| Autor: |
Narayana I. Narasimhan, John A. Wagner, Nancy G. B. Agrawal, Jacqueline B. McCrea, John Palcza, Kyriakos P. Papadopoulos, Anthony W. Tolcher, Sheila Breidinger, Mark Stroh, Deborah Panebianco, Jennifer Talaty, Amita Patnaik, Michele Trucksis, Richard Lush, Keith Orford, Punam Sandhu |
| Rok vydání: |
2014 |
| Předmět: |
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| Zdroj: |
The Journal of Clinical Pharmacology. 54:1256-1262 |
| ISSN: |
0091-2700 |
| Popis: |
Ridaforolimus, a unique non-prodrug analog of rapamycin, is a potent inhibitor of mTOR under development for cancer treatment. In vitro data suggest ridaforolimus is a reversible and time-dependent inhibitor of CYP3A. A model-based evaluation suggested an increase in midazolam area under the curve (AUC(0- ∞)) of between 1.13- and 1.25-fold in the presence of therapeutic concentrations of ridaforolimus. The pharmacokinetic interaction between multiple oral doses of ridaforolimus and a single oral dose of midazolam was evaluated in an open-label, fixed-sequence study, in which cancer patients received a single oral dose of 2 mg midazolam followed by 5 consecutive daily single oral doses of 40 mg ridaforolimus with a single dose of 2 mg midazolam with the fifth ridaforolimus dose. Changes in midazolam exposure were minimal [geometric mean ratios and 90% confidence intervals: 1.23 (1.07, 1.40) for AUC(0-∞) and 0.92 (0.82, 1.03) for maximum concentrations (C(max)), respectively]. Consistent with model predictions, ridaforolimus had no clinically important effect on midazolam pharmacokinetics and is not anticipated to be a perpetrator of drug-drug interactions (DDIs) when coadministered with CYP3A substrates. Model-based approaches can provide reasonable estimates of DDI liability, potentially obviating the need to conduct dedicated DDI studies especially in challenging populations like cancer patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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