Imatinib- Glivec
Rationale
Preclinical Data
In vitro experiments with human CML-derived neoplastic cell lines show that Glivec® inhibits the growth of Ph+ cells that express BCR-ABL. When cultured in the presence of increasing concentrations of Glivec, BCR-ABL–positive leukaemic cell lines show a dose-dependent inhibition of proliferation, whereas BCR-ABL–negative tumour cell lines are unaffected.1,2 These data suggest that inhibition of BCR-ABL tyrosine kinase activity by Glivec is specific and able to reverse BCR-ABL–positive leukaemic cell growth. In murine studies, Glivec inhibited tumour growth in mice inoculated with BCR-ABL–positive tumours. Typically in these studies, tumours derived from BCR-ABL–positive murine myeloid cells began to grow in syngeneic mice within 1 week of inoculation. A statistically significant, dose-dependent reduction in tumour volume was seen in mice treated with Glivec compared with those treated with placebo (data on file, Novartis Pharma AG, Basel, Switzerland, 2001). The data suggest that Glivec has in vivo activity for treatment of BCR-ABL–positive leukaemia.3
Preclinical data from in vitro and in vivo studies showed that Glivec is a potent inhibitor of BCR-ABL tyrosine kinase at concentrations that were later shown to be attainable in patient blood plasma. These data spurred clinical investigations.
Pharmacokinetics and Pharmacodynamics
The pharmacokinetic and pharmacodynamic properties of Glivec have been evaluated in both healthy subjects and patients with CML, and data analysis for special populations has been performed. Potential drug-drug interactions with Glivec have also been investigated (Tables 1 and 2).4
| DRUGS THAT MAY INCREASE GLIVEC CONCENTRATION | DRUGS THAT MAY DECREASE GLIVEC CONCENTRATION |
|---|---|
| Clarithromycin Erythromycin Ketoconazole (Glivec: Cmax increased by 26%; AUC increased by 40%)* Itraconazole |
Carbamazepine Dexamethasone Phenobarbital St John’s wort Phenytoin Rifampin (Glivec: Cmax decreased by 54%; AUC decreased by 74%) |
*When administered in healthy subjects.
AUC, area under the time–concentration curve; Cmax, maximum concentration.
| Acetaminophen Triazolobenzodiazepines Cyclosporine HMG-CoA reductase inhibitors (eg, simvastatin: Cmax increased 2-fold; AUC increased 3.5-fold) |
Pimozide Warfarin Phenobarbital St John’s wort Dihydropyridine Ca++ channel blockers |
AUC, area under the time–concentration curve; Cmax, maximum concentration; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A.
References:
1. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
2. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380-394.
3. Le Coutre P, Mologni L, Cleris L, et al. In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. J Natl Cancer Inst. 1999;91:163-168.
4. Glivec® [summary of product characteristics]. Basel, Switzerland; Novartis AG; 2007. Available at:
http:/anti-infectives/Paris-Event/Live-Webcast.cfmwww.glivec.com/content/tools/espc.jsp.