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Effect of coadministration of ketoconazole, a strong CYP3A4 inhibitor, on pharmacokinetics and tolerability of motesanib diphosphate (AMG 706) in patients with advanced solid tumors.
- Source :
-
Investigational new drugs [Invest New Drugs] 2008 Oct; Vol. 26 (5), pp. 455-62. Date of Electronic Publication: 2008 Jun 24. - Publication Year :
- 2008
-
Abstract
- Motesanib diphosphate is a novel angiogenesis inhibitor selectively targeting vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor and stem cell factor receptor. The purpose of this phase 1b, drug-drug interaction study was to investigate the effect of ketoconazole, a strong inhibitor of the cytochrome P450 3A4 isoenzyme, on the pharmacokinetics and tolerability of motesanib diphosphate. Fourteen patients with advanced solid tumors refractory to standard treatment were enrolled and received motesanib diphosphate 50 mg once daily from day 1 through 15. Patients were randomized to receive a single oral dose of ketoconazole 400 mg either on day 8 (Sequence 1; n = 7) or day 15 (Sequence 2; n = 7), while pharmacokinetic samples were collected. After completion of this part (day 16), 13 patients received an escalated once-daily dose of motesanib diphosphate 125 mg. Evaluable pharmacokinetic data (n = 12) suggest that ketoconazole modestly increased motesanib exposure. The motesanib area under the concentration-time curve (AUC) from 0 to 24 h increased by 86% (90% CI, 1.50-2.29; P < 0.001) and the maximum plasma concentration (C (max)) by 35% (90% CI, 1.12-1.64; P = 0.02), compared with motesanib diphosphate administration alone. The tolerability profile (with or without ketoconazole coadministration) was consistent with that from other motesanib diphosphate monotherapy studies. Treatment-related adverse events were mild to moderate and commonly included fatigue (50% of patients), hypertension (43%), diarrhea (21%), dizziness (14%), paresthesia (14%), and vomiting (14%). Hypertension was the most common related grade 3 event (21%). No grade 4 or 5 treatment-related adverse events occurred.
- Subjects :
- Aged
Cross-Over Studies
Cytochrome P-450 CYP3A
Drug Administration Schedule
Female
Humans
Indoles adverse effects
Indoles pharmacokinetics
Ketoconazole administration & dosage
Male
Middle Aged
Niacinamide administration & dosage
Niacinamide adverse effects
Niacinamide pharmacokinetics
Oligonucleotides
Cytochrome P-450 CYP3A Inhibitors
Indoles administration & dosage
Ketoconazole pharmacology
Neoplasms drug therapy
Niacinamide analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0167-6997
- Volume :
- 26
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Investigational new drugs
- Publication Type :
- Academic Journal
- Accession number :
- 18574557
- Full Text :
- https://doi.org/10.1007/s10637-008-9144-1