An evaluation of the drug interaction potential of netupitant with digoxin.

e19530 Background: The new, highly selective neurokinin-1 receptor antagonist netupitant (NETU) has been developed to provide protection from nausea and vomiting in patients receiving emetogenic chemotherapy. There is evidence from in vitro studies that NETU is a substrate for and a weak inhibitor of the P-glycoprotein (Pgp). Pgp plays a major role in the pharmacokinetics of digoxin (DIG), a cardiac glycoside with a narrow therapeutic index. The possible interaction between NETU and Pgp has been assessed by analysing the effect of NETU on DIG pharmacokinetics. Safety parameters have also been assessed. Methods: This study was an open-label, fixed-sequence design to evaluate the effect of NETU on DIG at steady state in 16 healthy volunteers (8 male and 8 female). A loading dose of 3 x 0.5 mg DIG (0.5 mg every 6 hours) was given on day 1, followed by a daily oral dose of 0.25 mg DIG for 11 consecutive days (days 2-12); NETU was administered as single oral dose of 450mg on day 8. Serial blood and urine samples were collected for the determination of the pharmacokinetic parameters. Physical examination, vital signs, electrocardiogram (ECG), adverse events, clinical chemistry, hematology, urinalysis, and overall tolerability were reported. Results: Based on the AUC(0-24h) parameter at steady-state, the extent of DIG exposure was not influenced by NETU coadministration. The confidence interval of Cmin was within the 80-125% equivalence limits, while the observed Cmax was slightly over 125%, which was not considered clinically relevant. The excretion of DIG in urine was 57% after NETU coadministration compared to 55% of DIG alone. There were no gender-specific differences in the extent of absorption (AUC) for DIG, and no safety-related influence of DIG or NETU was observed on safety and laboratory assessments, vital signs, or ECG parameters. Based on historical data NETU pharmacokinetics was not affected by DIG coadministration. Conclusions: No clinically relevant interactions occurred between NETU and DIG. The results of this study suggest that the coadministration of NETU with Pgp substrates may not require dose adjustments. Study treatments were well tolerated.

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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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Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01082-10 ◽

2010 ◽

Vol 55 (1) ◽

pp. 326-330 ◽

Cited By ~ 24

Author(s):

José Moltó ◽

Marta Valle ◽

Cristina Miranda ◽

Samandhy Cedeño ◽

Eugenia Negredo ◽

...

Keyword(s):

High Performance ◽

Geometric Mean ◽

Echinacea Purpurea ◽

The Body ◽

Pharmacokinetic Parameters ◽

Root Extract ◽

Open Label ◽

Fixed Sequence ◽

Time Curve ◽

Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

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Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1152 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1152-1155 ◽

Cited By ~ 16

Author(s):

Kevin W. Garey ◽

Charles A. Peloquin ◽

Paul G. Godo ◽

Anne N. Nafziger ◽

Guy W. Amsden

Keyword(s):

Steady State ◽

Healthy Subjects ◽

High Performance ◽

Pharmacokinetic Parameters ◽

Steady State Concentration ◽

Open Label ◽

Time Curve ◽

Data Analyses ◽

Concentration Time ◽

State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

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Evaluation Of Drug Interaction Profile Of Idelalisib and Its Major Circulating Metabolite, GS-563117, In Healthy Subjects

Blood ◽

10.1182/blood.v122.21.5574.5574 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5574-5574

Author(s):

Feng Jin ◽

Michelle Robeson ◽

Huafeng Zhou ◽

Candra Moyer ◽

Sibylle Wilbert ◽

...

