Drug–drug interaction between tacrolimus and caspofungin in Chinese kidney transplant patients with different CYP3A5 genotypes

Abstract

Background:

The effect of drug–drug interaction between tacrolimus and caspofungin on the pharmacokinetics of tacrolimus in different CYP3A5 genotypes has not been reported in previous studies.

Objectives:

To investigate the effect of caspofungin on the blood concentration and dose of tacrolimus under different CYP3A5 genotypes.

Design:

We conducted a retrospective cohort study in The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital from January 2015 to December 2022. All kidney transplant patients were divided into the combination or non-combination group based on whether tacrolimus was combined with caspofungin or not. Patients were subdivided into CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3) and CYP3A5 non-expressers (CYP3A5*3/*3).

Methods:

Data from the combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. A total of 200 kidney transplant patients receiving tacrolimus combined with caspofungin or not were enrolled in this study. Statistical analysis was conducted on the dose-corrected trough concentrations (C₀/D) and dose requirements (D) of tacrolimus using independent sample two-sided t-test and nonparametric tests to investigate the impact on patients with different.

Results:

In this study, the C₀/D values of tacrolimus were not significantly different between the combination and non-combination groups (p = 0.054). For CYP3A5 expressers, there was no significant difference in tacrolimus C₀/D or D values between the combination and non-combination groups (p = 0.359; p = 0.851). In CYP3A5 nonexpressers, the C₀/D values of tacrolimus were significantly lower in the combination than in the non-combination groups (p = 0.039), and the required daily dose of tacrolimus was increased by 11.11% in the combination group.

Conclusion:

Co-administration of caspofungin reduced tacrolimus blood levels and elevated the required daily dose of tacrolimus. In CYP3A5 non-expressers, co-administration of caspofungin had a significant effect on tacrolimus C₀/D values. An approximate 10% increase in the weight-adjusted daily dose of tacrolimus in CYP3A5 non-expressers is recommended to ensure the safety of tacrolimus administration.

Plain language summary

Differential drug interactions of caspofungin on tacrolimus in Chinese kidney transplant patients with different CYP3A5 genotypes

Why was the study done? Currently, there have been studies reporting the effect of caspofungin on tacrolimus blood concentrations, but the conclusions are conflicting, and no study has focused on the effect of CYP3A5 genotypes on the drug-drug interaction. We explored a number of research questions: 1. Does caspofungin have an effect on the pharmacokinetics of the immunosuppressant tacrolimus? 2. How does CYP3A5*3, which affects tacrolimus metabolism significantly, affect tacrolimus blood concentration levels? 3. How should the dose of tacrolimus be adjusted when combined with caspofungin?

What did the researchers do? By reviewing literature, we understood the problems related with the kidney transplant patients better, which led to the development of strict inclusion and exclusion criteria. The patients (from January 2015 to December 2022) were categorized into combination and non-combination groups according to whether they were co-administered with caspofungin or not. The results of the study were analyzed using SPSS 22.0.

What did the researchers find? The study finally included 200 patients. We found no statistically significant differences in the dose-corrected trough concentrations (C₀/D) and dose requirements (D) of tacrolimus between the combination and non-combination groups. However, in patients with CYPA5*3/*3 genotype, tacrolimus C₀/D values were significantly lower in the combination group than in the non-combination group, and the required daily tacrolimus dose was increased.

What do the findings mean? This study has found that co-administration of caspofungin in patients with CYP3A5*3/*3 genotype resulted in a significant decrease in the C₀/D value of tacrolimus, therefore, an appropriate increase in the daily dose of tacrolimus is recommended. The implication is that it is important and necessary to monitor the concentrations of tacrolimus and the CYP3A5 genotypes, and adjust the dose when combined or discontinuing with caspofungin in kidney transplant patients.

