Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders

Abstract

Posaconazole (PCZ) is effective in preventing and salvage treatment invasive fungal infections in patients with hematologic disorders. However, PCZ displays highly variable individual pharmacokinetics affecting its efficacy and safety. To investigate the correlation between PCZ concentration and efficacy and safety, the following key influencing factors were explored. A total of 285 trough plasma concentrations (C min ) of 81 Chinese patients receiving PCZ oral suspension for prophylaxis or treatment of invasive fungal infections were collected in this study. The relationships between C min values and clinical response and hepatotoxicity were investigated as well as the incidence of clinical response under different C min values of PCZ with a logistic regression model. The concentration of PCZ showed remarkable differences among patients with haematologic disorders. PCZ C min values of 0.76 and 1.0 µg/mL were both associated with an over 80% probability of successful response to prophylaxis and treatment of fungal infections, respectively. No association between C min values and hepatotoxicity was noted ( P > 0.05). Gender, albumin, and co-administration of proton pump inhibitor (PPI) were identified as independent factors influencing PCZ C min by multiple linear regression analysis. Furthermore, patients’ C-reactive protein (CRP), albumin, and co-administration of PPI exhibited significant effects on the therapeutic window of patients receiving PCZ for prophylaxis. The plasma concentration is closely associated with therapeutic efficacy of PCZ. It is necessary to adjust the dosing regimens based on PCZ C min to obtain an optimal therapeutic response.

Dose Optimisation of Posaconazole and Therapeutic Drug Monitoring in Pediatric Patients

“…Among patients receiving PCZ for the treatment of IFI, PCZ concentrations among patients who failed therapy (0.53 μg mL −1 ) were lower than those who treated successfully (1.06 μg mL −1 ) ( p = 0.024). In our previous study, PCZ C min values of 1.0 μg mL −1 was associated with a >80% probability of successful treatment response ( Jia et al, 2020 ). Similar to a multicenter study of PCZ treatment of IFIs in juvenile (<18 years) with IFIs [the success rate was (5/8) 62.5%] ( Krishna et al, 2007 ), the current study found that 79.2% of patients (19/24) successfully responded to PCZ treatment.…”

“…Dose adjustments were taken according to the current guidelines and the manufacturer’s recommendations ( Vicenzi et al, 2018 ). PCZ trough plasma concentrations were determined using a previously described ultra-high-performance liquid chromatograph-tandem mass spectrometry method (UPLC-MS/MS, Waters, United States) ( Jia et al, 2020 ). The analytical range was 0.025–5.00 μg mL −1 .…”

“…Our previous research which conducted in adults demonstrated that a number of factors exhibited significant effects on PCZ C min including gender, albumin and interactions with co-medications, leading to high inter-individual and intra-individual variability in plasma concentrations. A 25.9% lower in the exposure of the oral PCZ suspension was reported when administered with proton pump inhibitors (PPIs) in adults ( Dolton et al, 2014 ; Jia et al, 2020 ). However, fewer data are available in children and most of them are based on adult experience for pediatric patients.…”

Characteristics of Mucormycosis in Hematological Patients and a Death Prediction Model

“…The guidelines recommend PCZ as primary prophylaxis drug in high-risk immunocompromised patients, but in our study, all 31 patients had received voriconazole for antifungal prophylaxis before the onset of mucormycosis. There is only PCZ oral suspension in our hospital, and the PCZ plasma concentration is usually insufficient, which may be lead to poor clinical effectiveness ( Jia et al, 2020 ). Therefore, the doctors in our hospital often choose voriconazole to prevent fungal infections.…”

“…PCZ plasma concentration in some patients was monitored, but 50% of that did not reach 1.0 mmol/L. Previous studies have shown that insufficient PCZ plasma concentration indicated a high failure rate of prophylaxis and therapy of invasive fungal disease ( Chae et al, 2015 ; Jia et al, 2020 ). Insufficient PCZ plasma concentration may also be an important factor in the high mortality of patients in our study; however, in our study, only some patients had measured PCZ plasma concentration, so it has not been used to establish the death prediction model.…”