Effect of multiple-dose erythromycin on everolimus pharmacokinetics

Kovarik, John M.; Beyer, D.; Bizot, Marie-Noelle; Jiang, Qiudi; Shenouda, Magdy; Schmouder, Robert

doi:10.1007/s00228-004-0866-5

Cited by 39 publications

(21 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation supports prior evidence pointing to a critical contribution of hepatocellular uptake carriers in the in vivo handling of CYP3A4 probes, and provides a mechanistic explanation for previously reported drug-drug interaction studies involving erythromycin. 10,11,38 Our results also suggest that the ability of erythromycin to predict the clearance of other CYP3A4 substrates will be compromised if differences in transporter affinities are not identified and fully taken into account. It logically follows that only once all factors contributing to the clearance of a particular CYP3A4 substrate drug are known, including non-metabolic determinants such as reliance on hepatic uptake transporters, should the clinical applicability and usefulness of erythromycin as a probe drug be considered.…”

Section: Discussionmentioning

confidence: 88%

OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

Lancaster

Bruun

Peer

et al. 2012

Clin Pharmacol Ther

View full text Add to dashboard Cite

Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-REx 293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wildtype) with a Km of ~13 µM, and its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans, the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a genotype-dosage dependent decline in erythromycin metabolism (P = 0.0072). These results suggest that impaired OATP1B1 function can alter erythromycin metabolism independently of changes in CYP3A4 activity.

show abstract

Section: Discussionmentioning

confidence: 88%

OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

Lancaster

Bruun

Peer

et al. 2012

Clin Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…The concomitant administration of everolimus with the strong CYP inhibitor ketoconazole increased AUC 15-fold in humans [29]. The moderate CYP inhibitors erythromycin, verapamil, and cyclosporine increased AUC 2.7–4.5 fold [15, 18, 30], and the weak inhibitor atorvastatin caused no change in everolimus AUC [31]. In vitro studies with human liver microsomes indicate that sorafenib is a moderate inhibitor of several CYP isoenzymes including CYP3A4, CYP2C19, and CYP2D6 [16].…”

Section: Discussionmentioning

confidence: 99%

Physiologically based pharmacokinetic models for everolimus and sorafenib in mice

Pawaskar

Straubinger

Fetterly

et al. 2013

Cancer Chemother Pharmacol

View full text Add to dashboard Cite

Purpose Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. Methods Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach. Results PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. Conclusions The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.

show abstract

“…Everolimus is metabolized in the gut and liver by CYP3A4; therefore, concomitant administration of other CYP3A inhibitors such as verapamil, ketoconazole, and erythromycin may lead to drug–drug interactions 68–70. Routine therapeutic drug monitoring is recommended to guide dose adjustments when everolimus is coadministered with other CYP3A inhibitors 71.…”

Section: Everolimusmentioning

confidence: 99%

The role of everolimus in liver transplantation

Ganschow¹,

Pollok²,

Jankofsky³

et al. 2014

CEG

View full text Add to dashboard Cite

During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.

show abstract

Effect of multiple-dose erythromycin on everolimus pharmacokinetics

Abstract: Multiple-dose erythromycin increased single-dose everolimus blood levels by an average 4.4-fold (range, 2.0-12.6). During erythromycin treatment, a compensatory everolimus dose reduction should be made guided by everolimus therapeutic drug monitoring.

Cited by 39 publications

References 6 publications

OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

OATP1B1 Polymorphism as a Determinant of Erythromycin Disposition

Physiologically based pharmacokinetic models for everolimus and sorafenib in mice

The role of everolimus in liver transplantation

Contact Info

Product

Resources

About