Evaluation of the effect of P‐glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours

Abstract

Aims In vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed. Methods Thirty‐six patients were enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin], n = 17). Patients in both arms received 2 single oral doses of talazoparib (0.5 mg, Arm A; 1 mg, Arm B) alone and with multiple daily oral doses of itraconazole (Arm A) or rifampicin (Arm B). Results Coadministration of itraconazole and talazoparib increased talazoparib area under the plasma concentration–time profile from time 0 extrapolated to infinity by ~56% and maximum observed plasma concentration by ~40% relative to talazoparib alone. Coadministration of rifampicin and talazoparib increased talazoparib maximum observed plasma concentration by approximately 37% (geometric mean ratio 136.6% [90% confidence interval 103.2–180.9]); area under the curve was not affected relative to talazoparib alone (geometric mean ratio 102.0% [90% confidence interval 94.0–110.7]). Talazoparib had an overall safety profile consistent with that observed in prior studies in which talazoparib was administered as a single dose. Conclusion Coadministration of itraconazole increased talazoparib plasma exposure compared to talazoparib alone. A reduced talazoparib dose is recommended if coadministration of potent P‐gp inhibitors cannot be avoided. Similar exposure was observed when talazoparib was administered alone and with rifampicin suggesting that the effect of rifampicin on talazoparib exposure is limited.

The Effect of Renal Impairment on the Pharmacokinetics and Safety of Talazoparib in Patients with Advanced Solid Tumors

“…Considering the prolonged half-life of talazoparib (101.3 h) [ 12 ] and that multiple-dose PK parameters were the primary endpoints of this study, only PK results after multiple administrations of talazoparib (Day 22) are presented in this manuscript (Table 2 ). The PK results after a single dose of talazoparib (Day 1) are provided in Electronic Supplementary Table 2 for completeness.…”

“…The pharmacokinetic (PK) profile of talazoparib has been characterized in prior clinical studies conducted in patients with advanced tumors [9][10][11][12]. In these studies, talazoparib was rapidly absorbed following oral administration, with a median time to first occurrence of maximum observed plasma concentration (T max ) ranging from approximately 1.0 to 2.0 h postdose [9,11].…”

Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules

“…ITC acts mainly by inhibiting the Hedgehog (Hh) pathway (Wei et al., 2020 ), tumor growth and angiogenesis and by inducting apoptosis and autophagy (Li et al., 2019 ; Wei et al., 2020 ). ITC also inhibits the P-glycoprotein efflux pump, reversing chemoresistance (Correia et al., 2018 ; Elmeliegy et al., 2020 ). Prospective clinical trials of different cancers including prostate cancer, basal cell carcinoma, ovarian cancer, and triple-negative breast cancer documented clinical benefits of ITC (Tsubamoto et al., 2017 ).…”

Radiosynthesis and Evaluation of Talazoparib and Its Derivatives as PARP-1-Targeting Agents

“…Even though no data is available for the retention of radiolabeled rucaparib derivatives-[ 18 F]FTT [ 7 ] and [ 125 I]KX1 [ 31 ] in tumors over 2 h, the fast clearance of radioactivity from spleens after 2 h and before 4 h indicates that the retention of radioactivity in targets will be less than 4 h. The long retention of [ 18 F]talazoparib in the tumors is consistent with literature reports: (1) Talazoparib significantly attenuated intratumoral PAR concentration at 2 and 8 h time points, with a partial recovery at 24 h [ 20 ]; (2) Pretreatment with talazoparib can block PARP-1 radioligand uptake up to 24 h before the administration of the radioligand [ 32 ]. Radioactivity was cleared from the blood within 4 h. High uptake of [ 18 F]talazoparib, however, was observed in the liver, spleen, kidney, and pancreas after 4 h and was only slightly reduced at 8 h. In general, high uptake in the above organs was commonly observed at early times for previously reported PARP-1 radioligands but quickly washed out after 2 h. Since talazoparib has been reported as a substrate of P-glycoprotein (P-gp) [ 33 ], brain uptake was extremely low (0.05 ± 0.01 %ID/gram at 4 h), which is consistent with other reports [ 34 ]. The uptake in bone marrow is high at 4 and 8 h, and bone marrow toxicity is reported for talazoparib.…”

“…(2) Pretreatment with talazoparib can block PARP-1 radioligand uptake up to 24 h before the administration of the radioligand [32]. Radioactivity was cleared from the blood within 4 h. High uptake of [ 18 F]talazoparib, however, was observed in the liver, spleen, kidney, and pancreas after 4 h and was only slightly reduced at 8 h. In general, high uptake in the above organs was commonly observed at early times for previously reported PARP-1 radioligands but quickly washed out after 2 h. Since talazoparib has been reported as a substrate of P-glycoprotein (P-gp) [33], brain uptake was extremely low (0.05 ± 0.01 %ID/gram at 4 h), which is consistent with other reports [34]. The uptake in bone marrow is high at 4 and 8 h, and bone marrow toxicity is reported for talazoparib.…”