasciolla C AD - IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy. FAU - Perrone, Salvatore AU - Perrone S AUID- ORCID: 0000-0001-8196-0481 AD - Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy. FAU - Verga, Luisa AU - Verga L AD - Azienda Ospedaliera San Gerardo, Monza, Italy. FAU - Armiento, Daniele AU - Armiento D AD - University Campus Bio-Medico and, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Del Principe, Maria Ilaria AU - Del Principe MI AD - Department of Biomedicine and Prevention, Hematology, Tor Vergata University, Rome, Italy. FAU - Fracchiolla, Nicola S AU - Fracchiolla NS AD - Fondazione IRCCS Ca' Grande Ospedale Maggiore Policlinico, Milan, Italy. FAU - Salvatorelli, Emanuela AU - Salvatorelli E AUID- ORCID: 0000-0001-9805-4100 AD - University Campus Bio-Medico di Roma, Roma, Italy. FAU - Lupisella, Santina AU - Lupisella S AD - Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Terrenato, Irene AU - Terrenato I AD - Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy. FAU - Busca, Alessandro AU - Busca A AD - Department of Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera Universitaria Citta' della Salute e della Scienza, Torino, Italy. FAU - Minotti, Giorgio AU - Minotti G AUID- ORCID: 0000-0002-5678-6175 AD - University Campus Bio-Medico and, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. FAU - Pagano, Livio AU - Pagano L AD - Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. LA - eng PT - Journal Article PT - Multicenter Study DEP - 20230728 PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - ID912S5VON (midostaurin) RN - 6TK1G07BHZ (posaconazole) RN - 0 (Antifungal Agents) RN - R10H71BSWG (Micafungin) RN - EC 2.7.10.1 (FLT3 protein, human) RN - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) SB - IM MH - Humans MH - Antifungal Agents/adverse effects MH - Micafungin/therapeutic use MH - Prospective Studies MH - *Leukemia, Myeloid, Acute/drug therapy/genetics/diagnosis MH - *Neutropenia MH - fms-Like Tyrosine Kinase 3/genetics PMC - PMC10582652 COIS- The authors declared no competing interests for this work. EDAT- 2023/07/29 11:50 MHDA- 2023/10/23 12:45 PMCR- 2023/07/28 CRDT- 2023/07/29 02:45 PHST- 2023/06/09 00:00 [received] PHST- 2023/07/06 00:00 [accepted] PHST- 2023/10/23 12:45 [medline] PHST- 2023/07/29 11:50 [pubmed] PHST- 2023/07/29 02:45 [entrez] PHST- 2023/07/28 00:00 [pmc-release] AID - CTS13595 [pii] AID - 10.1111/cts.13595 [doi] PST - ppublish SO - Clin Transl Sci. 2023 Oct;16(10):1876-1885. doi: 10.1111/cts.13595. Epub 2023 Jul 28.