Keywords

caspofungin CYP3A5 kidney transplant tacrolimus

Introduction

Tacrolimus, a calcineurin inhibitor with a 23-element macrolide structure, is currently widely used as a first-line immunosuppressive agent after kidney transplantation to reduce the incidence of graft rejection.^1,2 The triple immunosuppressive regimen of tacrolimus/mycophenate/glucocorticoid is the primary treatment for preventing rejection after kidney transplantation. Tacrolimus has a very narrow therapeutic window. Blood concentrations above the upper limit of the therapeutic window may increase the risk of adverse reactions and even toxicity, while concentrations below the therapeutic window may lead to insufficient immunosuppression or graft rejection.^3,4 Therefore, monitoring tacrolimus concentrations is particularly important for predicting the outcomes of pharmacotherapy in kidney transplant recipients and has become a routine protocol in clinical practice. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A family. Previous studies reporting POR*28 and ABCB1 are limited or with contradictory conclusions.⁵ In the CYP3A family, CYP3A4 and CYP3A5 are thought to be relevant in adults. CYP3A7 is only expressed in fetal liver, and CYP3A43 is of uncertain significance.⁵ For CYP3A4 gene variants, CYP3A4*22 and CYP3A4*1B are not suitable for evaluating their effect on tacrolimus efficacy in Chinese due to their near-zero mutation rate in Asian populations,^6,7 and CYP3A4*18B was dependent on CYP3A5 genotype.⁸ CYP3A5 gene is highly polymorphic in the East Asian population⁹ and is one of the important factors affecting the blood concentrations of tacrolimus.^10,11 Among them, the frequency of the CYP3A5*3 allele is about 0.742, while the gene frequencies of both CYP3A5*6 and CYP3A5*7 alleles are less than 0.001 in Asian populations, so only the CYP3A5*3 genotype was considered in this study.⁵ Individuals carrying at least one functional allele are referred to as CYP3A5 expressers (CYP3A5*1/*1 and CYP3A5*1/*3 genotypes), while those carrying two non-functional alleles are referred to as CYP3A5 non-expresser (CYP3A5*3/*3 genotype). The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that kidney transplant recipients be individualized tacrolimus therapy based on CYP3A5 genotypes.⁵ In addition, other factors such as drug–drug interactions (DDIs) and the patient’s characteristics including body mass index (BMI), days post-transplant, and hematocrit (HCT) may also influence tacrolimus plasma concentrations.^12,13

Invasive fungal infection (IFI) is an important cause of morbidity and mortality in solid organ transplant recipients because of the use of immunosuppressants and postoperative health deterioration. Invasive Candidiasis (53%) and invasive Aspergillosis (19%) were the most common pathogens of IFI.¹⁴ Echinocandins have been widely used for fungal infection in kidney transplant patients due to their good safety and efficacy.¹⁵ Caspofungin, the first echinocandin agent on the market with a strong antifungal effect against azole-resistant Candida, is highly recommended for the treatment of invasive Candidiasis (including Candidemia in neutropenic and non-neutropenic patients).¹⁶ Caspofungin is a poor substrate for CYP450 enzymes. Although interactions of echinocandins are generally rare, caspofungin has greater interactions with other drugs than micafungin and anidulafungin.¹⁷ Studies have shown that the maximum blood concentration (Cmax) of tacrolimus can be reduced (up to 20%) when caspofungin is used in combination, which may also require adjustment of the tacrolimus dose.¹⁸ However, little is known about the effects of caspofungin on tacrolimus drug interactions under different genotypes of CYP3A5. Therefore, the purpose of this study was to evaluate the effect of caspofungin on tacrolimus blood concentrations and daily doses in kidney transplant patients with different genotypes of CYP3A5 and to further guide the dose adjustment of tacrolimus when combined with caspofungin.

Methods

Study design

This single-center retrospective cohort study was conducted in The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.¹⁹ In-patients receiving kidney transplants in the Department of Urology from January 2015 to December 2022 were included. The inclusion criteria were as follows: (1) at least 18 years old, (2) first kidney transplant, and (3) taking a tacrolimus-based triple immunosuppressive regimen (tacrolimus + mycophenolate sodium + glucocorticoids). Exclusion criteria were as follows: (1) patients with multiple organ transplants, (2) patients receiving drugs that affect the blood concentrations of tacrolimus (e.g. strong enzyme inhibitors or inducers of cytochrome 450 enzyme including rifampin, phenytoin sodium, carbamazepine, azoles or Wuzhi capsules), (3) patients with severe hepatic dysfunction [serum alanine aminotransferase (ALT) levels >3 times of the upper normal limit or total bilirubin (TBIL) >2 mg/dL, or known hepatic cirrhosis, etc.] or severe gastrointestinal disease (e.g. severe gastric ulcer, gastric perforation, ulcerative colitis, gastric bypass, banding or gastric sleeve), (4) patients who were pregnant or breastfeeding, and (5) patients with the significant rejection of transplanted organs or death from other causes within 1–2 months after the operation.

