To the best of our knowledge, this is the first study to analyze the impact of oral POS on the concentration of oral and/or intravenous CsA simultaneously in the largest number of patients. We observed that, regardless of the administration route of CsA (oral or intravenous), oral POS could significantly influence the blood concentrations of CsA by 0.45 to 4.55-fold in recipients undergoing allogeneic HSCT. Tremendous inter-individual variability was observed in the fold change in the CsA C/D ratio, with the coefficient variation ranging from 32.3–55.7%. We also investigated the tendency of CsA levels over time after POS initiation, with the C/D ratio reaching a steady state 8–20 days after the initiation of POS.
Wide inter-individual variability in the magnitude of drug interaction between POS and CsA was observed in our program. Similar to the results of previous studies, the C/D ratio of CsA with POS co-therapy increased by 1 to 2 times in most patients across various subgroups when compared to that without POS. One study assessed four heart transplant recipients on a regular regimen of CsA and found that the AUC0-τ of CsA increased by 1.3-fold at the initiation of POS therapy[14]. In another study conducted in 41 blood and marrow transplant recipients, the authors reported that after 30 days of combined treatment, POS led to a 50% reduction in CsA dose and an approximate doubling of the C/D ratio[7]. Robinson et al. performed a retrospective and prospective study in patients undergoing allogeneic HSCT[15]. They demonstrated a high incidence of cyclosporin-related toxicity when patients received CsA and POS concomitantly. As recommended in the POS package insert, CsA should be reduced by 25% at the initiation of combined treatment with POS. Our results, together with those of previous studies, demonstrate that POS could increase the concentration of CsA, leading to related toxic reactions. Therefore, caution should be exercised when CsA is co-administered with POS.
The administration route of CsA did not significantly affect the change in the CsA C/D ratio in our study. The highest coefficient of variation of fold change after POS co-medication was observed in the group receiving oral CsA. Since CYP3A4 enzymes are present in the small intestine and liver, intestinal and hepatic enzymes are major interaction sites during the oral administration of CsA. In patients following HSCT co-administered voriconazole, Atiq et al. found that the bioavailability of orally administered CsA was nearly 100%, possibly due to the inhibition of CYP3A4 enzymes in the gut wall by voriconazole[5]. Therefore, intestinal CYP3A4 may play an essential role in oral CsA metabolism. Additionally, orally administered POS inhibited P-glycoprotein activity in the small intestine, increasing the blood concentrations of oral CsA[9, 16]. The large inter-individual variability in the oral absorption and first-pass effect of CsA is also one of the reasons for the extensive variation in the C/D ratio in orally administered CsA.
Because of the long half-lives of azoles, most reach steady-state concentrations after 5–7 days and exhibit their maximal effect on enzyme inhibition. Nara et al. investigated the interactions between itraconazole and orally administered calcineurin inhibitors over seven days[11]. They reported that the dose-adjusted trough concentrations of tacrolimus and CsA significantly increased from day 3 and stabilized on day 5 after itraconazole initiation. In the study by Cho et al., the highest C/D ratio of sirolimus was observed 9–12 days after POS initiation, and a new steady state was reached in approximately 17–20 days[10]. Currently, it has not been clarified how long the interaction reaches a steady state after coadminisration with CsA and POS. Our study observed that the time required for the C/D ratio of CsA to reach a plateau after POS initiation was similar under various scenarios. After concomitant administration of POS, the C/D ratio of CsA slowly increased and gradually plateaued at approximately 8–20 days. The influence of POS on CsA levels, in our opinion, is associated with the steady state of POS, which is considered to be eight days based on the half-life of approximately 35h provided in POS instruction.
Immunosuppressive agents, such as tacrolimus, sirolimus, and CsA, are frequently used to prevent and treat graft-versus-host-disease (GVHD) in transplant recipients. As these medications are substrates of cytochrome P450-3A4 (CYP3A4), POS may increase their exposure. In a study of 15 patients following HSCT, the author suggested a 33–50% empirical sirolimus dose reduction to maintain therapeutic drug concentrations when using sirolimus and POS concurrently[17]. However, Greco et al. concluded that the sirolimus dose should be reduced by 55–70% when posaconazole is introduced[18]. This may be due to the large interpatient variability in sirolimus pharmacokinetics, especially when co-administered with strong CYP3A4 inhibitors. Similarly, POS can lead to an increase in the tacrolimus concentration. Vanhove et al. found a 4.4-fold increase in tacrolimus C/D levels upon POS initiation in solid organ recipients[13]. Similar results have been observed in patients undergoing HSCT. Collin et al. recommended that it was necessary to reduce the tacrolimus dose by 50% empirically with concomitant use of POS[19], while a 50–75% dose reduction was advised by Peksa et al[20]. Consistent with Fucheng Cheng, we recommended an initial empirical CsA dose reduction of 30–40% based on our results[9]. In summary, owing to the posaconazole-related inhibition of CYP3A4 activity, the interaction between POS and immunosuppressive drugs is an essential consideration in the clinical management of transplant recipients. Dose reduction of immunosuppressants is necessary to sustain the therapeutic levels of the drug and reduce adverse events associated with increased concentrations.
