Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients

Cossart, Amelia R.; Cottrell, Neil; Campbell, Scott; Isbel, Nicole M.; Staatz, Christine E.

doi:10.21037/tau.2018.10.16

Cited by 20 publications

(14 citation statements)

References 93 publications

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“…The currently high immunosuppressive load given to transplant recipients results in a very low rejection rate, but is associated with high rates of infections and cancer 42,43 . In 2009, Badowski et al retrospectively analyzed the effect of a reduction in the dose of mycophenolate mofetil (MMF) and tacrolimus in the first year in kidney recipients aged 60 and older 44 .…”

Section: Discussionmentioning

confidence: 99%

Longitudinal immune profile reveals reduced function of pro-inflammatory monocytes with age following kidney transplantation

Désy

Vallin

Béland

et al. 2021

American Journal of Transplantation

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Toxicity of immunosuppression, notably the risk of infection, increases with age. However, the dynamic changes in innate immune response following transplantation are unclear. Based on recent observations, we hypothesized that pro‐inflammatory capacity would decrease with age. We analyzed approximately 300 PBMC samples collected longitudinally in 45 de novo, adult kidney recipients and performed detailed phenotypic and functional profiling of monocytes and T cell subsets. Inflammatory response to TLR4 stimulation and indirect allostimulation using mismatched HLA peptides were assessed. In patients aged ≥56 years, TNF‐α production by intermediate monocytes was similar to that in younger patients early posttransplant, but diminished substantially later. Adjusted analyses suggested that this was not attributable to confounding factors. In contrast, the alloimmune response to HLA peptides measured by IFN‐γ in CD4+ T cells and TNF‐α in monocytes was stable over time, but was low in older recipients. Measurement of CD80‐86 surface expression revealed no signal for a lower costimulation capacity of APCs. These results suggest that older recipients have a reduced function of their innate pro‐inflammatory immune cells posttransplant while maintaining a stable, low alloimmune response over time. The effect of reduced immunosuppressant doses on preventing this phenomenon needs to be clarified.

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Section: Discussionmentioning

confidence: 99%

Longitudinal immune profile reveals reduced function of pro-inflammatory monocytes with age following kidney transplantation

Désy

Vallin

Béland

et al. 2021

American Journal of Transplantation

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“…Furthermore, risk may be further compounded by the increased chance of recipients having multiple comorbidities (Wu et al, 2005), as well drug-drug interactions (from medicines used for these comorbidities) (Huang et al, 2009;Boesmueller et al, 2011). Consequently, from the level of current evidence, it is thought that lower calcineurin inhibitor targets in elderly recipients may reduce the side effect potential without impacting patient and graft survival, however, studies have yet to confirm this (Danovitch et al, 2007;Dreyer et al, 2015;Cossart et al, 2019).…”

Section: Transplant Outcomes In the Elderlymentioning

confidence: 99%

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

et al. 2021

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This review summarizes how possible age-related changes in tacrolimus and cyclosporine pharmacokinetics and pharmacodynamics may influence drug dosing and monitoring in the elderly, and highlights how micro-sampling may be useful in this cohort in the future. Advancing biological age leads to physiological changes that can affect drug absorption, distribution, metabolism and excretion, as well as immune system responsiveness. Some studies have shown that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors, suggesting that doses may need to be lowered in elderly recipients. Only one study has examined how aging effects drug target enzyme activity and demonstrated that age does not correlate with the calcineurin inhibitor half-maximal inhibitory concentration. Several studies have shown elderly kidney transplant recipients have increased risk of both morbidity and mortality, compared to younger adults due to increased susceptibility to immunosuppressant side effects, particularly cardiovascular disease, infection and malignancy. Current immunosuppressant dosing and monitoring protocols often make no adjustments for age. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established. Blood draw by micro-sampling may be useful for drug monitoring in this cohort in the future, as blood collection is minimally invasive and less painful than venepuncture. Micro-sampling could also make further pharmacokinetic, pharmacodynamics and outcome studies in the elderly more feasible.

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“…The COVID-19 treatment protocols include antiviral drugs causing many DDIs, especially pharmacokinetics in nature. Inhibition of the cytochrome P450 enzyme system leading to a surge in serum concentrations of CNIs may increase the risk of side effects, including neurotoxicity and nephrotoxicity (5). Examination of COVID-19 patients on antivirals can help us study the effect of lopinovir/ritonivir, which was previously mainly used in AIDS patients, in a wider aspect.…”

Section: Introductionmentioning

confidence: 99%

Drug-drug Interactions in Kidney Transplant Patients with Coronavirus Disease 2019: A Report of Two Cases and Literature Review

Khamas

Ramezanzadeh

Jafari

2021

ircmj

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On February 19, 2020, the first confirmed case of Coronavirus disease 2019, known as COVID-19, was identified in Iran. Afterward, the disease spread rapidly throughout the country. Some of the cases were asymptomatic, some had mild to severe symptoms, and some of them died. Transplant patients are highly at risk due to long-term immunosuppressive therapy, and precise treatment approaches are needed to not only cure the disease but also protect graft function. This study reports two kidney transplant patients with COVID-19 pneumonia, both of whom showed respiratory and gastrointestinal symptoms. High cyclosporine and tacrolimus trough levels were observed despite initial dose reduction. After a treatment program containing reduced immunosuppressant dose and the addition of pulsatile hydrocortisone, these patients recovered effectively. We also discuss the importance of drug-drug interactions related to COVID-19 treatment protocol medications, especially with immunosuppressants, in these patients. In conclusion, frequent monitoring of the trough levels of calcineurin and mammalian target of rapamycin inhibitors during hospitalization is recommended since it helps to determine the ideal treatment and prevent serious clinical toxicity.

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Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients

Cited by 20 publications

References 93 publications

Longitudinal immune profile reveals reduced function of pro-inflammatory monocytes with age following kidney transplantation

Longitudinal immune profile reveals reduced function of pro-inflammatory monocytes with age following kidney transplantation

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

Drug-drug Interactions in Kidney Transplant Patients with Coronavirus Disease 2019: A Report of Two Cases and Literature Review

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