The enrolled kidney transplant patients were divided into combination groups or non-combination groups based on whether caspofungin was used in combination with tacrolimus or not.

Data collection and patient treatment

The data were collected from the HIS (Hospital Information System). Demographic and biochemical characteristics of patients in both groups were collected, including male, age, height, weight, days post-transplant, ALT, aspartate aminotransferase, TBIL, serum creatinine (Cr), estimated glomerular filtration rate (eGFR), red blood cell count (RBC), albumin (ALB), hemoglobin (HGB), HCT, CYP3A5 genotypes, trough concentration (C₀) and dose (D) of tacrolimus after combined with caspofungin, and drug use in combination at each trough measurement. eGFR was calculated by the CKD-EPI formula based on the serum creatinine at the start of caspofungin treatment [For women with a plasma creatinine ≤ 0.7, (plasma creatinine/0.7)^−0.329 × (0.993)^age (× 166 if black; × 144 if white or other); for women with a plasma creatinine >0.7, (plasma creatinine/0.7)^−1.209 × (0.993)^age (× 166 if black; × 144 if white or other); for men with a plasma creatinine ≤0.9; (plasma creatinine/0.9)^−0.411 × (0.993)^age (× 163 if black; × 141 if white or other); for men with a plasma creatinine >0.9, (plasma creatinine/0.9)^−1.209 × (0.993)^age (× 166 if black; × 144 if white or other)]. Hepatic dysfunction was defined as the serum ALT higher than three times the upper normal limit, TBIL higher than 2 mg/dL, or known hepatic cirrhosis at the time of being enrolled. The patients’ blood was collected in the morning before taking tacrolimus to ensure that the measured values were trough concentrations. Measurement of tacrolimus trough values was performed in our hospital laboratory using a uniform fluorescence polarization immunoassay, usually at 1- to 2-day intervals. The relative standard deviation of the results was less than 6%. The trough concentrations measured at least 3 days after the administration or dose adjustment of tacrolimus were chosen for the non-combination group because tacrolimus concentrations generally reach to a steady state 2–3 days after the dosage. The C₀ values of tacrolimus in the combination group were recorded when 1 week of treatment with co-administered caspofungin was completed and tacrolimus concentrations had reached a steady state.

Patients were treated with a post-transplant immunosuppression protocol according to The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline.²⁰ More specifically, intravenous methylprednisolone sodium succinate was administered the day after transplantation with an initial dose of 500 mg/day, which was evenly tapered to 40 mg/day during the first week. During the second week, methylprednisolone tablets were given sequentially at 40 mg/day, which was gradually reduced to 16 mg/day as the maintenance dose. Immunosuppression was maintained with oral mycophenolate sodium 720 mg, twice daily. Tacrolimus was taken orally twice a day at an initial dose of 0.05–0.25 mg/kg/day. Dosages were adjusted based on tacrolimus C₀ of the patients and clinical situation. Target tacrolimus trough levels in the first month following kidney transplantation were 6–15 ng/mL, 8–15 ng/mL in the first 2–3 months, 7–12 ng/mL in the 4–6 months after transplantation, and 5–10 ng/mL after the first 6 months.²¹ For the patients in the combination group, the dosage of caspofungin was 70 mg intravenous injection once on the first day after surgery and 50 mg intravenous injection once a day starting from the second day. The patient’s medication was strictly monitored by the nursing team to ensure good adherence.

