The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors.

Abstract

PURPOSE:

This 2-arm, phase 1, crossover study compared the relative bioavailability of two dovitinib (TKI258) capsule formulations [anhydrate clinical service form (CSF) and monohydrate final market image (FMI); Arm 1] and determined the effect of food on dovitinib exposure (Arm 2).

METHODS:

Patients with advanced solid tumors were enrolled in one of the 2 arms. Arm 1 randomized patients to a single 500-mg dose of either CSF or FMI followed by 7 days of rest and 500 mg of the other formulation. Arm 2 patients received 300 mg of FMI once daily and were randomized to follow one of six meal sequences, each with three prandial conditions: low fat (LF), high fat (HF), or no meal (NM).

RESULTS:

Twenty-three and 37 patients were enrolled and 19 and 21 were evaluable in Arms 1 and 2, respectively. In Arm 1, the adjusted geometric means for FMI had small reductions relative to CSF [area under the plasma concentration-time curve (AUClast) decreased by 12%, maximum concentration (C max) decreased by 3%]. In Arm 2, the HF meal versus NM showed a 2% increase in the adjusted geometric mean for AUClast and a 5% decrease for C max. The LF meal versus NM comparison showed 9 and 6% increases for AUClast and C max, respectively. Overall, common adverse events included nausea, vomiting, diarrhea, and fatigue.

CONCLUSIONS:

Systemic exposure to dovitinib was similar for the FMI and CSF capsule formulations. Additionally, since prandial conditions did not affect the systemic exposure, dovitinib can be taken with or without food.

• Authors: Sunil Sharma, Carolyn D Britten, Joanne Mortimer, Swarupa Kulkarni, Michelle Quinlan, Angela Liu, Jeffrey W Scott, Daniel George
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 74 Issue 4 Pg. 867-74 (Oct 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25193431 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
• Antineoplastic Agents
• Benzimidazoles
• Capsules
• Dietary Fats
• Quinolones

Topics

• Administration, Oral
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Benzimidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Biological Availability
• Capsules
• Cross-Over Studies
• Dietary Fats (adverse effects)
• Female
• Food Analysis (methods)
• Food-Drug Interactions
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Quinolones (administration & dosage, adverse effects, pharmacokinetics)
• Therapeutic Equivalency
• Treatment Outcome