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Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption.
Pediatr Transplant 2003; 7(4):282-8PT

Abstract

BACKGROUND

There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC0-4) in the first week post-transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post-dose (C2) provides the optimal single-time point marker for AUC0-4. Clinically, dose management based on C2 level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling in de novo renal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes.

METHODS

This open-label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatric de novo renal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral) according to local protocol. Twelve-hour pharmacokinetic profiles (8-16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post-transplant.

RESULTS

Thirty-two patients were recruited (median age 10 yr, range 3-18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C2 correlated more closely with AUC0-4 and with AUC0-12 than did the pre-dose cyclosporin concentration (C0, or trough). Patients achieving C2 > 1.5 microg/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C2 < 1.5 microg/mL (P < 0.05). Binary logistic regression analysis showed that C2 level >1.7 microg/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC0-4, C2) showed no adverse effects of higher/increased exposure on creatinine or GFR.

CONCLUSIONS

C2 level provides a more reliable marker for CsA exposure than C0 in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C2 target of 1.7 microg/mL appears appropriate in this population during the immediate post-transplant period in order to maximize clinical benefit.

Authors+Show Affiliations

Renal Unit, Great Ormond Street Hospital for Children, NHS Trust, Great Ormond Street, London WC1N 3JH, UK. trompr@gosh.nhs.ukNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12890006

Citation

Trompeter, Richard, et al. "Longitudinal Evaluation of the Pharmacokinetics of Cyclosporin Microemulsion (Neoral) in Pediatric Renal Transplant Recipients and Assessment of C2 Level as a Marker for Absorption." Pediatric Transplantation, vol. 7, no. 4, 2003, pp. 282-8.
Trompeter R, Fitzpatrick M, Hutchinson C, et al. Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption. Pediatr Transplant. 2003;7(4):282-8.
Trompeter, R., Fitzpatrick, M., Hutchinson, C., & Johnston, A. (2003). Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption. Pediatric Transplantation, 7(4), pp. 282-8.
Trompeter R, et al. Longitudinal Evaluation of the Pharmacokinetics of Cyclosporin Microemulsion (Neoral) in Pediatric Renal Transplant Recipients and Assessment of C2 Level as a Marker for Absorption. Pediatr Transplant. 2003;7(4):282-8. PubMed PMID: 12890006.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Longitudinal evaluation of the pharmacokinetics of cyclosporin microemulsion (Neoral) in pediatric renal transplant recipients and assessment of C2 level as a marker for absorption. AU - Trompeter,Richard, AU - Fitzpatrick,Margaret, AU - Hutchinson,Carol, AU - Johnston,Atholl, PY - 2003/8/2/pubmed PY - 2003/12/5/medline PY - 2003/8/2/entrez SP - 282 EP - 8 JF - Pediatric transplantation JO - Pediatr Transplant VL - 7 IS - 4 N2 - BACKGROUND: There are important differences in CsA pharmacokinetics between adult and pediatric patients, such that pharmacokinetic data can not necessarily be extrapolated from the adult to the pediatric setting. Research in adult renal transplant patients has shown that adequate cyclosporin exposure (AUC0-4) in the first week post-transplant is important for successful clinical outcome, and that cyclosporin concentration at 2 h post-dose (C2) provides the optimal single-time point marker for AUC0-4. Clinically, dose management based on C2 level results in a low incidence of acute rejection in the adult renal transplant population. The study reported here undertook pharmacokinetic profiling in de novo renal transplant patients over a period of 6 months and retrospectively assessed alternative monitoring strategies based on pharmacokinetic findings and clinical outcomes. METHODS: This open-label, observational, prospective study was carried out at four UK transplant centers over a period of 6 months in pediatric de novo renal transplant recipients receiving the microemulsion formulation of cyclosporin (Neoral) according to local protocol. Twelve-hour pharmacokinetic profiles (8-16 blood samples each) were performed on days 5 and 14 and at weeks 4, 13 and 26 post-transplant. RESULTS: Thirty-two patients were recruited (median age 10 yr, range 3-18 yr). At 6 months, patient survival was 100% and graft survival was 91%. The incidence of clinically determined acute rejection was 41% (13 of 32). Six patients discontinued Neoral before 6 months: three due to graft loss, one due to rejection, one due to renal toxicity and one due to hypertrichosis. At all time points studied, C2 correlated more closely with AUC0-4 and with AUC0-12 than did the pre-dose cyclosporin concentration (C0, or trough). Patients achieving C2 > 1.5 microg/mL by the fifth postoperative day experienced no acute rejection in the first 6 months, compared with a 50% rejection rate among patients with C2 < 1.5 microg/mL (P < 0.05). Binary logistic regression analysis showed that C2 level >1.7 microg/mL was associated with approximately 90% probability of freedom from acute rejection. Analysis of renal function across patients grouped according to cyclosporine exposure (AUC0-4, C2) showed no adverse effects of higher/increased exposure on creatinine or GFR. CONCLUSIONS: C2 level provides a more reliable marker for CsA exposure than C0 in pediatric renal transplant recipients, and is more closely predictive of acute rejection risk. A C2 target of 1.7 microg/mL appears appropriate in this population during the immediate post-transplant period in order to maximize clinical benefit. SN - 1397-3142 UR - https://www.unboundmedicine.com/medline/citation/12890006/Longitudinal_evaluation_of_the_pharmacokinetics_of_cyclosporin_microemulsion__Neoral__in_pediatric_renal_transplant_recipients_and_assessment_of_C2_level_as_a_marker_for_absorption_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&amp;sid=nlm:pubmed&amp;issn=1397-3142&amp;date=2003&amp;volume=7&amp;issue=4&amp;spage=282 DB - PRIME DP - Unbound Medicine ER -