Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomic responses in patients with advanced renal cancer

Boni, Joseph; Leister, Cathie; Bender, Gregor; Fitzpatrick, Virginia; Twine, Natalie C.; Stover, Jennifer A.; Dorner, Andrew J.; Immermann, Fred; Burczynski, Michael E.

doi:10.1016/j.clpt.2004.08.025

Cited by 74 publications

(58 citation statements)

References 15 publications

(31 reference statements)

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“…The relative PK profiles of CCI-779 and rapamycin observed in the present study are in agreement with those observed in patients with breast and/or renal cancers (Raymond et al, 2004;Boni et al, 2005). The antitumor efficacy of CCI-779 was associated with significantly suppressed tumor vascular density and macrophage burden (Figs.…”

Section: Discussionsupporting

confidence: 79%

Multimodal Biomarker Investigation on Efficacy and Mechanism of Action for the Mammalian Target of Rapamycin Inhibitor, Temsirolimus, in a Preclinical Mammary Carcinoma OncoMouse Model: A Translational Medicine Study in Support for Early Clinical Development

Wang

Zhan²,

Zhao³

et al. 2011

J Pharmacol Exp Ther

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The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administered in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 Ϯ 14% from 8 to 10 weeks, p Ͻ 0.05, and 26 Ϯ 17% from 11 to 13 weeks, p Ͻ 0.01), compared with 493 Ϯ 160 and 376 Ϯ 50% increases, respectively, in vehicle-treated groups. Temsirolimus reduced tumor vascular density, 36 to 48 and 58 to 60%, p Ͻ 0.05, by the Texas red-dextran method or CD31-positive vessel count, respectively. Temsirolimus reduced tumor macrophage burden by 46% at 13 weeks (p Ͻ 0.05). Temsirolimus inhibited (p Ͻ 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors.

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Section: Discussionsupporting

confidence: 79%

Multimodal Biomarker Investigation on Efficacy and Mechanism of Action for the Mammalian Target of Rapamycin Inhibitor, Temsirolimus, in a Preclinical Mammary Carcinoma OncoMouse Model: A Translational Medicine Study in Support for Early Clinical Development

Wang

Zhan²,

Zhao³

et al. 2011

J Pharmacol Exp Ther

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“…Notwithstanding the lower 5 mg dose administered in this study, the types of adverse events observed were not dissimilar to those seen in studies of temsirolimus in patients with cancer, although a greater percentage of cancer patients had thrombocytopaenia, rash, and mucositis (Atkins et al, 2004;Hidalgo et al, 2006) than did the healthy subjects in this study. Previous studies have suggested that the incidence and severity of some adverse events are proportional to the exposure to temsirolimus (Boni et al, 2005;Chang et al, 2005). In a population PK safety analysis of patients receiving 25, 75, or 250 mg of temsirolimus weekly, clinically interesting associations between AUC sum and adverse event severity were observed for thrombocytopaenia (P ¼ 0.007), pruritus (P ¼ 0.011), and hypertriglyceridaemia (P ¼ 0.040) (Boni et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have suggested that the incidence and severity of some adverse events are proportional to the exposure to temsirolimus (Boni et al, 2005;Chang et al, 2005). In a population PK safety analysis of patients receiving 25, 75, or 250 mg of temsirolimus weekly, clinically interesting associations between AUC sum and adverse event severity were observed for thrombocytopaenia (P ¼ 0.007), pruritus (P ¼ 0.011), and hypertriglyceridaemia (P ¼ 0.040) (Boni et al, 2005). Based on both logistic regression analyses, where predicted drug concentrations can estimate the probability of adverse events, and the tolerability of temsirolimus over a wide dose range, the likelihood of severe toxicity occurring from this type of drug interaction is thought to be low with the 25-mg dose.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Leister¹,

Burns²,

Hug³

2008

Br J Cancer

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Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (C max ) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUC sum (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.

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“…Boni et al [35] conducted an evaluation of the population PK of temsirolimus, estimating PK parameters and PD associations of exposure parameters with safety (and clinical activity) from a randomized, double-blind, multicenter trial. In the dose-escalation phase II trial, 50 patients were treated with temsirolimus at doses of 25 mg, 75 mg, or 250 mg i.v.…”

Section: Relationship Between Rcc Targeted Therapy-associated Pharmacmentioning

confidence: 99%

Treatment-Associated Adverse Event Management in the Advanced Renal Cell Carcinoma Patient Treated with Targeted Therapies

Ravaud

2011

The Oncologist

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Targeted therapy for advanced renal cell carcinoma (RCC) has recently expanded the available treatment options for patients with these malignancies. The rapid introduction of novel treatment options into clinical practice within a relatively short time frame has created some new challenges pertaining to adverse event (AE) management in patients with advanced RCC. Accumulating safety data from the pivotal phase III clinical trials of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab plus interferon, VEGF receptor tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have served to characterize the toxicity profiles of these novel agents. Overall, it is evident that RCC-directed targeted therapy differs from immunotherapy and cytotoxic chemotherapy in terms of a number of unique nonhematologic AEs (some of which have not been traditionally encountered in oncology practice) and that there are distinctions within and across the various classes of agents with respect to the most prominent AEs and the risk for less common but serious complications. Although treatment-associated AEs are common, the majority of AEs reported during clinical trial experiences were grade 1 or 2 in severity and manageable with intervention in the form of supportive measures and/or dosage modification. Therefore, despite the relatively complex AE profiles of RCC-directed targeted therapy, patient education, consistent monitoring with a focus on early detection by health care providers (oncologists, general physicians, nurses), and the application of emerging AE management strategies may allow for prolonged treatment in most patients with advanced RCC. The Oncologist 2011;16(suppl 2):32-44

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Population pharmacokinetics of CCI-779: Correlations to safety and pharmacogenomic responses in patients with advanced renal cancer

Cited by 74 publications

References 15 publications

Multimodal Biomarker Investigation on Efficacy and Mechanism of Action for the Mammalian Target of Rapamycin Inhibitor, Temsirolimus, in a Preclinical Mammary Carcinoma OncoMouse Model: A Translational Medicine Study in Support for Early Clinical Development

Multimodal Biomarker Investigation on Efficacy and Mechanism of Action for the Mammalian Target of Rapamycin Inhibitor, Temsirolimus, in a Preclinical Mammary Carcinoma OncoMouse Model: A Translational Medicine Study in Support for Early Clinical Development

Differential effects of ketoconazole on exposure to temsirolimus following intravenous infusion of temsirolimus

Treatment-Associated Adverse Event Management in the Advanced Renal Cell Carcinoma Patient Treated with Targeted Therapies

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