Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children

Filler, Guido; Feber, Janusz; Lepage, Nathalie; Weiler, Gundo; Mai, Ingrid

doi:10.1034/j.1399-3046.2002.02039.x

Cited by 66 publications

(64 citation statements)

References 29 publications

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“…In our study this variability was illustrated by the lack of correlation between the dose, adjusted to body size, and drug exposure, expressed as 0-12 h AUC (r=0.04), confirming the need for PK monitoring. This last finding agrees with adult experience [13] and with previous studies in children [7,8,[14][15][16][17][18]. Intravariability of Tac exposure was not further investigated, as a sufficiently narrow 95% confidence interval (CI) could not be obtained.…”

Section: Discussionsupporting

confidence: 90%

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Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients

2010

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Because tacrolimus (Tac) has a narrow therapeutic index and highly inter- and intra-individual variable pharmacokinetic (PK) characteristics, monitoring of drug exposure is recommended, but limited data are available on the kinetics of Tac in paediatric renal transplant recipients, especially of limited sampling strategies. To investigate the correlation between Tac trough level (TL) and the 0-12 h area under the curve (AUC), and the value of abbreviated AUC monitoring, we evaluated 12 h PK profiles in 27 children at least 1 year after transplantation. There was a significant discrepancy between Tac TLs and 0-12 h AUC (r = 0.60). Every time point, different from C(0), gave a better prediction for the drug exposure, with C(4) and C(6) as best predictors (r = 0.93 and r = 0.92, respectively). The 0-12 h AUC was estimated with great precision by the use of a two- or three-point sampling strategy, and the latter is more time-point independent. In paediatric renal transplant recipients on Tac maintenance therapy, whose condition is stable, Tac TL is not a reliable tool for the estimation of drug exposure. Abbreviated monitoring, especially at three points in time, give reliable predictions of the complete 0-12 h AUC. We suggest a 0-12 h AUC of around 150 ng x h/ml for stable paediatric renal transplant recipients 1 year after transplantation and around 100 ng x h/ml in the following years. Target AUC values should be further established for paediatric transplant recipients according to the time after transplantation.

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Section: Discussionsupporting

confidence: 90%

“…Previous reports show that coefficients of determination (r 2 ) between AUC and C 0 vary between 0.30 and 0.79 [7,8,[14][15][16][17][18]. The observed differences may originate from differences in sample size and the time after transplantation that the studies were performed.…”

Section: One-point Sampling Strategymentioning

confidence: 65%

Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients

2010

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“…It has already been reported that C2 and, in particular, C4 concentrations yield significantly better correlations with the AUC and that a limited sampling approach, which utilises C1, C2 and C6 or C0, C1, C2 and C4, permits an excellent prediction of the AUC [28]. It is interesting to note that the first three time-point model does not utilise the C0.…”

Section: Discussionmentioning

confidence: 93%

The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients

et al. 2006

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The aims of our trial were to study the pharmacokinetics of tacrolimus in paediatric kidney transplant recipients. The study comprised 25 patients (median age 13 years, range 2-20 years) followed for 12 months; five pharmacokinetics profiles (within the first and second week and after 1 month, 6 months and 12 months) were obtained. Patients were divided into two groups: six children<6 years old and 19 older children. Tacrolimus was given at an initial dose of 0.15 mg/kg twice a day. Blood samples were drawn before and 1 h, 2 h, 3 h, 4 h, 6 h, 9 h and 12 h after drug administration. Patient and kidney survival rates were 100% at 1 year. At 6 months and 12 months creatinine clearance was 68.5+/-16.3 ml/min per 1.73 m2 and 64.0+/-15.2 ml/min per 1.73 m2 body surface area, respectively. Tacrolimus trough levels were 7.8+/-1.9 ng/ml and 7.3+/-2.5 ng/ml. The area under the concentration-time curve for 0 h to 12 h (AUC0-12) normalised to a dose of 0.15 mg/kg, increased with time from the kidney transplantation and stabilised after the 6th month post-transplantation. During the first month after transplantation the normalised tacrolimus concentration-time profiles were significantly greater in the older children (P<0.05); the actual doses were significantly greater in the younger children (P<0.05). In conclusion, initial doses of 0.15 mg/kg twice a day orally are safe and guarantee a satisfactory degree of immunosuppression, with our therapeutic regimen. Children<6 years old need to start with a 50% higher tacrolimus dose to achieve the same pharmacokinetic and immunosuppressive results.

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“…Because measurement of the total AUC requires repeated blood sampling and is time-consuming and expensive, many surrogates have been developed for AUC determination. These include the 2 h post-dose concentration (C 2 ) monitoring [17,18,19,20] and limited sampling strategies that estimate the absorption phase or the complete AUC for CsA in adults [21,22] and children [23,24,25,26,27].…”

Section: Introductionmentioning

confidence: 99%

Cyclosporine A monitoring ? how to account for twice and three times daily dosing

et al. 2005

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Cyclosporine A (CsA) dose-interval pharmacokinetic profiles, performed 1-4 years post-transplantation, were collected from 74 renal transplanted children. Forty patients were on three times daily dosing (t.i.d.) and 34 on twice daily dosing (b.i.d.). Regression models for prediction of area under the curve (AUC) using 1-3 concentration time points as independent variables were developed. With similar weight-adjusted single doses (mg kg(-1)) of CsA, t.i.d. dosing resulted in a trough-concentration (C0) similar to that from b.i.d. dosing, but a 30% lower 2 h post-dose concentration (C2). For b.i.d. dosing the relationship between C0 and AUC was poor (r2=0.23) and the prediction error was large (5.8+/-33.5%). For t.i.d. dosing the relationship was better (r2=0.79), but prediction error was still large (4.5+/-24.9%). For C2 relationships were similar to those for the b.i.d. (r2=0.59) and t.i.d. (r2=0.63) groups, but explained modestly the variations of AUC (prediction error=2.6+/-16.8% b.i.d., 4.8+/-23.2% t.i.d.). Both C0 and C2 are useful monitoring methods when CsA is administered t.i.d. If the aim is similar specified daily drug exposure, the target C2 should be roughly 30% smaller in t.i.d. dosing than in b.i.d. dosing and the target C0 could be similar. The prediction error of AUC can be large in individual patients when using single time-point determinations, however. The use of multiple time points reduces the variation, but is less feasible.

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Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children

Cited by 66 publications

References 29 publications

Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients

Pharmacokinetics of tacrolimus in stable paediatric renal transplant recipients

The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients

Cyclosporine A monitoring ? how to account for twice and three times daily dosing

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