Kidney transplant recipients who take the antifungal drug caspofungin alongside their immunosuppressant medications may need closer monitoring of tacrolimus and mycophenolic acid blood levels, according to a self-controlled observational study published in the European Journal of Medical Research. The study found that concomitant caspofungin use was associated with a significant 22.8 percent reduction in tacrolimus pre-dose concentrations and an exploratory 31.4 percent increase in mycophenolic acid levels, while cyclosporine concentrations showed no statistically significant change.

The research team, led by Yan Wang and Qianting Yang, included 37 patients on cyclosporine A, 121 on tacrolimus, and 131 on mycophenolate mofetil in their paired analysis. All participants were kidney transplant recipients who received their immunosuppressants both with and without concomitant caspofungin at different times. The investigators measured steady-state pre-dose concentrations, known as C0 values, using either immunoassay or liquid chromatography-tandem mass spectrometry. Blood samples were routinely collected in the morning immediately before the morning dose, following standard clinical therapeutic drug monitoring practice.

The self-controlled design is a key strength of the study. Rather than comparing different groups of patients, the researchers performed paired comparisons between concentrations measured during caspofungin co-administration and after caspofungin discontinuation in the same patients. This approach helps control for stable individual characteristics that could otherwise confound the results. To further account for time-varying confounders, the team constructed a linear mixed-effects model.

The tacrolimus finding was the most statistically robust. Patients on tacrolimus had a mean pre-dose concentration of 7.9 plus or minus 7.2 nanograms per milliliter without caspofungin compared with 6.1 plus or minus 4.2 nanograms per milliliter during co-administration, a paired difference of minus 1.8 nanograms per milliliter with a 95 percent confidence interval of minus 3.2 to minus 0.4 and a P value of 0.014. Because tacrolimus has a narrow therapeutic index, even a modest drop in exposure could theoretically increase the risk of rejection if clinicians are unaware of the interaction, although the study did not assess clinical outcomes such as rejection episodes.

For mycophenolic acid, the active metabolite of mycophenolate mofetil, the paired analysis showed a mean concentration of 3.5 plus or minus 2.3 milligrams per liter without caspofungin versus 4.6 plus or minus 2.8 milligrams per liter during co-administration. This represents a paired difference of plus 1.1 milligrams per liter with a 95 percent confidence interval of 0.15 to 2.05 and a P value of 0.024. The researchers emphasized that this is an exploratory finding that should be interpreted with caution given the limitations of pre-dose concentration monitoring for mycophenolic acid, and it does not establish an increase in total mycophenolic acid exposure.

Cyclosporine A told a different story. The mean pre-dose concentration was 167.8 plus or minus 69.0 nanograms per milliliter without caspofungin and 146.6 plus or minus 86.6 nanograms per milliliter during co-administration, a 12.6 percent decrease. However, the paired difference of minus 21.2 nanograms per milliliter carried a 95 percent confidence interval spanning minus 54.8 to 12.4 and a P value of 0.208, meaning the change was not statistically significant. This aligns with the systematic review component of the study, which found that caspofungin has no significant effect on cyclosporine concentrations in most published reports.

The systematic literature review summarized 11 published studies on interactions between caspofungin and the three immunosuppressants. Across these studies, caspofungin reduced tacrolimus concentrations by 20 to 23 percent, with variability that may depend on CYP3A5 genotype, and increased mycophenolic acid concentrations by approximately 30 percent. No antagonism was observed in any study. The authors noted that the potential tacrolimus-caspofungin interaction may depend on CYP3A5 genotype, but no pharmacogenetic testing was performed in their own cohort, so this remains a hypothesis requiring confirmation in studies with directly measured genotype.

Safety indicators were compared between the combination therapy period and the immunosuppressant monotherapy period using paired t-tests or Wilcoxon signed-rank tests. Serum creatinine was higher and estimated creatinine clearance was lower during caspofungin co-administration than during immunosuppressant monotherapy in all three cohorts, with all P values below 0.001. Platelet counts were also lower in all cohorts during co-administration, with P values below 0.001. The researchers were careful to characterize these as descriptive temporal associations only. Given the observational design and multiple potential confounders, including acute illness and the early post-transplant period, these findings 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, and no severe adverse events attributable to the combination were observed. The authors concluded that monitoring of renal function and platelet count may be clinically prudent in this population as a precautionary measure, and that monitoring of tacrolimus, mycophenolic acid, renal function, and platelet count during caspofungin co-administration is a reasonable precautionary clinical consideration. Importantly, they advised that dose adjustments should be guided primarily by measured concentrations and overall clinical status rather than protocol-driven percentage-based adjustments.

The study addresses an unresolved question in transplant pharmacology. Caspofungin is frequently used for prophylaxis or treatment of invasive fungal infections in solid organ transplant recipients, often concomitantly with cyclosporine A, tacrolimus, and mycophenolate mofetil. However, the magnitude and clinical significance of drug-drug interactions between caspofungin and these immunosuppressants have remained incompletely characterized, and existing literature has reported conflicting findings. Moreover, the impact of concomitant caspofungin on the safety profile of immunosuppressants had not been systematically evaluated before this work. By combining a self-controlled paired analysis with a systematic review of the published evidence, the study offers transplant clinicians a more consistent picture: expect lower tacrolimus levels and higher mycophenolic acid levels when caspofungin is on board, keep a watchful eye on renal function and platelet counts, and rely on measured drug concentrations rather than fixed percentage rules when adjusting immunosuppressant doses.

Subject of Research: Drug-drug interactions between the antifungal caspofungin and immunosuppressants in kidney transplant recipients

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

Article References: Wang, Y., Wang, N., Cai, Y., Xie, J., Li, Y., Li, Y., Li, S., Feng, L., Dong, Y., & Yang, Q. (2026). Effect of caspofungin on pre-dose concentrations of immunosuppressants in kidney transplant recipients: a self-controlled observational study. European Journal of Medical Research. https://doi.org/10.1186/s40001-026-05414-5

Image Credits: AI Generated

DOI: 10.1186/s40001-026-05414-5

Keywords: caspofungin, tacrolimus, cyclosporine, mycophenolic acid, kidney transplantation, drug-drug interactions, therapeutic drug monitoring, immunosuppressants, renal function, platelet count, self-controlled study, transplant pharmacology