Investigation of Pharmacokinetic DDI Between Olaparib and Metformin

Cancer Chemotherapy and Pharmacology. 2024 Jan; 93 (1): 79-88.

Authors: Stanisławiak-Rudowicz J, Karbownik A, Szkutnik-Fiedler D, Otto F, Grabowski T, Wolc A, Grześkowiak E, Szałek E.

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.

• 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 hours.
• High-performance liquid chromatography (HPLC) with ultraviolet (UV) detection after a liquid-liquid extraction with a mixture of 1-butanol: n-heptane (50:50, v/v) was applied to measure the concentrations of metformin in the rats' plasma. Olaparib in the plasma samples was quantified with ultra-high-performance liquid chromatography.
• The following pharmacokinetic parameters of olaparib and metformin were calculated with the Pkanalix 2023R1 software (Lixoft, France): the elimination rate constant (k_e), the absorption rate constant (k_a), the half-life in the elimination phase (t_1/2), the area under the concentration-time curve from zero to the last measurable concentration (AUC_0-t), the area under the plasma concentration-time curve from zero to infinity (AUC_0-∞), the apparent plasma drug clearance (Cl/F), and the apparent volume of distribution (V_d/F). The maximum plasma concentration (C_max) and the time to reach the C_max (t_max) were obtained directly from the measured values.
• Browse our recommendations

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.

• When metformin was co-administered with olaparib, the AUC_0-t and AUC_0-∞ of metformin increased by 159.8% and 74.1%, respectively, as compared with the administration of metformin alone. In the presence of olaparib, the C_max of metformin increased by 177.8%, whereas the V_d/F (65.1%) and Cl/F (43.4%) of metformin decreased. However, there were no significant differences between the two groups in the values of the other pharmacokinetic parameters. The values of the I_MET+OLA/II_MET ratio for C_max, AUC_0-t, and AUC_0-∞ were 2.78, 2.59, and 1.74, respectively.
• In comparison with the control group, the V_d/F (from 22.49 ± 24.81 to 12.51 ± 11.61 l) and Cl/F (from 7.84 ± 15.21 to 2.62 ± 2.07 l/h) of olaparib decreased when it was co-administered with metformin, but there was no statistical significance (p = 0.5995 and 0.8336, respectively). The values of the I_MET+OLA/II_MET ratio for C_max, AUC_0-t, and AUC_0-∞ were: 1.08, 0.99, and 1.02, respectively.

Fig. 1 Left: Metformin plasma concentration-time profiles (mean ± SD) in the rats that received metformin (II_MET) and metformin + olaparib (I_MET+OLA); Right: Olaparib plasma concentration-time profiles (mean ± SD) in the rats which received olaparib (III_OLA) and metformin + olaparib (I_MET+OLA).

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.

In Vitro DMPK Services

In Vivo DMPK Services

Reference

1. Stanisławiak-Rudowicz J, et al. (2024). "Bidirectional pharmacokinetic drug interactions between olaparib and metformin." Cancer Chemother Pharmacol. 93 (1): 79-88.

For research use only. Not for any other purpose.