Genotyping

The presence of CYP3A5*3 was detected using a TaqMan real-time polymerase chain reaction (RT-PCR) assay (Applied Biosystems, Foster City, CA, USA). Genomic deoxyribonucleic acid was extracted from the blood samples using the TIANamp Blood DNA Kit (DP348; TIANGEN Biotech, Beijing, China) according to the manufacturer’s instructions. The primers and sequences for CYP3A5*3 are as follows: forward primers (5′-CCTGCCTTCAATTTTCACT-3′); reverse primers (5′-GGTCCAAACAGGGAAGAGGT-3′). To validate the RT-PCR results, CYP3A5*3 (rs776746) was confirmed via Sanger sequencing using a 3730XL Genetic Analyzer (Applied Biosystems, Foster City, CA, USA).

Statistical analysis

The method of propensity score matching was used to match the baseline data of kidney transplantation patients in the combination and non-combination groups at 1:1, to obtain a new dataset with successful matching. Normality was tested using the Shapiro–Wilk test. Continuous data with normal distributions were represented as mean ± standard deviation (SD), and comparison between groups was performed by independent sample two-sided t-test. The median and interquartile range were used to represent continuous data with abnormal distributions, and a nonparametric test was used to compare between groups. Categorical data were expressed as frequency and percentages, and the chi-square test was used for comparison between groups. p < 0.05 represents a significant difference. All analyses were performed using the International Business Machine Statistical Product Service Solutions software package SPSS 22.0. Figures were generated using the Microsoft Office software package Microsoft Visio (version 2013) and the GraphPad Software package GraphPad Prism (version 8).

Results

Patient recruitment and baseline information

A total of 1524 patients who underwent kidney transplantation were screened, of which 308 were excluded due to receiving the immunosuppressive regimen without tacrolimus, and 166 were excluded for not receiving caspofungin for fungal infection. In the remaining patients, those who lacked data of C₀ of tacrolimus, combined with strong cytochrome enzyme inhibitors or inducers, suffered from severe liver dysfunction or died within 1 month after kidney transplantation were excluded. Finally, 476 kidney transplant recipients were enrolled in this study, among whom 171 were for the combination group and 305 for the non-combination group. The enrolling process is shown in Figure 1.

Figure 1.

Flow chart of participants in the study.

The combination and the non-combination groups were matched with propensity scores to reduce confounding by SPSS 22.0. Sex of birth, age, BMI, CYP3A5*3, days post-transplant, ALB, HCT, HGB, and RBC were strongly correlated with the C₀/D values of tacrolimus,^22–26 so these variables were used as covariates for propensity score matching. Finally, 100 cases were successfully matched in the combination and non-combination groups, respectively. In the combination group, there were 76 males, aged 39.00 (30.00, 50.00) years old with a BMI of 23.43 (20.76, 25.36) kg/m². In the non-combination group, there were 72 males, aged 38.50 (31.00, 48.00) years old and an average BMI of 23.16 (20.98, 26.18) kg/m². The groups were not significantly different when comparing the recipient age, male, BMI, days post-transplant, liver, and renal function at the baseline. The demographic and baseline characteristics of both groups are shown in Table 1.

Table 1.

Baseline clinical characteristics of the study population.

Indicators	Combination group (n = 100)	Non-combination group (n = 100)	p Value
Sex of birth (male/female)	76/24	72/28	0.519
Age (years)	39.00 (30.00, 50.00)^b	38.50 (31.00, 48.00)^b	0.769
BMI (kg/m²)	23.43 (20.76, 25.36)^b	23.16 (20.98, 26.18)^b	0.582
Days post-transplant	9.00 (7.00, 23.50)^b	10.00 (8.00, 19.50)^b	0.291
Organ dysfunction
Hepatic dysfunction	0	0	/
eGFR (mL/min/1.73 m⁻²)	58.46 ± 28.09^a	58.53 ± 25.33^a	0.985
ALB	38.20 (36.30, 41.20)^b	38.50 (35.60, 41.95)^b	0.736
RBC (10¹²/L)	3.44 (3.07, 3.87)^b	3.55 (3.08, 3.88)^b	0.524
HGB (g/L)	106.00 (95.00, 118.50)^b	108.00 (93.00, 119.00)^b	0.658
HCT (%)	0.33 (0.30, 0.37)^b	0.33 (0.30, 0.37)^b	0.516
PPI combination (n)	68	58	0.143
Primary disease (n)
Diabetes nephropathy	26	23	0.622
PKD	2	4	0.678
IgA nephropathy	17	15	0.700
Glomerulonephritis	48	52	0.572
Congenital solitary kidney	2	0	0.477
Other	5	5	1.000

Mean ± SDs.

