Pharmacokinetics and Safety of Single Oral Doses of Sirolimus (Rapamycin) in Healthy Male Volunteers

Brattström, C; Säwe, Juliette; Jansson, B.; Lönnebo, Anna; Nordin, Jan; Zimmerman, James J.; Burke, James T.; Groth, Carl G.

doi:10.1097/00007691-200010000-00006

Cited by 56 publications

(52 citation statements)

References 11 publications

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“…The toxicities encountered therefore may have reflected the additive and/or cumulative effects of both drugs. The mean whole blood terminal disposition half-life for rapamycin is reportedly 82 ± 12 hours [23]. The terminal half-life for rapamycin observed in our study averaged 42 ± 24 hours.…”

Section: Cci-779supporting

confidence: 43%

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

et al. 2004

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SummaryObjectives: CCI-779 is an ester of the immunosuppressive agent sirolimus (rapamycin) that causes cell-cycle arrest at G1 via inhibition of key signaling pathways resulting in inhibition of RNA translation. Antitumor activity has been demonstrated using cell lines and animal models of malignant glioma. Patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) can have altered metabolism of drugs like CCI-779 that are metabolized through the hepatic cytochrome P450 enzyme system. The objectives of this study were to determine the pharmacokinetic profile and the maximum tolerated dose of CCI-779 in patients with recurrent malignant gliioma taking EIAEDs. Study design: The starting dose of CCI-779 was 250 mg intravenously (IV) administered weekly on a continuous basis. Standard dose escalation was performed until the maximum tolerated dose was established. Toxicity was assessed using the National Cancer Institute common toxicity criteria. Results: Two of 6 patients treated at the second dose level of 330 mg sustained a dose-limiting toxicity: grade III stomatitis, grade 3 hypercholesterolemia, or grade 4 hypertriglyceridemia. The maximum tolerated dose was reached at 250 mg IV. Pharmacokinetic profiles were similar to those previously described, but the area under the whole blood concentration-time curve of rapamycin was 1.6 fold lower for patients on EIAEDs. Conclusions: The recommended phase II dose of CCI 779 for patients on enzyme-inducing antiepileptic drugs is 250 mg IV weekly. A phase II study is ongoing to determine the efficacy of this agent.

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Section: Cci-779supporting

confidence: 43%

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

et al. 2004

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“…The mTOR inhibitor rapamycin was the ideal tool to answer the posed question because it is one of the most potent and specific kinase inhibitors known (30) and absorbed rapidly with peak plasma concentrations reached after ϳ60 min (42).…”

Section: Discussionmentioning

confidence: 99%

The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man

et al. 2007

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The nutrient-sensitive kinase mammalian target of rapamycin (mTOR) and its downstream target S6 kinase (S6K) are involved in amino acid-induced insulin resistance. Whether the mTOR/S6K pathway directly modulates glucose metabolism in humans is unknown. We studied 11 healthy men (29 years old, BMI 23 kg/m 2 ) twice in random order after oral administration of 6 mg rapamycin, a specific mTOR inhibitor, or placebo. An amino acid mixture was infused to activate mTOR, and somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia (ϳ100 pmol/l, 0 -180 min) and prandial-like peripheral hyperinsulinemia (ϳ450 pmol/l, 180 -360 min). Glucose turnover was assessed using D-[6,6-2 H 2 ]glucose infusion (n ‫؍‬ 8). Skeletal muscle biopsies were performed at baseline and during prandial-like peripheral hyperinsulinemia (n ‫؍‬ 3). At low peripheral hyperinsulinemia, whole-body glucose uptake was not affected by rapamycin. During prandial-like peripheral hyperinsulinemia, rapamycin increased glucose uptake compared with placebo by 17% (R dԽ300 -360 min , 75 ؎ 5 vs. 64 ؎ 5 mol ⅐ kg ؊1 ⅐ min ؊1 , P ‫؍‬ 0.0008). Rapamycin affected endogenous glucose production neither at baseline nor during low or prandial-like peripheral hyperinsulinemia. Combined hyperaminoacidemia and prandial-like hyperinsulinemia increased S6K phosphorylation and inhibitory insulin receptor substrate-1 (IRS-1) phosphorylation at Ser312 and Ser636 in the placebo group. Rapamycin partially inhibited this increase in mTOR-mediated S6K phosphorylation and IRS-1 Ser312 and Ser636 phosphorylation. In conclusion, rapamycin stimulates insulin-mediated glucose uptake in man under conditions known to activate the mTOR/S6K pathway. Diabetes 56:1600-1607, 2007 T ype 2 diabetes is closely linked to obesity and insulin resistance (1-3). In addition to polygenic predisposition, environmental factors including quality and quantity of food supply, dietary behavior, and physical activity are of major importance for the development of type 2 diabetes (4,5). The availability of nutrients plays a pivotal role in the modulation of insulin action (6,7). In industrialized countries, nutrient excess comprises high intake of not only fat but also proteins (8). A chronic excess in protein intake is associated with insulin resistance, glucose intolerance, and type 2 diabetes (9 -12). We have shown that a short-term rise in plasma free fatty acids (FFAs) (13-15) or amino acids (16 -18) leads to decreased insulin-stimulated whole-body glucose disposal, which is preceded by an impaired rise in intramuscular glucose-6-phosphate concentrations and followed by reduction in rates of glycogen synthesis. These findings indicate that both FFAs and amino acids directly inhibit skeletal muscle glucose transport/phosphorylation (17).The mammalian target of rapamycin (mTOR) pathway (19) could be involved in sensing of nutrient availability and modulation of insulin action in vivo. Recent reports indicate that the activity of the mTOR pathway is increased in rodent models ...