Keyword(s):

Single Dose ◽

Vital Signs ◽

Therapeutic Index ◽

Major Metabolite ◽

Employment Equity ◽

Metabolizing Enzymes ◽

Relevant Concentration ◽

Multiple Doses ◽

Equity Ownership

Abstract Abstract 5574 Background Idelalisib (IDELA) is a potent PI3K inhibitor in Phase 3 development for hematologic malignancies. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. In vitro, IDELA inhibits Pgp (IC50: 7.7 mM), OATP1B1 (IC50: 10.1 mM), OATP1B3 (IC50: 7.0 mM), but is not an inhibitor of common metabolizing enzymes and other uptake or secretory transporters at clinically relevant concentration. GS563117 shows time-dependent inhibition of CYP3A (IC50: 5.1 mM, KI: 0.18 mM, and kinact: 0.033 min-1), but is not an inhibitor of other common metabolizing enzymes, or of uptake or secretory transporters at clinically relevant concentration. The present study evaluated the potential for IDELA to affect Pgp and OATP1B1/OATP1B3, GS-563117 to affect CYP3A, and effect of a strong inducer, rifampin, on IDELA pharmacokinetics (PK). Methods Probe substrates of Pgp (digoxin), OATP1B1/1B3 (rosuvastatin), and CYP3A (midazolam) were each given orally as a single dose either alone or in combination with multiple doses of IDELA 150 mg BID. Additionally, a single dose of IDELA 150 mg was administered either alone or in combination with multiple doses of rifampin at 600 mg QD. Plasma exposures of digoxin, rosuvastatin, midazolam and 1'-hydroxy midazolam, rifampin, IDELA, and GS-563117 were determined using LC/MS/MS. Analysis of variance (ANOVA) using a mixed-effects model was fitted to the natural logarithmic transformation of PK parameters. The 90% confidence intervals were constructed for the ratio of geometric means of PK parameters when each of the probe drugs (or IDELA) is dosed in combination with IDELA (or rifampin) versus when dosed alone, with 70-143% defined as the lack of interaction boundaries. Safety assessments were performed throughout the study. Results A total of 24 subjects were enrolled in the study and randomized to two cohorts. The majority of subjects were male, white, and median age was 38. The most frequently reported adverse events (AE) were headache (∼25% subjects) and pyrexia (∼17%). Treatment-emergent Grade 3 increase in transaminases occurred in 5/24 subjects, and were reversible. Two subjects experienced serious AE following completion of study treatment. There were no clinically significant changes in vital signs or safety ECGs. Digoxin and rosuvastatin PK were unaffected when given in combination with IDELA 150 mg BID vs dosing alone (Table 1). Coadministration with IDELA resulted in increased plasma exposures of midazolam increased and decreased 1'-OH-midazolam consistent with the in vitro finding of CYP3A inhibition by IDELA's major metabolite, GS-563117. Coadministration of IDELA with rifampin caused a substantial decrease in IDELA and GS-563117 exposures, indicating greater contribution of CYP3A to IDELA metabolism under a strongly induced state. Conclusion GS-563117, which is the major metabolite of IDELA, is a moderate inhibitor of CYP3A; accordingly, caution is necessary when coadministering narrow therapeutic index agents that are CYP3A substrates with IDELA. Coadministration of strong inducers of CYP3A with IDELA should also be avoided to prevent decreased exposure to IDELA. Overall, IDELA and its metabolite do not affect common intestinal, hepatic or renal drug transporters. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Moyer:Gilead Sciences: Employment, Equity Ownership. Wilbert:Gilead Sciences: Employment, Equity Ownership. Murray:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

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A drug-drug interaction (DDI) study to assess the effect of oral galeterone on the pharmacokinetics (PK) of oral midazolam.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.316 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 316-316

Author(s):

Karen J. Ferrante ◽

Douglas B Jacoby ◽

Daryl Sonnichsen

Keyword(s):

