An Evaluation of the Drug Interaction Potential of Encorafenib in Combination With Binimetinib Using the Inje
Joseph Piscitelli1, Micaela B Reddy1, Lance Wollenberg1
1Pfizer Inc, San Diego, California, USA.
Abstract:
A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of single and multiple oral doses of encorafenib on the single oral dose pharmacokinetics (PK) of the cytochrome P450 (CYP) enzyme probe substrates, losartan (CYP2C9), midazolam (CYP3A4), caffeine (CYP1A2), omeprazole (CYP2C19), and dextromethorphan (CYP2D6) administered as a cocktail (Inje). This study was conducted, post-approval, in patients with BRAF V600-mutant advanced solid tumors, and aimed to address the remaining uncertainty in the DDI potential of encorafenib as a perpetrator of these CYP enzymes. Study participants received the cocktail on Days -7, 1, and 14 and continuous doses of encorafenib (450 mg q.d.) and binimetinib (45 mg b.i.d.) starting on Day 1. PK sampling and urine collection were conducted from 0 to 8 hours on cocktail administration days. PK parameters were calculated for each participant using noncompartmental analysis of concentration-time data or amount excreted for urine parameters. At steady-state encorafenib plasma concentrations, midazolam plasma Cmax and AUClast decreased by 74% and 82%, respectively. No clinically significant DDIs were observed at encorafenib steady-state concentrations with the other probe substrates of interest. The results from this clinical study indicate that encorafenib is a strong inducer of CYP3A (≥ 80% decrease in midazolam area under the curve (AUC)) at steady state. Based on these results regarding co-administration with encorafenib, sensitive substrates of CYP3A should be avoided or dose adjusted based on the recommendations of their approved product labeling. This information has been included in the updated prescribing information for encorafenib.
Insights
Encorafenib strongly induces CYP3A, significantly reducing midazolam levels. This drug interaction necessitates caution when co-administering encorafenib with sensitive CYP3A substrates, requiring dose adjustments or avoidance.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Drug Metabolism
Background:
- Encorafenib is used for BRAF V600-mutant advanced solid tumors.
- The drug interaction potential of encorafenib as a perpetrator of cytochrome P450 (CYP) enzymes requires further evaluation.
- A clinical study was conducted post-approval to address uncertainties regarding encorafenib's DDI potential.
Purpose of the Study:
- To evaluate the effect of encorafenib on the pharmacokinetics (PK) of multiple CYP probe substrates.
- To assess encorafenib's potential as a perpetrator of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
- To provide data for safe co-administration of encorafenib with other medications.
Main Methods:
- A clinical DDI study administered a cocktail of CYP probe substrates (losartan, midazolam, caffeine, omeprazole, dextromethorphan) with encorafenib.
- Participants with BRAF V600-mutant advanced solid tumors received single and multiple doses of encorafenib.
- Pharmacokinetic parameters were determined using noncompartmental analysis of plasma and urine data.
Main Results:
- Encorafenib significantly reduced midazolam (CYP3A4 substrate) Cmax by 74% and AUC by 82% at steady-state.
- No clinically significant drug-drug interactions were observed with other CYP probe substrates.
- Encorafenib was identified as a strong inducer of CYP3A at steady-state concentrations.
Conclusions:
- Encorafenib is a strong CYP3A inducer, leading to substantial reductions in the exposure of sensitive CYP3A substrates.
- Co-administration of encorafenib with sensitive CYP3A substrates should be approached with caution, potentially requiring dose adjustments.
- Updated prescribing information for encorafenib now includes recommendations regarding CYP3A interactions.
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