Effect of fluconazole on the pharmacokinetics of fuzuloparib: an open-label, crossover study in Chinese healthy male volunteers

Purpose Fuzuloparib (AiRuiYi TM , formerly fluzoparib, SHR3162) is a new orally active poly adenosine diphosphate ribose polymerase (PARP) inhibitor. It has multiple pharmacological activities in breast, ovarian, and prostatic cancer. Fuzuloparib is mainly metabolized through the enzyme CYP3A4 may s...

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Vydané v:	Cancer chemotherapy and pharmacology Ročník 89; číslo 1; s. 141 - 148
Hlavní autori:	Chen, Xue, Yang, Feng, Zhao, Jiao, Tang, Qi, Heng, Jianfu, Deng, Jun, Zhang, Jin, Chen, Yong, Li, Kunyan, Wang, Jing
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2022 Springer Nature B.V
Predmet:	Adenosine Adult Antifungal agents Aspartate transaminase Breast cancer Cancer Research Clinical Trial Report Cross-Over Studies Cytochrome P-450 CYP3A Inhibitors - adverse effects Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics Fluconazole Fluconazole - adverse effects Fluconazole - pharmacokinetics Healthy Volunteers Humans Hyperlipidemia Male Medicine Medicine & Public Health Middle Aged Oncology Ovarian cancer Pharmacokinetics Pharmacology/Toxicology Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - adverse effects Poly(ADP-ribose) Polymerase Inhibitors - pharmacokinetics Prostate cancer Ribose Transaminase Fluconazole CYP3A4 Drug–drug interaction (DDI) Fuzuloparib PARP inhibitor
ISSN:	0344-5704, 1432-0843, 1432-0843
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Shrnutí:	Purpose Fuzuloparib (AiRuiYi TM , formerly fluzoparib, SHR3162) is a new orally active poly adenosine diphosphate ribose polymerase (PARP) inhibitor. It has multiple pharmacological activities in breast, ovarian, and prostatic cancer. Fuzuloparib is mainly metabolized through the enzyme CYP3A4 may slow fuzuloparib metabolism and increase its concentrations in blood. We evaluated the pharmacokinetics and tolerability of fuzuloparib by fluconazole, which is a broad antifungal agent and a moderate inhibitor of CYP3A4. Methods In this study, the effects of CYP3A4 inhibition on the pharmacokinetics of fuzuloparib were assessed in a total of 20 healthy Chinese male subjects in an open-label, two-period, single-sequence, crossover study. Results Pharmacokinetic parameters, including the maximal plasma concentration ( C max ) , the plasma concentration–time curve from time 0 to last measurable area under concentration (AUC 0−t ), and from time 0 to infinity (AUC 0−∞ ), were increased by 32.4%, 104.5%, and 109.6%, with corresponding 90% confidence intervals of (23–43%), (93–116%), and (98–122%), respectively, when fluconazole was combined with fuzuloparib compared to fuzuloparib alone. There was also a slight increase in the incidence of treatment emergent adverse events, including hyperlipidemia and elevated aspartate transaminase. Conclusion The fuzuloparib is 150 mg b.i.d in clinics use. Our results suggest that fuzuloparib could well be tolerated when administered as a single 20 mg oral dose alone or co-administered with 400 mg fluconazole in healthy male subjects. It is recommended to avoid using moderate CYP3A4 inhibitors together with fuzuloparib or instead of 50 mg when necessary.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0344-5704 1432-0843 1432-0843
DOI:	10.1007/s00280-021-04376-1