Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology.
Article Details
- CitationCopy to clipboard
Bruin MAC, Sonke GS, Beijnen JH, Huitema ADR
Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology.
Clin Pharmacokinet. 2022 Dec;61(12):1649-1675. doi: 10.1007/s40262-022-01167-6. Epub 2022 Oct 11.
- PubMed ID
- 36219340 [ View in PubMed]
- Abstract
Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. Poly (ADP-ribose) polymerase inhibitors are potent inhibitors of the PARP enzymes with comparable half-maximal inhibitory concentrations in the nanomolar range. Olaparib and rucaparib are orally dosed twice a day, extensively metabolized by cytochrome P450 enzymes, and inhibitors of several enzymes and drug transporters with a high risk for drug-drug interactions. Niraparib and talazoparib are orally dosed once a day with a lower risk for niraparib and a minimal risk for talazoparib to cause drug-drug interactions. All four PARP inhibitors show moderate-to-high interindividual variability in plasma exposure. Higher exposure is associated with an increase in toxicity, mostly hematological toxicity. For talazoparib, exposure-efficacy relationships have been described, but for olaparib, niraparib, and rucaparib this relationship remains inconclusive. Further studies are required to investigate exposure-response relationships to improve dosing of PARP inhibitors, in which therapeutic drug monitoring could play an important role. In this review, we give an overview of the pharmacokinetic properties of the four PARP inhibitors, including considerations for patients with renal dysfunction or hepatic impairment, the effect of food, and drug-drug interactions. Furthermore, we focus on the pharmacodynamics and summarize the available exposure-efficacy and exposure-toxicity relationships.
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.