Sirolimus and everolimus intestinal absorption and interaction with calcineurin inhibitors: a differential effect between cyclosporine and tacrolimus

Lamoureux, Fabien; Picard, Nicolas; Boussera, Belkacem; Sauvage, François‐Ludovic; Marquet, Pierre

doi:10.1111/j.1472-8206.2011.00957.x

Cited by 32 publications

(14 citation statements)

References 40 publications

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“…Michaelis–Menten kinetics was incorporated in our model to describe the saturable absorption. This is consistent with a previous study on intestinal absorption, which demonstrated a concentration‐dependent and saturable transepithelial transport of sirolimus across Caco‐2 monolayers 25 . The mechanism of absorption is not very clear, and the model could be further understood once the drug transport mechanisms are elucidated 25 .…”

Section: Discussionsupporting

confidence: 90%

“…This is consistent with a previous study on intestinal absorption, which demonstrated a concentration-dependent and saturable transepithelial transport of sirolimus across Caco-2 monolayers. 25 The mechanism of absorption is not very clear, and the model could be further understood once the drug transport mechanisms are elucidated. 25 Cummins et al 26 studied the cellular pharmacokinetics of sirolimus in CYP3A4-transfected Caco-2 cells.…”

Section: Discussionmentioning

confidence: 99%

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Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer

Cohen

House

et al. 2012

CPT Pharmacom & Syst Pharma

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Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis–Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer

Cohen

House

et al. 2012

CPT Pharmacom & Syst Pharma

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“…53,54 Conversely, P-gp up-regulation appears to protect proximal renal tubular cells from cadmium-induced apoptosis. 55 Although mTOR inhibitors are well known to act simultaneously like CNIs as substrates, and as inhibitors for P-gp, 46,52,56,57 similar associations between P-gp expression and everolimus nephrotoxicity have not been reported so far.…”

Section: Case Discussion and Review Of The Literaturementioning

confidence: 99%

Untitled

2015

Exp Clin Transplant

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Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transitionmediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

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“…No correlation has been observed between sirolimus blood concentrations and bodyweight, gender, age, or dose [16]. Intestinal CYP3A metabolism and intestinal P-gp counter-transport, intestinal membrane permeability, and hepatic first-pass all affect bioavailability and probably also influence sirolimus absorption because the drug is a substrate for these enzymes and transporters [17] (Fig. 2) …”

Section: Pharmacokinetics Absorptionmentioning

confidence: 97%