Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study
Aims: This phase I open-label study aimed to evaluate the effects of multiple oral doses of itraconazole, a potent CYP3A4 inhibitor, and rifampicin, a CYP3A4 inducer, on the pharmacokinetics of a single oral dose of senaparib. Senaparib is a novel and highly potent poly-(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor and a known substrate of CYP3A4. The study was conducted in healthy male Chinese volunteers (HMV) to better understand how these drugs interact.
Methods: Adult healthy male volunteers were enrolled into either the itraconazole (n = 16) or rifampicin (n = 16) group. In Period 1, each participant received a single oral dose of 40 mg senaparib (itraconazole group) or 100 mg senaparib (rifampicin group). In Period 2, the same dose of senaparib was coadministered with itraconazole (200 mg) or rifampicin (600 mg), respectively. The primary endpoints were the pharmacokinetic parameters of senaparib exposure, including maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC).
Results: Coadministration of senaparib with itraconazole resulted in a significant increase in senaparib exposure, as indicated by an approximate 79% increase in Cmax and a 2.8-fold increase in AUC. In contrast, coadministration with rifampicin significantly reduced both Cmax and AUC of senaparib by about 59% and 83%, respectively. For its major metabolites, M9 and M14, the Cmax was slightly increased, but AUC was reduced in both cases. All treatment-emergent adverse events were mild (grade ≤2), irrespective of the treatment administered.
Conclusion: In Chinese healthy male volunteers, the exposure to senaparib was notably increased when coadministered with the CYP3A4 inhibitor itraconazole and significantly reduced when coadministered with the CYP3A4 inducer rifampicin. These findings suggest that concomitant use of senaparib with strong CYP3A4 inhibitors or inducers should be avoided to prevent altered pharmacokinetics and potential changes in therapeutic efficacy.