The correlation between posaconazole concentrations and clinical response is well-established [14, 18, 19]. POS delayed-release tablets and injections have effectively addressed issues related to variability and inconsistent bioavailability [23]. However, POS remains an essential alternative for patients who cannot swallow. Several factors, including high-fat meals, gastric pH and motility, diarrhea, and mucositis, have been identified as influences on POS concentrations [13]. Unlike other azoles, posaconazole is predominantly metabolized by UDP-glucuronosyltransferase (UGT) 1A4 rather than phase 1 CYP450 enzymes, and acts as an inhibitor and substrate of the P-glycoprotein (P-gp) transporter. Inhibitors (such as cyclosporine and quinidine) or inducers (such as rifampicin and certain anticonvulsants) of these pathways can significantly alter posaconazole levels, affecting therapeutic efficacy. TDM is recommended to ensure posaconazole efficacy [17].
Our study found that while esomeprazole or rabeprazole significantly decreased POS Cmin and C/D ratios, there were no significant differences in the occurrence of bIFIs between the groups. However, these PPIs did reduce the frequency distribution of effective POS concentrations, resulting in more patients with plasma concentrations below 500 ng/mL. Research has demonstrated the impact of intragastric pH on posaconazole levels; for example, pantoprazole and lansoprazole significantly decrease plasma POS concentrations [19], and similar effects were observed with omeprazole and lansoprazole, which is consistent with our findings [20]. Further investigation of specific formulations revealed that esomeprazole tablets and injections, as well as rabeprazole injections, markedly reduced POS Cmin. Injectable forms, being faster-acting, may have a greater impact on Cmin compared to other formulations. Therefore, patients taking POS are advised to avoid injectable PPIs. Our findings also indicate that POS Cmin decreases with prolonged co-administration of POS and PPIs, suggesting that close monitoring of posaconazole concentrations by physicians and pharmacists is crucial during long-term use.
The probable or proven IFI incidence was 6.4%, and these patients had a mean posaconazole concentration of 1,022 ng/mL before bIFIs. Only two patients had concentrations below 700 ng/mL, and one had a concentration below 500 ng/mL before diagnosis. There were no significant differences in the duration of prophylactic POS administration between patients who developed IFIs and those who did not (10 days vs. 14 days, p = 0.146). A study found that only one of the nine allogeneic hematopoietic cell transplant recipients taking posaconazole had a mean concentration of less than 700 ng/mL shortly before the diagnosis of breakthrough infection [24]. Similarly, among patients with acute myeloid leukemia/myelodysplastic syndrome receiving venetoclax and posaconazole, five of seven patients who acquired IFI within one cycle of venetoclax had reached steady-state therapeutic trough levels (700 ng/mL) [25].
Five patients in this study developed bIFIs due to causes other than POS concentration not reaching the recommended preventive level. Corticosteroids (dexamethasone and methylprednisolone) were administered to these patients simultaneously with POS. Furthermore, one patient had diabetes, and four underwent chemotherapy, circumstances that could have potentially contributed to infections in confirmed patients [3], although the concentrations were sufficient. It should be noted that the genotype could also contribute to infections after low POS concentrations. Unlike patients with wild-type UGT1A4, UGT1A4 *3 is associated with decreased POS absorption [26].
In this study, a patient in the terminal stages of myelodysplastic syndrome receiving POS and amphotericin B therapy succumbed to respiratory failure resulting from a mixed fungal and bacterial infection. A higher percentage of low concentrations occurred in POS treatment patients compared to prophylactic patients. This could be because these patients were more seriously ill. Most were taking immunosuppressive drugs such as steroids and experiencing hypoalbuminemia, which could lead to a decrease in POS concentrations [27, 28]. Furthermore, in critically ill patients receiving an intravenous formulation of posaconazole, the therapeutic threshold (1,000 ng/mL) was only reached in 26% of all concentrations. Exposure to posaconazole in critically ill individuals also differs from that in non-critically ill hematological patients [29]. Hospitalized patients diagnosed with a fungal disease had a higher prevalence of TDM than those without [30]. Patients who undergo treatment may require more frequent TDM than those on prophylaxis, suggesting a possible need to increase the POS treatment dose.
In our study, patients with hepatotoxicity had lower POS concentrations, and 85.7% were taking medications known to cause hepatotoxicity. Simultaneous use of drugs with known risks of liver damage was identified as a possible contributing factor to the development of hepatotoxicity in patients treated with posaconazole [31]. Patients treated with POS concentrations greater than 5,000 ng/mL experienced a higher frequency of hepatotoxicity and a high incidence of symptomatic ADRs [32]. However, concentrations greater than 5,000 ng/mL were observed in only one patient in our study, and this patient did not develop hepatotoxicity. A network meta-analysis found that, while posaconazole ranked the worst among interventions, there were no statistically significant differences in increased liver enzymes between any antifungal drug and placebo [33].
Elevated posaconazole trough concentrations in lung transplant recipients were not associated with altered liver function [34]. In allogeneic hematopoietic cell transplant recipients receiving posaconazole, a retrospective study found no statistically significant differences in liver function tests between the initial phase and the end of treatment [24]. These findings may suggest that posaconazole-induced hepatotoxicity is modest and reversible, but patients with higher concentrations still need careful follow-up. Recent research has also suggested an association between posaconazole and pseudohyperaldosteronism, which can manifest with proteinuria [35–38]. However, this association was not observed in our study.
This study examined the effects of pantoprazole, ilaprazole, rabeprazole, omeprazole, and esomeprazole on POS blood concentrations and the distribution of effective concentrations. Subsequent analysis focused on PPI formulations (esomeprazole and rabeprazole) that significantly impacted POS concentrations. Esomeprazole magnesium enteric-coated tablets, esomeprazole sodium for injection, and rabeprazole sodium for injection was the only formulation that significantly reduced POS trough concentrations (Cmin).
This study has several limitations. First, its retrospective design is susceptible to confounders, which may affect the validity of the findings. The lack of specific data on lansoprazole use restricts our ability to assess its impact on posaconazole concentrations or prophylactic efficacy. Second, there was no follow-up with patients who received adjusted POS doses due to inadequate concentrations, limiting our understanding of the long-term effects of dose adjustments. These factors require caution when interpreting the results and underscore the need for methodological improvements in future research.