Geometric Mean ◽

Point Estimate ◽

Open Label ◽

Fixed Sequence ◽

Geometric Means ◽

Fda Guidance ◽

Point Estimates ◽

Oral Midazolam ◽

Androgen Binding

316 Background: Galeterone (gal) is a semisynthetic steroid that targets androgen receptor (AR) signaling via increased AR protein degradation, inhibition of CYP17 activity, and inhibition of androgen binding to AR. Gal is a novel potential treatment for prostate cancer. In vitro, gal competitively inhibits CYP3A4 (IC50 = 5.5 μM; midazolam as substrate). This clinical study evaluated whether multiple daily doses of gal alter the single-dose PK of midazolam, a sensitive probe substrate for functional CYP3A4 intestinal and hepatic activity. Methods: In an open-label, fixed sequence, DDI study, 18 healthy male volunteers received midazolam 2 mg Day 1 and Day 5 and gal 2550 mg Days 2-5. Midazolam plasma PK was determined on Days 1 and 5. The effect of gal on the natural log-transformed Cmax, AUC0-inf, and AUC0-t of midazolam was assessed with a linear mixed-effects model; point estimates for geometric means, geometric mean ratios with 90% confidence intervals were determined. Safety was also monitored. Results: The Tmax of midazolam was not altered by gal coadministration. The < 2-fold increases in midazolam Cmax and AUCs were statistically significant. For Cmax, the point estimate of the geometric least squares (LS) mean ratio between the 2 treatments was 1.25 (90% CI: 1.05, 1.48). Higher ratios were observed for the AUC ratios, with LS mean ratio for AUC0-t of 1.57 (90% CI: 1.43, 1.73) and for AUC0-inf of 1.58 (90% CI: 1.42, 1.75). The mean midazolam t1/2 was approximately 76% higher with gal coadministration. Multiple doses of gal were well tolerated with no apparent effect on the safety of midazolam. Conclusions: Per FDA guidance, < 2-fold increases in midazolam Cmax and AUCs observed with gal coadministration support its classification as a weak inhibitor of CYP3A4. Given the similar or higher in vitro IC50’s for CYP2C8 and CYP2C19, respectively, a comparable or lesser degree of enzyme inhibition is expected for gal 2550 mg daily. Based on these results, concurrent CYP3A4, CYP2C8, and CYP2C19 substrates are not contraindicated in patients taking gal; caution is advised in patients receiving or initiating sensitive CYP3A4, CYP2C8, and CYP2C19 substrates, especially those with a narrow therapeutic range.

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Effect of Steady-State Faldaprevir on Pharmacokinetics of Atorvastatin or Rosuvastatin in Healthy Volunteers: A Prospective Open-Label, Fixed-Sequence Crossover Study

The Journal of Clinical Pharmacology ◽

10.1002/jcph.931 ◽

2017 ◽

Vol 57 (10) ◽

pp. 1305-1314 ◽

Cited By ~ 7

Author(s):

Fenglei Huang ◽

Kristell Marzin ◽

Rüdiger Koenen ◽

Klaus Peter Kammerer ◽

Natalja Strelkowa ◽

...

Keyword(s):

Steady State ◽

Crossover Study ◽

Healthy Volunteers ◽

Open Label ◽

Fixed Sequence

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Efficacy, metabolism and pharmacokinetics of Ro 15-5458, a forgotten schistosomicidal 9-acridanone hydrazone

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa247 ◽

2020 ◽

Vol 75 (10) ◽

pp. 2925-2932

Author(s):

Alexandra Probst ◽

Cécile Häberli ◽

Dionicio Siegel ◽

Jianbo Huang ◽

Seth Vigneron ◽

...

Keyword(s):

Oral Dose ◽

High Activity ◽

Liver Microsomes ◽

Human Hepatocytes ◽

Pharmacokinetic Parameters ◽

Maximum Plasma ◽

Drug Induced ◽

Stage Specificity ◽

Human And Mouse

Abstract Background Treatment of schistosomiasis, a neglected disease, relies on just one partially effective drug, praziquantel. We revisited the 9-acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound. Methods Ro 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice. We studied dose–response, hepatic shift and stage specificity. The metabolic stability of Ro 15-5458 was measured in the presence of human and mouse liver microsomes, and human hepatocytes; the latter also served to identify metabolites. Pharmacokinetic parameters were measured in naive mice. The efficacy of Ro 15-5458 was also assessed in S. haematobium-infected hamsters and S. japonicum-infected mice. Results Ro 15-5458 had single-dose ED50 values of 15 and 5.3 mg/kg in mice harbouring juvenile and adult S. mansoni infections, respectively. An ED50 value of 17 mg/kg was measured in S. haematobium-infected hamsters; however, the compound was inactive at up to 100 mg/kg in S. japonicum-infected mice. The drug-induced hepatic shift occurred between 48 and 66 h post treatment. A single oral dose of 50 mg/kg of Ro 15-5458 had high activity against all tested S. mansoni stages (1-, 7-, 14-, 21- and 49-day-old). In vitro, human hepatocytes produced N-desethyl and glucuronide metabolites; otherwise Ro 15-5458 was metabolically stable in the presence of microsomes or whole hepatocytes. The maximum plasma concentration was approximately 8.13 μg/mL 3 h after a 50 mg/kg oral dose and the half-life was approximately 4.9 h. Conclusions Ro 15-5458 has high activity against S. mansoni and S. haematobium, yet lacks activity against S. japonicum, which is striking. This will require further investigation, as a broad-spectrum antischistosomal drug is desirable.

