Tacrolimus oral bioavailability doubles with coadministration of ketoconazole*

Floren, Leslie Carstensen; Bekersky, Ihor; Benet, Leslie Z.; Mekki, Qais; Dressler, Dawna; Lee, Jean W.; Roberts, John P.; Hébert, Mary F.

doi:10.1016/s0009-9236(97)90150-8

Cited by 247 publications

(175 citation statements)

References 29 publications

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“…Two recent studies showed that with contemporary immunosuppressive regimens (tacrolimus, mycophenolate and steroids Ϯ antibody induction) low tacrolimus troughs in the first week post transplant were associated with a greater risk of acute rejection [5,6].To tailor therapy better, multiple clinical factors have been explored to determine their effects on tacrolimus pharmacokinetics. It is generally acknowledged that drug interactions, haematocrit, corticosteroid therapy, days post transplant, and race affect tacrolimus pharmacokinetics [3, [7][8][9][10]. It is also established that the cytochrome P4503A5 (CYP3A5)*1 allele is associated with significantly higher tacrolimus CL and lower systemic exposure [11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

147

163

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Patients with low tacrolimus troughs are at a higher risk of rejection while those with high troughs are at an increased risk for toxicity. Therefore, achieving the therapeutic range is important.• CYP3A5 genotype and days post transplant have been previously shown individually to be associated with tacrolimus troughs.WHAT THIS STUDY ADDS• This paper presents the first dosing model for tacrolimus using a combination of genetic and clinical factors in adult kidney transplant recipients. It was developed from one of the largest tacrolimus pharmacogenetic studies conducted to date (681 subjects and 11 823 trough concentrations).• We found that CL/F was significantly influenced by days post transplant, CYP3A5 genotype, transplantation at a steroid sparing centre, recipient age and the use of a calcium channel blocker.• Our large sample size enabled us to define the distinct differences in tacrolimus CL/F between three CYP3A5 genotype groups (*1/*1, *1/*3 and *3/*3).• This study is an important step towards using pharmacogenetic information in the clinical setting.AIM To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F).METHODS Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2 724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F.RESULTS The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h−1) was: 38.4 ×[(0.86, if days 6–10) or (0.71, if days 11–180)]×[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]× (0.70, if receiving a transplant at a steroid sparing centre) × ([age in years/50]−0.4) × (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate.CONCLUSIONS The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients.

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Section: Introductionmentioning

confidence: 99%

Dosing equation for tacrolimus using genetic variants and clinical factors

Passey

Birnbaum

Brundage

et al. 2011

Brit J Clinical Pharma

147

163

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“…Corticotherapy may also represent a significant underlying factor, since it uses the same isoenzymes of cytochrome P 450 for byotransformation (CYP3A4), leading to a decrease of tacrolimus level in the blood, having a slight enzymatic inductor effect [15]. Another important element is the age of renal allograft, the patients age at the moment of transplant, the medication administered for other comorbidities such as calcium-channel blockers (felodipine) for the treatment of hypertension -4 patients from group 1 and 2 patients from group 2 [16]; theophylline for the treatment of asthma -1 patient from group 1 [17], ketoconazole, inhibitor of CYP3A4, for the treatment of mycotic infections -2 patients from group 1 and 1 patient from group 2 [18],the patients' diet (grapefruit juice, intake of pomelo, foods that may act as enzymatic inhibitors of CYP3A4) [19,20], CYP3A4 polymorphism [21]. All of the above …”

Section: Discussionmentioning

confidence: 99%

The Monitoring of Immunosuppressive Therapy with Tacrolimus in Patients with Kidney Transplant, Based on the Pharmacokinetic Criteria

Mihai

Denise

Eugen

et al. 2015

Acta Medica Marisiensis

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Background: Therapeutic drug monitoring (TDM) in patients with Chronic Kidney Disease (CKD) with kidney transplant, represents a major post transplant concern due to the characteristics of this special category of patients, particularities which can generate changes of the pharmacokinetic profile of the administered medication. Material and methods: The current study is a retrospective pharmacokinetic study, over a period of 50 months, including a group of 36 kidney transplanted patients with CKD. Tacrolimus blood concentration was determined by a validated high-performance liquid chromatography method (HPLC), at a 12 hour time interval from the last administration of the immunosuppressive medication and before the following dose (Residual concentration, Cmin(trough)). Results: During the monitoring of therapy, based on the pharmacokinetic criteria, 252 measurements of blood concentration were determined, 58 of these being outside the therapeutic window. Conclusions:The results obtained show that it is mandatory to continue to monitor closely medical therapy based on the pharmacokinetic criteria in view of improving drug administration. The other ways of monitoring therapy: the clinical and biochemical criteria should not be overlooked. In addition, the interindividual variability of patients should be considered, as well as drug interaction which can alter the pharmacokinetics of tacrolimus.

