How do CYP3A4 inhibitors, inducers affect senaparib exposure in healthy adults?

Exposure of senaparib, a highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, is significantly increased when administered along with itraconazole and significantly decreased when taken together with rifampicin, reports a recent study involving healthy male volunteers (HMV) in China.

A phase I open-label study examined the impact of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib in adult HMV. The investigators enrolled participants to either the itraconazole (n=16) or rifampicin group (n=16).

In period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In period 2, the same dose was given together with itraconazole 200 mg and rifampicin 600 mg, respectively. Senaparib exposure parameters were the primary endpoints.

Coadministration with itraconazole resulted in a significant increase in the exposure of senaparib and in a decrease of its major metabolites M9 and M14. Maximum plasma senaparib concentration (C_max) rose by approximately 79 percent and the area under the concentration‒time curve (AUC) by about 2.8-fold.

On the other hand, coadministration with rifampicin led to a significant decrease in C_max and AUC of senaparib by about 59 percent and 83 percent, respectively. The C_max for both M9 and M14 was slightly higher, but AUC was lower.

In terms of treatment-emergent adverse events (AEs), most AEs were grade 2 or lower, regardless of the type of treatment given.

“It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4,” the investigators said.