Median and interquartile range.

ALB, albumin; BMI, body mass index; CRF, chronic renal failure; eGFR, estimated glomerular filtration rate; HCT, hematocrit; HGB, hemoglobin; IgA, immunoglobulin A; PKD, polycystic kidney disease; PPI, proton pump inhibitor; RBC, red blood cell count.

CYP3A5 genotyping

The genotype frequencies of the CYP3A5*3 polymorphisms of the recruited patients are summarized in Table 2. Among the 200 kidney transplant recipients, 3 (1.50%) recipients exhibited the CYP3A5*1/*1 genotype, 64 (32.00%) carried CYP3A5*1/*3, and 133 (66.50%) carried CYP3A5*3/*3. Therefore, the allelic frequencies of CYP3A5*1 and CYP3A5*3 were 17.50% (70/400) and 82.50% (330/400), respectively. The allele distribution of CYP3A5 was consistent with the Hardy-Weinberg equilibrium (χ² = 2.343; p = 0.126).

Table 2.

The CYP3A5 genotype distribution of kidney transplant patients.

n	Genotype (n/%)			Allele		p
	Genotype (n/%)			Frequency (%)
	CYP3A51/1	CYP3A51/3	CYP3A53/3	CYP3A51*	CYP3A53*
200	3/1.50	64/32.00	133/66.50	17.50	82.50	0.126

Effect of caspofungin on tacrolimus concentrations

Table 3 shows the effect of caspofungin on the required daily doses of tacrolimus under different CYP3A5 genotypes. To maintain tacrolimus C₀ in the ideal ranges, the required daily dose of tacrolimus was 4.17% higher in the combination group compared to the non-combination group (p = 0.544). Further analysis based on CYP3A5 genotypes showed that for patients with CYP3A5*1/*1 or CYP3A5*1/*3 genotype, the required daily dose of tacrolimus was 4.76% higher in combination group than in non-combination group (p = 0.851), whereas for patients with CYP3A5*3/*3 genotype, the required daily dose of tacrolimus was 11.11% higher in combination group than in non-combination group (p = 0.449).

Table 3.

Effect of caspofungin on the required daily dose of tacrolimus under different CYP3A5 genotypes.

Patients	Tacrolimus daily dose (mg/kg/day)			p
	Non-combination group	Combination group	% Change in dose	p
Total (n = 200)	0.096 (0.065, 0.113)	0.100 (0.070, 0.119)	+4.17	0.544
CYP3A51/1 or 1/3 (n = 67)	0.105 (0.071, 0.123)	0.110 (0.081, 0.123)	+4.76	0.851
CYP3A53/3 (n = 133)	0.090 (0.063, 0.108)	0.100 (0.066, 0.111)	+11.11	0.449

No significant difference in the C₀/D values of tacrolimus was found between the combination and the non-combination groups [109.71 (74.03, 134.00) ng/mL/(mg/kg/day) versus 118.93 (85.65, 157.39) ng/mL/(mg/kg/day), p = 0.054]. Further analysis based on CYP3A5 genotypes showed that in patients with CYP3A5*1/*1 or CYP3A5*1/*3 genotype, there was no significant difference in the C₀/D of tacrolimus between the combination and non-combination groups [91.58 (67.29, 131.36) ng/mL/(mg/kg/day) versus 100.80 (70.20, 138.45) ng/mL(mg/kg/day), p = 0.359], either; while for patients with CYP3A5*3/*3 genotype, the C₀/D values of tacrolimus were significantly lower in the combination group than in the non-combination group [116.21 (81.11, 134.00) ng/mL/(mg/kg/day) versus 126.50 (101.34, 158.18) ng/mL/(mg/kg/day), p = 0.039], as shown in Figure 2.

Figure 2.

Tacrolimus dose-adjusted trough concentrations between combination and non-combination groups with different CYP3A5 genotypes (p < 0.05 denotes a significant difference between corresponding data).

In patients with CYP3A5*3/*3 genotype, the C₀/D values of tacrolimus were significantly lower in the combination group than in the non-combination group (p = 0.039), while in patients with CYP3A5*1, no statistical difference was found between the two groups (p = 0.359).

