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.

Trial registration: ClinicalTrials.gov NCT03077607.

Keywords: P-glycoprotein; breast cancer; cancer; drug interaction; pharmacokinetics.

Conflict of interest statement

M.E., C.‐H.C., A.P., H.S. and D.W. are employees of Pfizer and receive stock and stock options as part of their employment.

© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1

Study design and patient assignment. BID, twice a day; EXT, extension study MDV3800–13/C3441010; FU, follow‐up; QD, once daily; PK, pharmacokinetics; SCR, screening

Figure 2

Median plasma talazoparib concentration–time profile following a single dose of talazoparib alone and with multiple doses of itraconazole (semilogarithmic, A; linear, B) or following a single dose of talazoparib with multiple doses of rifampicin (semilogarithmic, C; linear, D). Concentration values below the lower limit of quantification were set to zero. Only pharmacokinetic samples collected within the 10% of the scheduled time point are included