Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

Dansirikul, C.; Duffull, Stephen B.; Morris, Raymond G.; Tett, S. E.

doi:10.1111/j.1365-2125.2005.02473.x

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…Although rapamycin and tacrolimus bind to the same target protein, they also inhibit unrelated signalling pathways allowing them to be used in combination 183 . High blood levels of mTOR inhibitors lead to myelosuppression and are associated with hyperlipidaemia and type 2 diabetes, consistent with the role of mTOR in the regulation of metabolism 184 .…”

Section: Targeting Kinases: In the Beginningsupporting

confidence: 56%

Protein kinases: drug targets for immunological disorders

et al. 2023

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Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton’s tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.

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Section: Targeting Kinases: In the Beginningsupporting

confidence: 56%

Protein kinases: drug targets for immunological disorders

et al. 2023

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“…Bone marrow toxicity occurred in a dose-dependent fashion [ 198 , 199 ] and occurred in 20% of KTR receiving sirolimus [ 12 ]. Various studies on sirolimus have reported that trough level greater than 12 to 16 microgram l −1 has an association with leucopenia and thrombocytopenia [ 12 , 200 ]. Hematological manifestation is more common in first 4-8 weeks [ 12 , 201 ].…”

Section: Insight Into Etiology Of Hematological Cytopenia and Subsmentioning

confidence: 99%

Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians

Khalil

Khan

et al. 2018

Journal of Transplantation

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Drug-induced hematological cytopenia is common in kidney transplantation. Various cytopenia including leucopenia (neutropenia), thrombocytopenia, and anemia can occur in kidney transplant recipients. Persistent severe leucopenia or neutropenia can lead to opportunistic infections of various etiologies. On the contrary, reducing or stopping immunosuppressive medications in these events can provoke a rejection. Transplant clinicians are often faced with the delicate dilemma of balancing cytopenia and rejection from adjustments of immunosuppressive regimen. Differentials of drug-induced cytopenia are wide. Identification of culprit medication and subsequent modification is also challenging. In this review, we will discuss individual drug implicated in causing cytopenia and correlate it with corresponding literature evidence.

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“…Worthy of mention, the statistical analyses showed that SRL AUC values provided greater predictive efficacy than the corresponding SRL trough concentrations 8 . In partial agreement with these results, it was recently documented that in renal transplant recipients, white blood cell count and hematocrit were significantly lower when SRL concentration exceeded therapeutic drug concentrations 9 . Along the same line, studies involving transplant patients given everolimus—the novel SRL analogue—have consistently shown significant associations between everolimus trough concentrations or AUC values and clinical outcomes, in terms of either acute rejection episodes or drug‐related toxicity 10 , 11 .…”

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confidence: 54%

Limited Sampling Strategies for the Estimation of Sirolimus Daily Exposure in Kidney Transplant Recipients on a Calcineurin Inhibitor—Free Regimen

Cattaneo

Cortinovis

Baldelli

et al. 2009

The Journal of Clinical Pharma

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Sirolimus (SRL) is a novel immunosuppressive agent characterized by a narrow therapeutic index. Monitoring of SRL concentrations is mandatory to optimize drug dosing. The area under the concentration-time curve (AUC) is generally accepted as the best pharmacokinetic marker of daily drug exposure. Assessment of full SRL AUC, however, requires the collection of multiple blood samples, imposing both time and cost constraints. Limited sampling strategies (LSS) may be of clinical relevance to improve the therapeutic drug monitoring of SRL. In this study, stepwise multiple regression analysis is conducted on 30 SRL pharmacokinetic profiles obtained from kidney transplant recipients on a cyclosporine-free regimen, and different LSS equations are identified based on 2 or 3 sampling points collected within the first 6 hours after drug intake. The performance of these equations is tested in a separate validation set (n=30). Most of the proposed algorithms are associated with good correlations with the measured AUC and acceptable bias and imprecision. Two equations--based on 2 time points collected within the first 4 hours after dosing--are identified that reliably predict SRL exposure in routine clinical practice compared with the traditional C0-based approach. These tools provide additional information to optimize SRL therapeutic drug monitoring in renal transplant recipients.

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Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

Cited by 7 publications

References 14 publications

Protein kinases: drug targets for immunological disorders

Protein kinases: drug targets for immunological disorders

Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians

Limited Sampling Strategies for the Estimation of Sirolimus Daily Exposure in Kidney Transplant Recipients on a Calcineurin Inhibitor—Free Regimen

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