Bidirectional pharmacokinetic drug interactions between olaparib and metformin

Olaparib 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 AUC_0→∞ (area under the curve) ratio was determined (the ratio between AUC_0→∞ in the presence of the perpetrator and AUC_0→∞ without the presence of the perpetrator).

Male Wistar rats were assigned to three groups (eight animals in each group), which were orally administered: metformin and olaparib (I_MET+OLA), vehiculum with metformin (II_MET), and vehiculum with olaparib (III_OLA). 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.

Metformin did not affect the olaparib PK parameters. The AUC_0→∞ I_MET+OLA/III_OLA ratio was 0.99. Olaparib significantly increased the metformin C_max (by 177.8%), AUC_0→t (by 159.8%), and AUC_0→∞ (by 74.1%). The AUC_0→∞ I_MET+OLA/II_MET ratio was 1.74.

A 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.