Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours.
Article Details
- CitationCopy to clipboard
Elmeliegy M, Lang I, Smolyarchuk EA, Chung CH, Plotka A, Shi H, Wang D
Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours.
Br J Clin Pharmacol. 2020 Apr;86(4):771-778. doi: 10.1111/bcp.14178. Epub 2020 Jan 7.
- PubMed ID
- 31770456 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Talazoparib ATP-binding cassette sub-family G member 2 Protein Humans UnknownSubstrateDetails Talazoparib P-glycoprotein 1 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareTalazoparibLumacaftor The serum concentration of Talazoparib can be increased when it is combined with Lumacaftor. TalazoparibIsavuconazole The serum concentration of Talazoparib can be increased when it is combined with Isavuconazole. TalazoparibVandetanib The serum concentration of Talazoparib can be increased when it is combined with Vandetanib. TalazoparibPalbociclib The serum concentration of Talazoparib can be increased when it is combined with Palbociclib. TalazoparibDacomitinib The serum concentration of Talazoparib can be increased when it is combined with Dacomitinib.