Absolute Bioavailability of Esaxerenone and Food Effects on its Pharmacokinetics After a Single Oral Dose in Healthy Japanese Subjects: An Open-Label Crossover Study

Abstract Background Antimicrobial resistance to available oral antibiotics is becoming progressively more common, precipitating the need for additional treatment options as step-down from initial intravenous (IV) therapy as well as for treatment of infections in the community. Sulopenem (CP-70,429) is a thiopenem antibiotic active against quinolone non-susceptible and ESBL-producing Enterobacteriaceae. As the key pharmacokinetic-pharmacodynamic variable correlating with efficacy for penem antibiotics is time above minimum inhibitory concentration (T > MIC), we examined the utility of probenecid, an OAT-1 inhibitor of β-lactam excretion, on the pharmacokinetic (PK) parameters for the oral prodrug of sulopenem, sulopenem etzadroxil Methods Twelve healthy males and females received a single oral dose of 500 mg sulopenem etzadroxil as powder in bottle either alone or co-administered with a single oral dose of probenecid 500 mg in a crossover design with a washout period of 6 days. All doses were administered under fasting conditions. Blood samples for plasma PK analysis were collected and PK parameters for sulopenem, the parent compound of sulopenem etzadroxil, were determined. Results Treatment Conclusion Probenecid increases the AUC of sulopenem by 28% in the fasted state and extends the mean time over MIC. Disclosures M. Dunne, Iterum Therapeutics: Employee and Shareholder, Salary. S. Aronin, Iterum Therapeutics: Employee and Shareholder, Salary. E. Dunzo, Parexel: Consultant, Consulting fee. S. Puttagunta, Iterum Therapeutics: Employee and Shareholder, Salary.

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Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-019-04015-w ◽

2019 ◽

Vol 85 (2) ◽

pp. 391-399 ◽

Cited By ~ 6

Author(s):

Song Mu ◽

Zhiyu Tang ◽

William Novotny ◽

Manal Tawashi ◽

Ta-Kai Li ◽

...

Keyword(s):

Steady State ◽

Oral Dose ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Single Oral Dose ◽

Kinase Inhibitor ◽

Clinical Activity ◽

Bruton’S Tyrosine Kinase ◽

Open Label ◽

Bruton's Tyrosine Kinase

Abstract Purpose Zanubrutinib (BGB-3111) is a potent Bruton’s tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown to be mainly metabolized through cytochrome P450 3A (CYP3A) in vitro. We evaluated the effect of steady-state rifampin (a strong CYP3A inducer) and steady-state itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics (PK), safety, and tolerability of zanubrutinib in healthy Asian and non-Asian subjects. Methods In this open-label, two-part clinical study, 20 participants received a single oral dose of zanubrutinib (320 mg) and oral rifampin (600 mg) in Part A, and 18 participants received a single oral dose of zanubrutinib (20 mg) and oral itraconazole (200 mg) in Part B. Serial blood samples were collected after administration of zanubrutinib alone and zanubrutinib in combination with rifampin or itraconazole for the measurement of PK parameters. Results Coadministration with rifampin decreased AUC0–∞ of zanubrutinib by 13.5-fold and Cmax by 12.6-fold. Coadministration with itraconazole increased the AUC0–∞ of zanubrutinib by 3.8-fold and Cmax by 2.6-fold. The PK of zanubrutinib was consistent between Asian and non-Asian subjects, and zanubrutinib was well tolerated in this study. Conclusions These results confirm that zanubrutinib is primarily metabolized by CYP3A in humans. The PK of zanubrutinib was comparable between Asian and non-Asian subjects and, therefore, no dose modifications are necessary for zanubrutinib in these ethnic populations.

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Effects of the Chinese Herbal Formulation (Liu Wei Di Huang Wan) on the Pharmacokinetics of Isoflavones in Postmenopausal Women

BioMed Research International ◽

10.1155/2015/902702 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Wirin Limopasmanee ◽

Sunee Chansakaow ◽

Noppamas Rojanasthien ◽

Maleeya Manorot ◽

Chaichan Sangdee ◽

...

Keyword(s):

Plasma Concentration ◽

Oral Dose ◽

Single Oral Dose ◽

Postmenopausal Women ◽

Pharmacokinetic Parameters ◽

Soy Milk ◽

Open Label ◽

Fixed Sequence ◽

Time Curve ◽

Oral Doses

A combination of soy isoflavones andLiu Wei Di Huang Wan(LWDHW) is potentially effective for postmenopausal women with intolerable vasomotor episodes who are not suitable candidates for hormonal therapy. The objective of this open-label, three-phase, crossover study was to determine the influence of both single and multiple oral doses of LWDHW on isoflavone pharmacokinetics in healthy postmenopausal women. Eleven subjects were assigned to receive the following regimens in a fixed sequence with washout periods of at least one week: Phase A, a single oral dose of soy milk; Phase B, a single oral dose of soy milk coadministered with LWDHW; and Phase C, multiple oral doses of LWDHW for 14 days followed by a single oral dose of soy milk. Blood samples were collected and mixed withβ-glucuronidase/sulfatase to hydrolyze isoflavone conjugates to their respective aglycones (i.e., daidzein and genistein) and were determined using high performance liquid chromatography. The pharmacokinetic parameters analyzed were maximal plasma concentrationCmax, time to reach peak concentrationTmax, area under the plasma concentration-time curve (AUC), and half-life (t1/2). The results found no statistically significant differences in pharmacokinetic parameters of daidzein and genistein among the three regimens.

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