Triazole antifungals, including voriconazole, itraconazole, and POS, are strong inhibitors of CYP3A isoenzymes and display pronounced interactions with immunosuppressants. Groll et al. reported that the strength of the inhibitory effect of POS on CYP3A4 is comparable to that of voriconazole[16]. Valenzuela et al. showed a 23.1% increase in the level of CsA in pediatric patients[12], and Masoumi et al. claimed that the CsA C/D ratio increased significantly by a factor of 1.4[21], when CsA was concurrently used with voriconazole in HSCT patients. A similar effect was observed for POS in our study, with an approximately 1.5-fold increase in the C/D ratio, which supports the findings of Groll et al[16, 22]. In comparison, a 2.7-fold increase in the concentration of CsA was observed with concomitant itraconazole, which was significantly higher than the value of CsA co-administered with voriconazole and POS. A plausible explanation could be that in addition to itraconazole having a stronger inhibitory effect on CsA by inhibiting CYP3A and Pg-glycoprotein activity, the metabolites of itraconazole also inhibit hepatic microsomal enzyme activity[11]. Other triazole antifungal drugs, such as fluconazole and isavuconazole, are considered moderate CYP3A4 inhibitors. In a more recent study by Tina et al., the authors found that fluconazole initiation led to a 25% reduction in the CsA dose to maintain the goal concentration[23]. A similar finding has been reported for isavuconazole, which resulted in a 29% increase in CsA exposure[24]. This is consistent with the moderate inhibition of CYP3A4 enzyme[23, 25]. Therefore, when CsA is combined with triazole antifungals, therapeutic drug monitoring and dose adjustment are necessary.
Consistent with earlier reports, our findings further confirmed that POS could lead to an increase in the CsA C/D ratio by a factor of 1.5 for the majority of patients. Of note, at the start of POS, 6% (7/118) of patients in our study showed more than a 3-fold increase in concentration, with two of them showing a 4-fold increase. Our results showed a wide variability in the fold increase in the CsA C/D ratio fluctuating between 0.4 and 4.5 fold after POS initiation. One possible reason is the variability in the pharmacokinetics of CsA, which is correlated with various factors, such as food intake, time since transplantation, liver function, bile flow, genetics, gastrointestinal state, and the application of combined drugs, causing inter-individual differences in the interaction between the two drugs.
We acknowledge that, because POS levels were not evaluated, we could not assess the relationship between the blood concentration of POS and its drug interaction with CsA. One report demonstrated that the apparent dose responsiveness of CYP3A inhibition with POS appeared to reflect the submaximal inhibition potential of CYP3A4 with lower exposure to POS. In a population pharmacokinetic study, Boonsathorn et al. found that immunosuppressants, including CsA, tacrolimus, sirolimus, and everolimus, did not affect the pharmacokinetics of POS [26]. In addition, the efficacy of azoles is closely related to their plasma concentrations; thus, no adjustment of the POS dose is required when combined with CsA[9, 14, 27]. This was also the case in our study, with a maintenance dose of 200 mg TID or 400 mg BID. In the future, studies on POS pharmacokinetics are required to define drug interactions further.
Despite the larger number of patients in this study, we cannot ignore some limitations. First, data on POS concentrations and genetic polymorphisms of patients were not available because of the retrospective nature of the analysis. Moreover, the association between blood POS and CsA levels could not be analyzed. In particular, oral suspensions of POS have a more complex absorption profile and may cause differential effects. In addition, after the impact of POS on CsA has reached a steady state, CsA concentrations are usually monitored once per week or per two weeks in our institution. Thus, the concentration of oral CsA was much lower after 20 days of coadministration, which may affect the trend of CsA concentration changes. Overall, data on the impact of POS on CsA pharmacokinetics are limited, and further analysis is essential to explore the trends detected in this retrospective program.