Discussion

In this study, we found that caspofungin decreased the blood concentrations of tacrolimus. The DDI between tacrolimus and caspofungin was stronger in CYP3A5 non-expressers than in CYP3A5 expressers, and the required daily dose of tacrolimus in combination with caspofungin was higher than in the non-combination group for CYP3A5 non-expressers.

The results obtained in the present study are consistent with those in studies in allogeneic hematopoietic stem cell, liver, and lung transplant recipients.^27–29 Data from these studies suggested that co-administration of caspofungin reduced the blood concentrations of tacrolimus. This might be because caspofungin is mainly metabolized as an inactive substance in the liver and serves as an inducer of liver drug-metabolizing enzymes, which can increase the metabolism of tacrolimus,²⁹ thereby reducing the concentration of tacrolimus^18,30 and increase the required dose of tacrolimus.³¹ But no statistically significant difference was found. By contrast, Cheng et al.²¹ obtained statistically significant results in their study, indicating that co-administration of caspofungin significantly reduced tacrolimus blood concentrations.

In addition, our study also examined the DDI between tacrolimus and caspofungin according to CYP3A5 genotyping. For CYP3A5 non-expressers, the C₀/D values of tacrolimus were significantly lower in patients treated with caspofungin than in patients without caspofungin, while we did not find such a difference in CYP3A5 expressers. As a result, the required daily dose of tacrolimus was elevated more in CYP3A5 non-expressers than in CYP3A5 expressers, indicating that the DDI between tacrolimus and caspofungin was stronger in CYP3A5 non-expressers. The results above suggest that enhanced monitoring of tacrolimus blood concentration levels is needed to better adjust the individual regimen of kidney transplant patients receiving caspofungin in combination with tacrolimus.

This study was characterized by propensity score matching to match the baseline data of the combination and non-combination groups to minimize the interference of confounding factors. In addition, this study is the first observational study to combine the DDI of tacrolimus with caspofungin and the CYP3A5 genotype in kidney transplant patients.

Limitations

There are some limitations to this observational study. First, the sample size of our study was conducted in a single center, which limits the generality of our findings. Second, the study only evaluated a Chinese kidney transplant population, so it is not clear whether the findings apply to other populations that may have other CYP3A5 variants. Third, only selected CYP3A5*3 for the study in an Asian population.

Conclusion

Co-administration of caspofungin is associated with accelerated tacrolimus metabolism, which decreases tacrolimus blood levels and increases tacrolimus dosage. For CYP3A5 expressers, co-administration of caspofungin had a minor effect on tacrolimus C₀/D values. For CYP3A5 non-expressers, co-administration of caspofungin significantly decreased tacrolimus C₀/D values, thereby elevating tacrolimus D values. Therefore, in kidney transplant patients with the CYP3A5*3/*3 genotype, it is recommended to consider increasing the dose of tacrolimus by approximately 10% when co-administration of caspofungin and to strengthen the monitoring of tacrolimus concentrations to ensure the safety of tacrolimus administration.

Footnotes

Acknowledgements

We would like to thank the staff at the Center for Big Data Research in Health and Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, for their valuable contribution.

Declarations

ORCID iD

Yundi Zhang

References

Flahault

Anglicheau

Loriot

, et al. Clinical impact of the CYP3A5 6986A>G allelic variant on kidney transplantation outcomes. Pharmacogenomics 2017; 18: 165–173.

Nair

Sarasamma

Gracious

, et al. Polymorphism of the CYP3A5 gene and its effect on tacrolimus blood level. Exp Clin Transplant 2015; 13(Suppl. 1): 197–200.

Liu

, et al. Long-term influence of CYP3A5, CYP3A4, ABCB1, and NR1I2 polymorphisms on tacrolimus concentration in Chinese renal transplant recipients. Genet Test Mol Biomarkers 2017; 21: 663–673.

Yan

Tang

, et al. Donor ABCB1 3435 C>T genetic polymorphisms influence early renal function in kidney transplant recipients treated with tacrolimus. Pharmacogenomics 2016; 17: 249–257.

