Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation

University Hospital, Essen30 enrolled

Overview

Recently, a new prolonged-release tablet version of tacrolimus (Envarsus®) using the so-called MeltDose™ (US Patent No. 7,217,431) drug-delivery technology has been approved as immunosuppressive medication for patients after kidney and liver transplantation in adults but not yet in children. Studies in adults proved that Envarsus® provides the same therapeutic effectiveness as the conventional immediate-release tacrolimus formulation (Prograf®) with improved bioavailability, a more consistent pharmacokinetic profile and reduced peak to trough which might result in reduced tacrolimus dosing and subsequently reduced CNI related toxicity. Furthermore, the once daily formulation might result in improved drug adherence. The aim of this study is to assess pharmacokinetic profiles of Envarsus® as well as effectiveness and tolerability of this drug in children and adolescents ≥ 8 and ≤ 18 years of age.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Pediatric Kidney Disease

Interventions

Eligibility

Sex: ALLMin age: 8 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. caucasian paediatric kidney transplant recipients (single-organ recipients) 2. aged ≥ 8 years but ≤ 18 years who are under tacrolimus (Prograf®) therapy and who are able to swallow tablets with a minimum dose of 0.75 mg / day Envarsus® 3. not less than 6 months after transplantation 4. stable kidney function (delta eGFR \< 10 ml/min/1.73 m2 (CKID formula) over the last 3 months) 5. women of childbearing potential and women without childbearing potential 6. patient/parents/legal guardian(s) must be capable of understanding purpose and risks of the study 7. signed informed consent obtained by patient and parents/legal guardians Exclusion Criteria: 1. coefficient of variation of tacrolimus trough levels \> 0.35 over the previous 6 months 2. pregnancy/breast feeding 3. instable kidney function 4. hypersensitivity to any of the components of the medications used 5. not eligible for any reason according to the investigator's valuation 6. known positive HIV-1 or HCV test 7. participation in another clinical trial (other investigational drugs or devices at the time of enrolment or within 30 days prior to enrolment)

Locations (4)

University Hospital Cologne, Pediatrics

Cologne, Germany

RECRUITING

University Hospital of Essen, Pediatrics II

Essen, Germany

RECRUITING

University Hospital of Hamburg-Eppendorf

Hamburg, Germany

RECRUITING

University Hospital of Heidelberg

Heidelberg, Germany

RECRUITING

Outcomes

Primary Outcomes

Full tacrolimus AUC

full tacrolimus AUC calculated from Tac measures before administration of drug and 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, 24 hours after administration of drug at the time point of 2 weeks (14±7 days) after end of build-up period for each patient under both treatments within two time periods with each a length of 4 weeks

Time frame: 4 weeks

Secondary Outcomes

Pharmacodynamic analysis

Assessment of efficacy in terms of residual expression of NFAT regulated genes, expressed as % of expression at C0 (time point before drug administration set at 100%) at 1.5, 2, 4, 6, 8, 12, 13.5, 14, 16, 20, 24 hours after administration of drug at the time point of 2 weeks (14±7 days) after end of build-up period for each patient under both treatments within two time periods with each a length of 4 weeks

Time frame: 4 weeks

Pharmacogenetic analysis

Number of patients with SNPs in selected genes (CYP3A4, CYP3A5, ABCD1)

Time frame: 4 weeks

Tacrolimus trough levels

Tacrolimus trough levels in ng/mL, compared intra- and interindividually.

Time frame: 4 weeks

Doses of prolonged-release tacrolimus

Doses of prolonged-release tacrolimus (Envarsus®) in ng/mL.

Time frame: 4 weeks

Number of patients with adverse event or toxicity

Cumulative dosage and signs of tacrolimus toxicity and adverse events. Potentially tacrolimus associated adverse events and toxicity are recorded individually and compared with individual tacrolimus AUCs. Special attention is taken e.g. towards metabolic (elevated concentration of blood glucose, fat), hematopoetic (cell counts), neurological (tremor, headache), renal (change in glomerular filtration rate), gastrointestinal (diarrhea, nausea), hepatic (cholestasis, elevated transaminases, blood clotting disorder), elevated blood pressure.

Time frame: 10 weeks

Number of adverse events or toxicity per patient

Special attention is taken e.g. towards metabolic (elevated concentration of blood glucose, fat), hematopoetic (cell counts), neurological (tremor, headache), renal (change in glomerular filtration rate), gastrointestinal (diarrhea, nausea), hepatic (cholestasis, elevated transaminases, blood clotting disorder), elevated blood pressure.

Time frame: 10 weeks

eGFR (CKiD formula)

eGFR (CKiD formula) comparing the two study phases

Time frame: 4 weeks

Treatment failure rate

composite endpoint: any patient who experienced death, graft failure, BPAR or lost to follow-up

Time frame: 10 weeks

limited sampling strategy (LSS)

LSS driven 24h-AUC estimation

Time frame: 4 weeks

Taxonomy of the gut microbiome

Taxonomy of the gut microbiome using metagenomic sequencing

Time frame: 10 weeks

Gut microbial metabolism

Functional assessment of the gut microbiome using LC-MS based metabolomics

Time frame: 10 weeks

Pharmacokinetics, Effectiveness and Tolerability of Prolonged-release Tacrolimus After Paediatric Kidney Transplantation

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts