Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations

Wehland, Markus; Bauer, Steffen; Brakemeier, Susanne; Burgwinkel, Philip; Glander, Petra; Kreutz, Reinhold; Lorkowski, Christine; Slowinski, Torsten; Neumayer, Hans H.; Budde, Klemens

doi:10.1097/fpc.0b013e32833ea085

Cited by 47 publications

(33 citation statements)

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“…In CYP3A5 pharmacogenetics, the daily dose was higher in CYP3A5 expressers than nonexpressers for both formulations. The AUC 0-24 , AUC [12][13][14][15][16][17][18][19][20][21][22][23][24] , and C 0 for Tac-QD, but not Tac-BID, were smaller, approximately 25%, 30%, and 35% respectively, in CYP3A5 expressers than nonexpressers. There were no differences in maximum blood concentration (C max ) and the observed time to reach the maximum blood concentration (T max ) (from 0 to 12 hours) between the two genotypes for each formulation.…”

Section: Resultsmentioning

confidence: 83%

“…To date, two studies have showed the controversial impact of CYP3A5 polymorphisms on the pharmacokinetics of switching from Tac-BID to Tac-QD in stable renal transplant recipients (14,15). This study is the first to show the effect of CYP3A5 polymorphisms on the pharmacokinetics of Tac-QD in de novo renal transplant patients.…”

Section: Discussionmentioning

confidence: 78%

“…To date, only two controversial studies have reported the impact of CYP3A5 polymorphisms on tacrolimus exposure after a switch from Tac-BID to Tac-QD. Wehland et al (14) showed that the mean trough level and dose-adjusted trough level of tacrolimus decreased significantly in nonexpressers but not in CYP3A5 expressers. Conversely, Glowacki et al (15) reported that tacrolimus exposure decreased significantly after a switch from Tac-BID to Tac-QD in CYP3A5 expressers.…”

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confidence: 99%

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Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

et al. 2012

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C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

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Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

et al. 2012

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“…CYP3A5 expressers) than in those with the CYP3A5*1/*1 genotype (CYP3A5 non-expressers) [19,27,36,61]. In contrast, two studies reported the opposite, that patients with the CYP3A5*3/*3 genotype (CYP3A5 non-expressers) were the ones who experienced the largest decrease in AUC 0-24 and/or C min following milligram-per-milligram-based conversion [32,38]. One study, which reported that conversion from Prograf Ò to Advagraf Ò resulted in a significant decrease in withinsubject variability in AUC 0-24 , found that this decrease was numerically greatest in patients with the CYP3A5*1 genotype (% CV down from 18.2 to 12.8 % on conversion in CYP3A5 expressers versus a decrease from 12.6 to 10.2 % on conversion in CYP3A5 non-expressers) [28].…”

Section: Xrmentioning

confidence: 94%

“…Factors in these traditional design studies reported to influence the pharmacokinetics of prolonged-release tacrolimus included patient CYP3A5 genotype status [17,19,27,28,32,36,38,61], age [51], race [57] and time after transplantation [17]. These same factors were also reported to be influential when immediate-release tacrolimus was administered twice daily [3].…”

Section: Xrmentioning

confidence: 99%

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

Staatz

Tett

2015

Clin Pharmacokinet

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Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®) XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®) XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies a...

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Performance of modified‐release tacrolimus after conversion in liver transplant patients indicates potentially favorable outcomes in selected cohorts

Considine¹,

Tredger²,

Heneghan³

et al. 2014

Liver Transpl

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Clinical outcomes, dose changes, and dose-equalized tacrolimus concentrations were examined sequentially in 129 liver transplantation (LT) recipients after successful conversion to once daily modified-release tacrolimus either early (within 1 month) or late (>1 month) after LT. The data were compared with data for a group of 60 patients maintained on twice daily conventional-release tacrolimus. Formulation-and time-dependent changes in dose requirements for once and twice daily tacrolimus differed after transplantation. A 1.7-fold initial increase in the median daily dose was required to achieve target tacrolimus concentrations in the early-conversion cohort (P 5 0.006), whereas a 1.25-fold increase was required for those converted later (P 5 0.013 and P < 0.001 for the difference). In the subsequent 2 months, the median daily dose fell by 20% in the early-conversion cohort, remained stable for the late-conversion cohort, but rose by 33% with conventional therapy. Lower median dose-equalized concentrations persisted for up to 3 months after the conversion to modified-release therapy. Sex, ethnicity, and the underlying liver disease did not significantly affect these variables. The frequency of treated biopsy-proven acute rejection episodes fell approximately 4-fold after the conversion to modified-release tacrolimus, most notably in the late-conversion cohort, which experienced a high incidence of rejection before conversion. Posttransplant increases in serum creatinine concentrations were smaller after the introduction of modified-release tacrolimus in the lateconversion group (0.7 versus 4 mg/mL for twice daily tacrolimus over 6 months). Reduced interpatient variability in tacrolimus concentrations was evident in the early-conversion cohort versus the twice daily cohort. A decline in intrapatient variability accompanied the reduction in acute rejection in the late-conversion cohort. Our data highlight potential benefits for the rejection rate and renal function on conversion to once daily modified-release tacrolimus late after LT. Liver Transpl 21:29-37, 2015. V C 2014 AASLD.

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Differential impact of the CYP3A51 and CYP3A53 alleles on pre-dose concentrations of two tacrolimus formulations

Cited by 47 publications

References 0 publications

Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

Comparison of Pharmacokinetics and Pharmacogenetics of Once- and Twice-Daily Tacrolimus in the Early Stage After Renal Transplantation

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients

Performance of modified‐release tacrolimus after conversion in liver transplant patients indicates potentially favorable outcomes in selected cohorts

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