Birdwell

Decker

Barbarino

, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther 2015; 98: 19–24.

Lee

Cheong

Kim

, et al. Screening of genetic polymorphisms of CYP3A4 and CYP3A5 genes. Korean J Physiol Pharmacol 2013; 17: 479–484.

Mohamed

Schladt

Guan

, et al. Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: a comparison of four ancestry groups. Am J Transplant 2019; 19: 2795–2804.

Zhang

Liu

Xue

, et al. The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients. Int J Clin Pharmacol Ther 2015; 53: 728–736.

Sallustio

Noll

, et al. Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients. Br J Clin Pharmacol 2021; 87: 3901–3909.

10.

Chen

Cheng

, et al. Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus. Transplant Proc 2009; 41: 1557–1561.

11.

Kuehl

Zhang

Lin

, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27: 383–391.

12.

Campagne

Mager

Tornatore

KM.

Population pharmacokinetics of tacrolimus in transplant recipients: what did we learn about sources of interindividual variabilities?

J Clin Pharmacol 2019; 59: 309–325.

13.

Schutte-Nutgen

Tholking

Suwelack

, et al. Tacrolimus – pharmacokinetic considerations for clinicians. Curr Drug Metab 2018; 19: 342–350.

14.

Pappas

Alexander

Andes

, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010; 50: 1101–1111.

15.

Pristov

Ghannoum

MA.

Resistance of Candida to azoles and echinocandins worldwide. Clin Microbiol Infect 2019; 25: 792–798.

16.

Pappas

Kauffman

Andes

, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62: e1–e50.

17.

Yeoh

Lee

Chew

, et al. Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation. Infect Drug Resist 2018; 11: 805–819.

18.

Sable

Nguyen

Chodakewitz

, et al. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl Infect Dis 2002; 4: 25–30.

19.

von Elm

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370: 1453–1457.

20.

Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9(Suppl. 3): S1–S155.

21.

Cheng

Tang

, et al. Effects of antifungal drugs on the plasma concentrations and dosage of tacrolimus in kidney transplant patients. Eur J Hosp Pharm 2022; 29: 202–206.

22.

Cheng

Wang

, et al. Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients. Pharmgenomics Pers Med 2021; 14: 1463–1474. 2021/11/27. DOI: 10.2147/pgpm.S337947.

23.

Ito

Okada

Hashita

, et al. Sex Differences in the Blood Concentration of Tacrolimus in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients with CYP3A5*3/*3. Biochem Genet 2017; 55: 268–277. 2017/03/23. DOI: 10.1007/s10528-017-9795-8.

24.

Kirubakaran

Stocker

Hennig

, et al. Population pharmacokinetic models of tacrolimus in adult transplant recipients: a systematic review. Clin Pharmacokinet 2020; 59: 1357–1392.

25.

Liu

, et al. Kidney podocyte-associated gene polymorphisms affect tacrolimus concentration in pediatric patients with refractory nephrotic syndrome. Pharmacogenomics J 2020; 20: 543–552.

26.

Onodera

Endo

Naito

, et al. Tacrolimus dose optimization strategy for refractory ulcerative colitis based on the cytochrome P450 3A5 polymorphism prediction using trough concentration after 24 hours. Digestion 2018; 97: 90–96.

27.

Groetzner

Kaczmarek

Wittwer

, et al. Caspofungin as first-line therapy for the treatment of invasive aspergillosis after thoracic organ transplantation. J Heart Lung Transplant 2008; 27: 1–6.

28.

Nishimoto

Koh

Tokuwame

, et al. Drug interactions and safety profiles with concomitant use of caspofungin and calcineurin inhibitors in allogeneic haematopoietic cell transplantation. Br J Clin Pharmacol 2017; 83: 2000–2007.

29.

Saner

Gensicke

Rath

, et al. Safety profile of concomitant use of caspofungin and cyclosporine or tacrolimus in liver transplant patients. Infection 2006; 34: 328–332.

30.

Singh

Limaye

Forrest

, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81: 320–326.

31.

Yang

Chen

, et al. Conversion ratio of tacrolimus switching from intravenous infusion to oral administration after lung transplantation. J Thorac Dis 2020; 12: 4292–4298.