Effect of Azole/Echinocandin Use on Tacrolimus Pharmacokinetics

Effect of Azole/Echinocandin Use on Tacrolimus Pharmacokinetics in Kidney Transplant Recipients

The purpose of this observational study is to analyze the extent and characteristics of drug interactions (focusing on azole antifungals and echinocandins) and genetic polymorphisms on tacrolimus blood concentrations in renal transplant recipients in order to provide a reference for the appropriate adjustment of tacrolimus dosing regimen to reduce the incidence of adverse drug reactions and rejection, and to improve the survival of transplanted kidneys.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant Patients
• Intervention / Treatment: Drug: Combined with voriconazole; Drug: Combined with caspofungin; Drug: Tacrolimus-alone treatment

Detailed Description

In this study, investigators investigated the effects of CYP3A5 and CYP2C19 gene polymorphisms on the trough concentration of tacrolimus after renal transplantation in recipients who were on a tacrolimus-based immunosuppressive regimen (tacrolimus + mescaline + glucocorticosteroid) after their first renal transplantation; investigators investigated the effects of antifungal drugs on the trough concentration of tacrolimus, and investigators also analyzed the effects of genetic factors on the drug-drug interactions between antifungal drugs and tacrolimus, with the aim of providing a basis of reference for the rational use of tacrolimus and antifungal drugs in the clinic.

• Study Type: Observational
• Enrollment (Actual): 507

Contacts and Locations

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China
      • ShanDong Provincial QianFoShan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study included patients who underwent renal transplantation at our hospital between 01.01.2015 and 04.01.2023 and were divided into the co-voriconazole group, co-carbophenazole group and tacrolimus alone group according to co-administration.

Description

Inclusion Criteria:

1. Patients with first kidney transplantation and intact CYP3A5 genotype;
2. Renal transplant recipients taking a tacrolimus-based triple immunosuppressive regimen (tacrolimus + sodium mescaline enteric-coated tablets + glucocorticoids) postoperatively;
3. Age ≥ 18 years.

Exclusion Criteria:

1. Missing and incomplete clinical information and postoperative follow-up data;
2. Multi-organ combined transplantation and secondary transplantation;
3. Postoperative simultaneous joint application of other drugs that affect the blood concentration of tacrolimus or voriconazole or caspofungin (e.g. pentoxifylline capsules, rifampicin, etc.);
4. Severe impairment of liver function or severe gastrointestinal diseases, gastrointestinal resection surgery, malabsorption syndrome;
5. Pregnant and lactating women;
6. Recipients with significant rejection of the transplanted organ or death due to other reasons within 1~2 months after surgery;
7. Poor compliance and accuracy of results (e.g., irregular blood collection times).

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Combined with voriconazole group; Methylprednisolone sodium succinate was administered intravenously the day after transplantation at an initial dose of 500 mg/day, with the dose being tapered evenly to 40 mg/day during the first week. During the second week, methylprednisolone tablets were administered continuously at a dose of 40 mg/day, after which the dose was tapered to 16 mg/day as a maintenance dose. Immunosuppression was maintained with oral mycophenolate sodium 720 mg twice daily. For renal transplant patients, the initial oral tacrolimus dose should be 0.15 - 0.30 mg/kg per day divided into morning and evening doses. The starting dose of voriconazole should be 400 mg twice a day, which should be changed to 200 mg twice a day from the next day as a maintenance dose.	Drug: Combined with voriconazole; Renal transplant patients taking tacrolimus-based triple immunotherapy and voriconazole drug combination.; Other Names: tacrolimus; methylprednisolone sodium succinate; mycophenolate sodium
Combined with caspofungin group; Methylprednisolone sodium succinate was administered intravenously the day after transplantation at an initial dose of 500 mg/day, with the dose being tapered evenly to 40 mg/day during the first week. During the second week, methylprednisolone tablets were administered continuously at a dose of 40 mg/day, after which the dose was tapered to 16 mg/day as a maintenance dose. Immunosuppression was maintained with oral mycophenolate sodium 720 mg twice daily. For renal transplant patients, the initial oral tacrolimus dose should be 0.15 - 0.30 mg/kg per day divided into morning and evening doses. 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.	Drug: Combined with caspofungin; Renal transplant patients taking a combination of tacrolimus-based triple immunotherapy and caspofungin drugs.; Other Names: tacrolimus; methylprednisolone sodium succinate; mycophenolate sodium
Tacrolimus-alone treatment group; Methylprednisolone sodium succinate was administered intravenously the day after transplantation at an initial dose of 500 mg/day, with the dose being tapered evenly to 40 mg/day during the first week. During the second week, methylprednisolone tablets were administered continuously at a dose of 40 mg/day, after which the dose was tapered to 16 mg/day as a maintenance dose. Immunosuppression was maintained with oral mycophenolate sodium 720 mg twice daily. For renal transplant patients, the initial oral tacrolimus dose should be 0.15 - 0.30 mg/kg per day divided into morning and evening doses.	Drug: Tacrolimus-alone treatment; Renal transplant patients treated with tacrolimus-based triple immunotherapy alone; Other Names: methylprednisolone sodium succinate; mycophenolate sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The C0/D values of tacrolimus	Body weight is in kilograms, D values are in mg/d, and the combination of body weight and D is the body weight-corrected D value in mg/kg/d, with a range of 0.15-0.30 mg/kg/d. The C0 for tacrolimus is in ng/ml, with a range of 5-15 ng/ml, and the combination of the C0 and body weight-corrected D values is the C0/D value, reported as (ng/ml)/(mg /kg/d) is reported.	2015.01.01-2023.04.01

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The D values of tacrolimus	Body weight was expressed in kilograms, D values were expressed in mg/d, and body weight and D were combined to give body weight-corrected D values in mg/kg/d, ranging from 0.15 to 0.30 mg/kg/d.	2015.01.01-2023.04.01

Collaborators and Investigators

• Sponsor: LI YAN

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Actual): January 1, 2023
• Study Completion (Actual): June 1, 2023

Study Registration Dates

• First Submitted: August 28, 2023
• First Submitted That Met QC Criteria: September 12, 2023
• First Posted (Actual): September 21, 2023

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: kidney transplant; voriconazole; tacrolimus; drug-drug interactions; caspofungin; CYP3A5; C0/D
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antineoplastic; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Calcineurin Inhibitors; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Caspofungin; Tacrolimus; Mycophenolic Acid; Voriconazole
• Other Study ID Numbers: QFS-LY-2023-TAC-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No