Utility of Pretransplantion Cyclosporine Pharmacokinetic Studies

Cooney, Gerard F.; Heifets, Michael; Bell, Alisa; Shaw, Les; LiBetti, Geri

doi:10.1097/00007691-199404000-00007

Therapeutic Drug Monitoring

1994

DOI: 10.1097/00007691-199404000-00007

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Utility of Pretransplantion Cyclosporine Pharmacokinetic Studies

Gerard F. Cooney

Michael Heifets²,

Alisa Bell³

et al.

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Cited by 8 publications

(2 citation statements)

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“…14 In pediatric renal transplant candidates older than 8 years, heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times and 1.6 times higher oral bioavailability, respectively, than did noncarriers. 15 Pharmacokinetic studies in adults have suggested that the correlation between the pre-and posttransplantation area under the blood concentration-time curve (AUC) of cyclosporine is poor, 16,17 possibly reflecting changes in cyclosporine pharmacokinetics after transplantation. For example, better absorption due to normalization of intestinal motility 18 and changes in the intestinal wall and liver activities of P-glycoprotein and CYP3A, subsequent to improved renal function, could alter the clearance and oral bioavailability of cyclosporine.…”

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confidence: 99%

Long‐Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

Fanta

Jönsson

Karlsson

et al. 2010

The Journal of Clinical Pharma

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To improve cyclosporine dose individualization, the authors carried out a comprehensive analysis of the effects of clinical and genetic factors on cyclosporine pharmacokinetics in 176 children before and up to 16 years after renal transplantation. Pretransplantation test doses of cyclosporine were given intravenously and orally, followed by blood sampling for 24 hours. After transplantation, cyclosporine was quantified at trough, 2 hours postdose, or with dose-interval curves. A 3-compartment population pharmacokinetic model was used to describe the data. Cyclosporine oral bioavailability increased more than 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1 to 1.5 years. Moreover, older children receiving cyclosporine twice daily as the gelatin capsule microemulsion formulation had an about 1.25 to 1.3 times higher bioavailability than did the younger children receiving the liquid formulation thrice daily. In 91 children with genetic data after transplantation, patients carrying the NR1I2 g.-25385C-g.-24381A-g.-205_-200GAGAAG-g.7635G-g.8055C haplotype had about one-tenth lower bioavailability, per allele, than did noncarriers (P = .039). The significance of the NR1I2 genotype warrants further study. In conclusion, by accounting for the effects of developmental factors (body weight), time after transplantation, and cyclosporine dosing frequency/formulation, it may be possible to improve individualization of cyclosporine dosing in children.

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mentioning

confidence: 99%

Long‐Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

Fanta

Jönsson

Karlsson

et al. 2010

The Journal of Clinical Pharma

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“…Although generally accepted target concentrations are derived empirically and correlation with the clinical outcome may be obscure (13), the prevailing practice has been to base dosing on monitoring of blood trough concentration. In an attempt to optimize initial CsA dosing and achieve target blood concentrations soon after Tx, individual pre‐Tx pharmacokinetic studies have been used, with controversial results (14, 15).…”

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confidence: 99%

Predictive value of pretransplantation cyclosporine pharmacokinetic studies on initial post‐transplantation dosing in pediatric kidney allograft recipients

Seikku

Hoppu

Jalanko

et al. 2003

Pediatric Transplantation

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Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age (<2, 2-8 and >8 yr), according to the predicted dose (within or outside +/-25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m2/d) for patients <2, 2-8, and >8 yr old] but the average B-CsA remained in the target range of 250-450 microg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R2 = 0.70) and adjustments to dosing were made during the next weeks (R2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients <2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.

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Optimizing the use of cyclosporine in renal transplantation

Sketris

Yatscoff²,

Keown³

et al. 1995

Clinical Biochemistry

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Utility of Pretransplantion Cyclosporine Pharmacokinetic Studies

Cited by 8 publications

References 0 publications

Long‐Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

Long‐Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

Predictive value of pretransplantation cyclosporine pharmacokinetic studies on initial post‐transplantation dosing in pediatric kidney allograft recipients

Optimizing the use of cyclosporine in renal transplantation

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