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“…It is also advantageous to develop new chemical entities with minimal DDI liabilities, so that package insert ("black box") warnings can be avoided and patient safety maximized as much as possible. The highly publicized market withdrawals of two DDI "victim" drugs, terfenadine and cerivastatin, were precipitated partially because of a drug interaction involving the inhibition of CYP3A4 and CYP2C8, respectively (Honig et al, 1993;Backman et al, 1994;Varhe et al, 1994;Gomez et al, 1995;Floren et al, 1997;Azie et al, 1998;Gorski et al, 1998;Greenblatt et al, 1998;Backman et al, 2002;Emoto et al, 2006). More recently, drug interactions involving the inhibition of tizanidine (CYP1A2-dependent), repaglinide (CYP2C8/CYP3A4-dependent), and fluticasone (CYP3A4-dependent) clearance have also received some attention (Niemi et al, 2003;Arrington-Sanders et al, 2006;Backman et al, 2006).…”

Section: Applicationmentioning

confidence: 99%

Antibodies as a Probe in Cytochrome P450 Research

Shou

Lu²

2009

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 (P450) is the superfamily of enzymes responsible for biotransformation of endobiotics and xenobiotics. However, their large isoform multiplicity, inducibility, diverse structure, widespread distribution, polymorphic expression, and broad overlapping substrate specificity make it difficult to measure the precise role of each individual P450 to the metabolism of drugs (or carcinogens) and hamper the understanding of the relationship between the genetic/environmental factors that regulate P450 phenotype and the responses of the individual P450s to drugs. The antibodies against P450s have been useful tools for the quantitative determination of expression level and contribution of the epitope-specific P450 to the metabolism of a drug or carcinogen substrate in tissues containing multiple P450 isoforms and for implications in pharmacogenetics and human risk assessment. In particular, the inhibitory antibodies are uniquely suited for reaction phenotyping that helps to predict human pharmacokinetics for clinical drugdrug interaction potential in drug discovery and development.Many enzyme systems exist in the liver and in extrahepatic tissues, such as intestine and kidney, that can contribute to the clearance of drugs from the systemic circulation. Among the various phase I and phase II drug-metabolizing enzymes, the cytochrome P450 (P450) enzymes play a key role in xenobiotic and endobiotic metabolic processing. It has been estimated that approximately two thirds of marketed drugs are metabolized by this enzyme system (Rendic and Di Carlo, 1997;Guengerich, 2003;Williams et al., 2004). In fact, members of three P450 subfamilies (CYP1, CYP2, and CYP3) are largely responsible for the metabolic clearance of drugs and xenobiotics (Rendic and Di Carlo, 1997;Guengerich, 2003;Williams et al., 2004). Multiplicity and overlapping substrate specificity of P450 have greatly complicated efforts at understanding the precise role of individual P450 isoforms in the metabolism of drugs and drug candidates. Therefore, over recent years, a variety of reagents and tools have been developed for in vitro and in vivo studies, and it is now possible to determine which specific P450 isoform(s) is (are) involved in the metabolism of a given compound (Rodrigues, 1999;Rodrigues and Rushmore, 2002;Lu et al., 2003;Williams et al., 2003). Given the importance of fraction of drug metabolized (f m ) in assessing the potential of in vivo drug-drug interaction (DDI), P450 reaction-phenotyping studies are conducted at multiple stages during drug discovery and development. Irrespective of the strategy, information related to P450-mediated metabolism is included in regulatory documents and the absorption, distribution, metabolism, and elimination (ADME) and DDI sections of the product label, where precautions concerning the coadministration of other drugs are listed along with recommendations for dose adjustment (Obach et al., 2006;Huang et al., 2007). Antibodies that are specific to individual P450s can be used to determine P450 pr...

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Tacrolimus oral bioavailability doubles with coadministration of ketoconazole*

Cited by 247 publications

References 29 publications

Dosing equation for tacrolimus using genetic variants and clinical factors

Dosing equation for tacrolimus using genetic variants and clinical factors

The Monitoring of Immunosuppressive Therapy with Tacrolimus in Patients with Kidney Transplant, Based on the Pharmacokinetic Criteria

Antibodies as a Probe in Cytochrome P450 Research

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