Pharmacokinetic Interaction Between Olaparib and Regorafenib in an Animal Model

Abstract

Background: Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant drug-drug interactions. Knowledge of the influence of membrane transporters and cytochrome P450 enzymes on the pharmacokinetics of drugs makes it possible to assess their impact on the efficacy and safety of therapy.

Purpose: The study aimed to evaluate the bilateral pharmacokinetic interactions of OLA and REG and its active metabolites after a single administration in healthy rats.

Methods: The study was performed in male Wistar rats (n = 24) randomly divided into three groups: one study group, I_REG+OLA (n = 8), received REG with OLA, and two control groups, II_REG (n = 8) and III_OLA (n = 8), received REG and OLA, respectively. The concentrations of OLA, REG, REG-N-oxide (M-2), and N-desmethyl-REG-N-oxide (M-5) were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The values of the pharmacokinetic parameters of OLA, REG, M-2, and M-5 were determined by non-compartmental analysis with linear interpolation.

Results: After OLA administration, the pharmacokinetic parameters of REG (AUC_0-∞, t_max, and t_0.5) increased significantly by 3.38-, 2.66-, and 1.82-fold, respectively. On the other hand, REG elimination parameters, i.e., k_el and Cl/F, were significantly reduced in the study group by 1.77- and 1.70-fold, respectively. In the study group, C_max and AUC_0-t values were also 7.22- and 8.86-fold higher for M-2 and 16.32- and 17.83-fold higher for M-5, respectively. The Metabolite M-2/Parent and Metabolite M-5/Parent ratios for C_max and AUC_0-t increased by 6.52-, 10.74-, 28-, and 13-fold, respectively. After administration of OLA with REG, the C_max, AUC_0-t, and AUC_0-∞ of OLA increased by 2.0-, 3.4-, and 3.4-fold, respectively, compared to the control group. Meanwhile, Cl/F and Vd/F of OLA were significantly decreased in the presence of REG.

Conclusions: OLA was shown to significantly affect the pharmacokinetics of REG and its active metabolites M-2 and M-5 in rats after co-administration of both drugs. There was also a significant effect of REG on the pharmacokinetics of OLA, which may have clinical relevance. The AUC ratios (study group/control group) were 3.41 and 3.39 for REG and OLA, respectively, indicating that REG and OLA were moderate inhibitors in this preclinical study. The results obtained need to be confirmed in clinical studies. This study may provide guidance on the safety of using both drugs in clinical practice.

Keywords: drug–drug interaction; olaparib; pharmacokinetics; rats; regorafenib.

Figure 1

Pharmacokinetic interaction between OLA and REG.

Figure 2

The REG plasma concentration–time profiles in rats after oral administration of a single dose of REG (20 mg/kg b.w.) to the II_REG group and REG + OLA (20 mg/kg b.w. + 100 mg/kg b.w.) to the I_REG+OLA group.

Figure 3

(A). The M-2 plasma concentration–time profiles in rats receiving REG (II_REG) and REG+OLA (I_REG+OLA). (B). The M-5 plasma concentration–time profiles in rats receiving REG (II_REG) and REG+OLA (I_REG+OLA).

Figure 3

(A). The M-2 plasma concentration–time profiles in rats receiving REG (II_REG) and REG+OLA (I_REG+OLA). (B). The M-5 plasma concentration–time profiles in rats receiving REG (II_REG) and REG+OLA (I_REG+OLA).

Figure 4

The OLA plasma concentration–time profiles in rats after oral administration of a single dose of OLA (100 mg/kg b.w.) to the III_OLA group and REG + OLA (20 mg/kg b.w. + 100 mg/kg b.w.) to the I_REG+OLA group.