Pharmacokinetics of immunosuppressants: a perspective on ethnic differences

Dirks, Nathanael L.; Huth, B.; Yates, Charles; Meibohm, Bernd

doi:10.5414/cpp42701

Cited by 115 publications

(74 citation statements)

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“…The findings on the CYP3A5 gene in our population are in agreement with literature data, according to which up to 90% of Caucasian subjects are homozygous for the non-functional variant CYP3A5 * 3 (10,11,24,25) 3 subjects is lower (~20-30%) in other ethnic groups, in particular among Africans and African Americans (10,11,(25)(26)(27). Regarding the ABCB1 gene polymorphisms, in the case of G2677T/A at exon 21, the total frequency of the variant T in our patients (41%) was similar to that of other Caucasian populations (40-50%) (19,20,(28)(29)(30) and different from that recorded in Africans and African Americans (0.9-13%) (30)(31)(32)(33).…”

Section: Discussionsupporting

confidence: 80%

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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Abstract. Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C 0 ) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5 For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C 0 levels were significantly lower in patients with one copy of the * 1 allele compared to those homozygous for the * 3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

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Section: Discussionsupporting

confidence: 80%

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

et al. 2011

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“…Variability in everolimus concentrations has been observed in different ethnic groups, with lower bioavailability in AfricanAmericans compared with Caucasians or non-AfricanAmericans (40). In the current study, 3 of the 26 evaluable patients were African-Americans (1 CLL, 1 natural killer cell/ T-cell leukemia, and 1 AML); none of whom achieved an objective response, although the patient with CLL did have a 33% reduction in lymphadenopathy after three cycles of therapy with everolimus.…”

Section: Discussionmentioning

confidence: 90%

Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies

Yee¹,

Zeng

Konopleva

et al. 2006

Clinical Cancer Research

271

172

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“…It is well documented that, largely because of a high frequency of the CYP3A5 genetic polymorphism (which acts to increase the clearance and lower the oral bioavailability of tacrolimus), blacks require higher tacrolimus drug doses to achieve the same drug level achieved by nonblacks. [20][21][22][23][24][25][26] Specifically, the wild-type gene CYP3A5*1, which allows significant production of cytochrome P450 3A5, is reportedly absent in 60% to 90% of nonblacks and yet is present in 55% of blacks. This may partially account for lower tacrolimus troughs and higher tacrolimus dose requirements among blacks.…”

Section: Discussionmentioning

confidence: 99%

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

et al. 2014

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LCP-Tacro is an extended-release formulation of tacrolimus designed for once-daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCPTacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty-seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. C max , C max /C min ratio, percent fluctuation and swing were significantly (P<0.001) lower and T max significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC 24 and C min correlation coefficients after 7 and 14 days of therapy were 0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; AUC 24 , area under the curve at 24 hours; C 24 , concentration at 24 hours; C avg , average concentration; C max , maximum concentration; C min , minimum concentration; CV, coefficient of variation; ECG, electrocardiogram; H&C, hematology and chemistry; PK, pharmacokinetic; RGM, ratio of geometric means; SAE, serious adverse event; SE, standard error; TDD, total daily dose; T max , time of the maximum concentration.Some of the data were presented at the

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Pharmacokinetics of immunosuppressants: a perspective on ethnic differences

Cited by 115 publications

References 0 publications

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Phase I/II Study of the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) in Patients with Relapsed or Refractory Hematologic Malignancies

Conversion from twice daily tacrolimus capsules to once daily extended‐release tacrolimus (LCP‐Tacro): Phase 2 trial of stable liver transplant recipients

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