Pharmacokinetic and Pharmacodynamic Considerations in Relation to Calcineurin Usage in Elderly Kidney Transplant Recipients

Cossart, Amelia R.; Isbel, Nicole M.; Scuderi, Carla; Campbell, Scott; Staatz, Christine E.

doi:10.3389/fphar.2021.635165

Cited by 7 publications

(2 citation statements)

References 69 publications

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“…CsA has a narrow therapeutic window and displays broad pharmacokinetic variability (Cossart et al, 2021). CYP3A4 is the Frontiers in Pharmacology frontiersin.org main metabolic pathway involved in the disposition of CsA.…”

Section: Discussionmentioning

confidence: 99%

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

Kong

Gao²,

Wang³

et al. 2023

Front. Pharmacol.

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The aim of this study is to investigate the effects of CYP3A4 genetic polymorphisms on the metabolism of cyclosporine (CsA) in vitro and identify drugs that interact with CsA. An enzymatic incubation system was developed to evaluate the kinetic parameters of CYP3A4 on CsA catalysis. A total of 132 drugs were screened to identify potential drug–drug interactions. Sprague–Dawley rats were used to determine the interaction between CsA and nimodipine and nisoldipine. The metabolite AM1 was measured by ultra-performance liquid chromatography–tandem mass spectrometry. The results demonstrate that 16 CYP3A4 variants (CYP3A4.7, 8, 9, 12, 13, 14, 16, 18, 19, 23, 24, 28, 31, 32, 33, and 34) have a lower metabolic capacity for CsA, ranging from 7.19% to 72.10%, than CYP3A4.1. In contrast, the relative clearance rate of CYP3A4.5 is significantly higher than that of CYP3A4.1. Moreover, CYP3A4.20 loses its catalytic ability, and five other variants have no significant difference. A total of 12 drugs, especially calcium channel blockers, were found to remarkably inhibit the metabolism of CsA with an inhibitory rate of over 80%. Nimodipine inhibits the activity of CsA in rat liver microsomes with an IC50 of 20.54 ± 0.93 μM, while nisoldipine has an IC50 of 16.16 ± 0.78 μM. In in vivo, three groups of Sprague–Dawley rats were administered CsA with or without nimodipine or nisoldipine; the AUC(0-t) and AUC(0-∞) of CsA were significantly increased in the nimodipine group but not obviously in the nisoldipine group. Mechanistically, the inhibition mode of nimodipine on cyclosporine metabolism is a mixed inhibition. Our data show that gene polymorphisms of CYP3A4 and nimodipine remarkably affect the metabolism of CsA, thus providing a reference for the precise administration of CsA.

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Section: Discussionmentioning

confidence: 99%

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

Kong

Gao²,

Wang³

et al. 2023

Front. Pharmacol.

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“…While several studies have explored the pharmacokinetics and pharmacodynamics of calcineurin inhibitors and have shown variable results on how PGx-directed dosing impacts clinical outcomes [ 11 , 12 ], to the best of our knowledge, there have not been any studies exploring how the PGx results may inform general medication management in patients after kidney transplant. Multiple studies showed an average number of prescribed medications for patients with end-stage renal disease between 10–12 [ 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

The Value of Pharmacogenomics for White and Indigenous Americans after Kidney Transplantation

et al. 2023

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Background: There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients’ perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients. Methods: Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained. Results: White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug–gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 (p = 0.012) and CYP2D6 (p = 0.012) activities. The Indigenous American patients had more normal CYP4F2 (p = 0.004) and lower VKORC (p = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts (p = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx. Conclusions: Kidney transplant recipients had several drug–gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.

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Evaluation of Patient‐Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules

Mandlekar,

Sutaria,

Yang

et al. 2024

Clin Pharma and Therapeutics

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Low‐volume sampling devices offer the promise of lower discomfort and greater convenience for patients, potentially reducing patient burden and enabling decentralized clinical trials. In this study, we determined whether low‐volume sampling devices produce pharmacokinetic (PK) data comparable to conventional venipuncture for a diverse set of monoclonal antibodies (mAbs) and small molecules. We adopted an open‐label, non‐randomized, parallel‐group, single‐site study design, with four cohorts of 10 healthy subjects per arm. The study drugs, doses, and routes of administration included: crenezumab (15 mg/kg, intravenous infusion), etrolizumab (210 mg, subcutaneous), GDC‐X (oral), and hydroxychloroquine (HCQ, 200 mg, oral). Samples were collected after administration of a single dose of each drug using conventional venipuncture and three low‐volume capillary devices: TassoOne Plus for liquid blood, Tasso‐M20 for dry blood, both applied to the arm, and Neoteryx Mitra® for dry blood obtained from fingertips. Serum/plasma concentrations from venipuncture and TassoOne Plus samples overlapped and PK parameters were comparable for all drugs, except HCQ. After applying a baseline hematocrit value, the dry blood concentrations and PK parameters for the two monoclonal antibodies were comparable to those obtained from venipuncture. For the two small molecules, two bridging strategies were evaluated for converting dry blood concentrations to equivalent plasma concentrations. A baseline hematocrit correction and/or linear regression‐based correction was effective for GDC‐X, but not for HCQ. Additionally, the study evaluated the bioanalytical data quality and comparability from the various collection methods, as well as patient preference for the devices.

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Pharmacokinetic and Pharmacodynamic Considerations in Relation to Calcineurin Usage in Elderly Kidney Transplant Recipients

Cited by 7 publications

References 69 publications

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

The Value of Pharmacogenomics for White and Indigenous Americans after Kidney Transplantation

Evaluation of Patient‐Centric Sample Collection Technologies for Pharmacokinetic Assessment of Large and Small Molecules

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