Bidirectional pharmacokinetic drug interactions between olaparib and metformin
CANCER CHEMOTHERAPY AND PHARMACOLOGY(2024)
Abstract
ObjectiveOlaparib is a PARP (poly-ADP-ribose polymerase) inhibitor used for maintenance therapy in BRCA-mutated cancers. Metformin is a first-choice drug used in the treatment of type 2 diabetes. Both drugs are commonly co-administered to oncologic patients with add-on type 2 diabetes mellitus. Olaparib is metabolized by the CYP3A4 enzyme, which may be inhibited by metformin through the Pregnane X Receptor. In vitro studies have shown that olaparib inhibits the following metformin transporters: OCT1, MATE1, and MATE2K. The aim of the study was to assess the influence of 'the perpetrator drug' on the pharmacokinetic (PK) parameters of 'the victim drug' after a single dose. To evaluate the effect, the AUC0 ->infinity (area under the curve) ratio was determined (the ratio between AUC0 ->infinity in the presence of the perpetrator and AUC0 ->infinity without the presence of the perpetrator).MethodsMale Wistar rats were assigned to three groups (eight animals in each group), which were orally administered: metformin and olaparib (IMET+OLA), vehiculum with metformin (IIMET), and vehiculum with olaparib (IIIOLA). Blood samples were collected after 24 h. HPLC was applied to measure the concentrations of olaparib and metformin. The PK parameters were calculated in a non-compartmental model.ResultsMetformin did not affect the olaparib PK parameters. The AUC0 ->infinity IMET+OLA/IIIOLA ratio was 0.99. Olaparib significantly increased the metformin Cmax (by 177.8%), AUC0 -> t (by 159.8%), and AUC0 ->infinity (by 74.1%). The AUC0 ->infinity IMET+OLA/IIMET ratio was 1.74.ConclusionsA single dose of metformin did not affect the PK parameters of olaparib, nor did it inhibit the olaparib metabolism, but olaparib significantly changed the metformin pharmacokinetics, which may be of clinical importance.
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Key words
Olaparib,Metformin,Pharmacokinetics,Drug-drug interactions
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