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1.
Clin Pharmacokinet ; 55(9): 1129-43, 2016 09.
Article in English | MEDLINE | ID: mdl-27138785

ABSTRACT

BACKGROUND: The aim of this study was to develop a population pharmacokinetic model of tacrolimus in paediatric patients at least 1 year after renal transplantation and simulate individualised dosage regimens. PATIENTS AND METHODS: We included 54 children with median age of 11.1 years (range 3.8-18.4 years) with 120 pharmacokinetic profiles performed over 2 to 4 h. The pharmacokinetic analysis was performed using the non-linear mixed-effects modelling software (NONMEM(®)). The impact of covariates including concomitant medications, age, the cytochrome P450 (CYP) CYP3A5*3 gene and the adenosine triphosphate binding cassette protein B1 (ABCB1) 3435 C→T gene polymorphism on tacrolimus pharmacokinetics was analysed. The final model was externally validated on an independent dataset and dosing regimens were simulated. RESULTS: A two-compartment model adequately described tacrolimus pharmacokinetics. Apparent oral clearance (CL/F) was associated with weight (allometric scaling) but not age. Children with lower weight and CYP3A5 expressers required higher weight-normalised tacrolimus doses. CL/F was inversely associated with haematocrit (P < 0.05) and γ-glutamyl transpeptidase (γGT) (P < 0.001) and was increased by 45 % in carriers of the CYP3A5*1 allele (P < 0.001). CL/F was not associated with concomitant medications. Dose simulations show that a daily tacrolimus dose of 0.2 mg/kg generates a pre-dose concentration (C 0) ranging from 5 to 10 µg/L depending on the weight and CYP3A5 polymorphism. The median area under the plasma concentration-time curve (AUC) corresponding with a tacrolimus C 0 of 4-8 µg/L was 97 h·µg/L (interquartile range 80-120). CONCLUSIONS: In patients beyond the first year after transplantation, there is a cumulative effect of CYP3A5*1 polymorphism and weight on the tacrolimus C 0. Children with lower weight and carriers of the CYP3A5*1 allele have higher weight-normalised tacrolimus dose requirements.


Subject(s)
Body Weight/physiology , Cytochrome P-450 CYP3A/genetics , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation , Tacrolimus/pharmacokinetics , Transplant Recipients , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Adolescent , Area Under Curve , Child , Child, Preschool , Cohort Studies , Female , Genotype , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Male , Metabolic Clearance Rate , Models, Biological , Netherlands/epidemiology , Polymorphism, Single Nucleotide , Retrospective Studies , Tacrolimus/administration & dosage , Tacrolimus/blood
2.
Acta Clin Belg ; 71(6): 455-457, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27169353

ABSTRACT

A 12-year-old Congolese girl presented with acute renal failure, edema, hypertension, hemoptysis, hematuria, and proteinuria after a history of throat infection. Renal ultrasound showed kidneys of normal size, with increased echogenicity of the cortical parenchyma and decreased corticomedullary differentiation. Other additional investigations showed pancytopenia with decreased complement (low C3 and C4). Antinuclear antibodies were strongly positive, including anti-double stranded DNA. Renal biopsy confirmed severe grade IV lupus nephritis. She was treated with high-dose steroids, mycophenolate mofetil and hydroxychloroquine, in addition to hemodialysis. After one week of intensive treatment, diuresis recovered and dialysis could be stopped after six sessions. We describe an uncommon case of severe lupus nephritis, presenting with terminal renal failure. Since the rarity of this disease presentation, other more common diagnoses have to be considered. Once the diagnosis of lupus nephritis is established, a choice has to be made between the different induction treatment protocols. The patient's ethnic background and other supportive therapies, such as the need for dialysis, can help to make this choice.


Subject(s)
Kidney Failure, Chronic/etiology , Kidney/diagnostic imaging , Lupus Nephritis/complications , Biopsy , Child , Disease Progression , Female , Humans , Kidney Failure, Chronic/diagnosis , Lupus Nephritis/diagnosis , Ultrasonography
3.
Pediatr Transplant ; 16(6): 613-8, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22694118

ABSTRACT

High intra-patient variability in TCL exposure is a risk factor for allograft loss and late acute rejection. We hypothesized that a higher intra-patient variability leads to a faster decline in GFR in pediatric renal transplant patients and that adolescents have a higher intra-patient variability due to poorer adherence. We included 69 children aged 3.5-18 yr who had undergone renal transplantation between April 1996 and May 2009 in two pediatric nephrology centers in the Netherlands. We analyzed TCL trough concentrations over a period of one yr and calculated TCL trough concentrations variability using VC. We investigated the correlation between the TCL trough concentrations variability and the decline in estimated GFR over four yr. The median intra-patient variability in TCL concentrations was 30.1% (range 8.6-77.6) and the mean GFR slope -3.8 mL/min/1.73 m(2) /yr. The VC correlated neither with the GFR slope, nor with the patients' age. However, children with late acute rejection had higher VC (p = 0.045). We were unable to provide evidence that a high variability in TCL exposure leads to a faster decline in renal function, although children with late acute rejection have a higher variability in TCL exposure. Adolescents do not have a higher intra-patient variability in TCL trough concentrations than younger children.


Subject(s)
Kidney Transplantation/methods , Renal Insufficiency/therapy , Tacrolimus/therapeutic use , Adolescent , Age Factors , Child , Child, Preschool , Female , Glomerular Filtration Rate , Graft Rejection , Graft Survival , Humans , Immunosuppressive Agents/therapeutic use , Infant , Kidney/physiology , Male , Patient Compliance , Reproducibility of Results , Treatment Outcome
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