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“…These studies have characterized rapamycin to be a drug with a relatively long half-life of more than 5 hours, with volume of distribution values that indicates a substantial proportion of the drug residing extravascularly [8,22,45,52]. Rapamycin is a lipophilic compound with a partition coefficient (X log P O/W ) of 5.77 and is highly distributed into the tissue as evidenced by the high volume of distribution value.…”

Section: Discussionmentioning

confidence: 99%

Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(ε-caprolactone) micelles of rapamycin

Yáñez

Forrest

Ohgami

et al. 2007

Cancer Chemother Pharmacol

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Purpose-To determine the pharmacokinetics, tissue, and blood distribution of rapamycin PEGblock-poly(ε-caprolactone) (PEG-b-PCL) micelle formulations with and without the addition of α-tocopherol compared to control rapamycin in Tween 80/PEG 400/N,N-dimethylacetamide (DMA) (7:64:29).Methods-Rapamycin was incorporated at 10% w/w into PEG-b-PCL micelles (5:10 kDa) using a solvent extraction technique. The co-incorporation of 2:1 α-tocopherol:PEG-b-PCL was also studied. Rapamycin was quantified utilizing LC/MS in a Waters XTerra MS C18 column with 32-desmethoxyrapamycin as the internal standard. Male Sprague Dawley rats (N = 4 per group; ~200 g) were cannulated via the left jugular and dosed intravenously (IV) with the rapamycin control and micelle formulations (10 mg/kg, 1:9 ratio for rapamycin to PEG-b-PCL). For tissue distribution 24 h after IV dosing, whole blood, plasma, red blood cells, and all the representative tissues were collected. The tissues were rapidly frozen under liquid nitrogen and ground to a fine powder. The rapamycin concentrations in plasma and red blood cells were utilized to determine the blood distribution (partition coefficient between plasma and red blood cells). For the determination of the pharmacokinetic parameters, blood, plasma, and urine samples were collected over 48 h. The pharmacokinetic parameters were calculated using WinNonlin® (Version 5.1) software.Results-Rapamycin concentrations were considerably less in brain after administration of both micelle formulations compared to a rapamycin in the Tween 80/PEG 400/DMA control group. There was a 2-fold and 1.6-fold increase in the plasma fraction for rapamycin micelles with and without α-tocopherol. There was a decrease in volume of distribution for both formulations, an increase in AUC, a decrease in clearance, and increase in half life respectively for rapamycin in PEG-b-PCL + Correspondence to: Glen S. Kwon; Neal M. Davies. Jaime A. Yáñez and M. Laird Forrest contributed equally to the work. NIH Public Access Author ManuscriptCancer Chemother Pharmacol. Author manuscript; available in PMC 2009 January 1. Conclusions-The decreased distribution into the brain of rapamycin in PEG-b-PCL micelles may ameliorate rapamycin neurotoxicity. Both micelle formulations increase rapamycin distribution in plasma, which could facilitate access into solid tumors. The micellar delivery systems of rapamycin impart in vivo controlled release, resulting in altered disposition, and dramatically reduced mortality.

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Pharmacokinetics and Safety of Single Oral Doses of Sirolimus (Rapamycin) in Healthy Male Volunteers

Cited by 56 publications

References 11 publications

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

Phase I/pharmacokinetic study of CCI-779 in patients with recurrent malignant glioma on enzyme-inducing antiepileptic drugs

The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man

Pharmacometrics and delivery of novel nanoformulated PEG-b-poly(ε-caprolactone) micelles of rapamycin

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