Effect of caspofungin on pre-dose concentrations of immunosuppressants in kidney transplant recipients: a self-controlled observational study

Caspofungin is frequently used for prophylaxis or treatment of invasive fungal infections in solid organ transplant recipients, often concomitantly with immunosuppressants such as cyclosporine A (CsA), tacrolimus (TAC), and mycophenolate mofetil (MMF). However, the magnitude and clinical significance of drug-drug interactions (DDIs) between caspofungin and these immunosuppressants remain incompletely characterized, and existing literature reports conflicting findings. Moreover, the impact of concomitant caspofungin on the safety profile of immunosuppressants has not been systematically evaluated. To evaluate the effect of caspofungin on the steady-state pre‑dose concentrations (C 0 ) of CsA, TAC, and mycophenolic acid (MPA, the active metabolite of MMF) using a self-controlled design, and to systematically summarize published evidence on these DDIs, and to compare the safety indicators between combination therapy and immunosuppressant monotherapy. This observational study included kidney transplant recipients who received immunosuppressants both with and without concomitant caspofungin. Immunosuppressant C 0 were measured by immunoassay or liquid chromatography-tandem mass spectrometry. Blood samples were routinely collected in the morning immediately before the morning dose, following standard clinical TDM practice. Paired comparisons were performed between concentrations during caspofungin co-administration and after caspofungin discontinuation in the same patients. Safety indicators including complete blood count, liver function, renal function, and cholesterol were compared between the two periods using paired t-tests or Wilcoxon signed-rank tests. A linear mixed-effects model was constructed to adjust for time-varying confounders. Additionally, a systematic literature review was conducted to summarize published studies on DDIs between caspofungin and CsA, TAC, and MMF. A total of 37 patients on CsA, 121 on TAC, and 131 on MMF were included in the paired analysis. Concomitant caspofungin use was associated with a non‑significant 12.6% decrease in CsA C 0 (paired difference: − 21.2 ng/mL, 95% CI − 54.8 to 12.4, P = 0.208), a significant 22.8% reduction in TAC C 0 (paired difference: − 1.8 ng/mL, 95% CI − 3.2 to − 0.4, P = 0.014), and an exploratory finding of a 31.4% increase in MPA C 0 (paired difference: + 1.1 mg/L, 95% CI 0.15 to 2.05, P = 0.024), which should be interpreted with caution given the limitations of pre-dose concentration monitoring for MPA and does not establish an increase in total MPA exposure. In safety analysis, serum creatinine was higher and estimated CLcr was lower during caspofungin co-administration than during immunosuppressant alone in all three cohorts (all P < 0.001), and platelet counts were also lower in all cohorts ( P < 0.001). These findings represent descriptive temporal associations only; given the observational design and multiple potential confounders, they do not establish causality and cannot be attributed to caspofungin or to any specific co-administered agent. Liver function parameters showed no clinically significant deterioration. No severe adverse events attributable to the combination were observed. Systematic review of 11 published studies revealed that caspofungin has no significant effect on CsA concentrations in most reports, reduces TAC concentrations by 20–23% (with CYP3A5 genotype-dependent variability), and increases MPA concentrations by approximately 30%. No antagonism was observed in any study. In this self-controlled analysis, caspofungin co-administration significantly reduced TAC exposure and increased MPA exposure in transplant recipients, while its effect on CsA was not statistically significant. Consistent temporal associations with renal function parameters and platelet counts were observed during co-administration, but these descriptive findings do not establish causality and should not be attributed to caspofungin or to any specific co-administered agent. Monitoring of renal function and platelet count may be clinically prudent in this population as a precautionary measure. Dose adjustments should be guided primarily by measured concentrations and overall clinical status, rather than protocol‑driven percentage‑based adjustments.