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The effect of multiple doses of ubrogepant on the pharmacokinetics of an oral contraceptive in healthy women: Results of an open-label, single-center, two-period, fixed-sequence study

Cephalalgia Reports ◽

10.1177/2515816320905082 ◽

2020 ◽

Vol 3 ◽

pp. 251581632090508 ◽

Cited By ~ 1

Author(s):

Chi-Chung Li ◽

John Palcza ◽

Jialin Xu ◽

Bob Thornton ◽

Wendy Ankrom ◽

...

Keyword(s):

Oral Contraceptive ◽

Drug Interactions ◽

Ethinyl Estradiol ◽

Geometric Mean ◽

Pharmacokinetic Parameters ◽

Adult Women ◽

Single Center ◽

Open Label ◽

Fixed Sequence ◽

Sequence Study

Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist for acute treatment of migraine. This study evaluated potential drug–drug interactions between ubrogepant and an oral contraceptive containing ethinyl estradiol (EE) and norgestimate (NGM). Methods: This open-label, single-center, two-period, fixed-sequence study enrolled healthy, postmenopausal or oophorectomized, adult women. In period 1, participants received a single oral dose of EE 0.035 mg/NGM 0.25 mg (EE-NGM) followed by a 7-day washout. In period 2, participants received oral ubrogepant 50 mg daily on days 1–14; single-dose EE-NGM was coadministered with ubrogepant on day 10. Pharmacokinetic parameters for plasma EE and norelgestromin (NGMN) were compared with and without ubrogepant. Results: Twenty-two participants aged 46–66 years were enrolled; 21 completed the study. Geometric mean ratios and 90% confidence intervals for the comparison of EE-NGM + ubrogepant to EE-NGM alone were contained within 0.80 and 1.25 for area under the plasma drug concentration–time curve (AUC) from time zero to infinity (AUC0–∞; 0.96 [0.91, 1.01]) and C max (0.91 [0.82, 1.004]) of NGMN and AUC0–∞ (0.97 [0.93, 1.01]) of EE, but not C max of EE (0.74 [0.69, 0.79]). Median t max of EE was delayed following EE-NGM + ubrogepant (3.0 h) versus EE-NGM alone (median of 1.5 h), whereas median t max of NGMN was unchanged (1.5 h). Geometric mean apparent terminal half-life ( t ½) was similar with and without ubrogepant for EE (23 vs. 21 h) and NGMN (36 h both conditions). All ubrogepant-related adverse events were mild or moderate. Conclusion: Ubrogepant did not demonstrate potential for clinically meaningful drug–drug interactions with an EE-NGM oral contraceptive. Trial registration: Not applicable (phase 1 trial)

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Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.1.30-37.2001 ◽

2001 ◽

Vol 45 (1) ◽

pp. 30-37 ◽

Cited By ~ 77

Author(s):

Brian M. Sadler ◽

Catherine Gillotin ◽

Yu Lou ◽

Daniel S. Stein

Keyword(s):

Human Immunodeficiency Virus ◽

Steady State ◽

Dose Range ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Pharmacokinetic Data ◽

Protease Enzyme ◽

Immunodeficiency Virus

ABSTRACT In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (C max,ss,C min,ss, and C avg,ss, respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0→∞ decreased linearly with dose and correlated significantly with treatment-associated decreases in α1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir Cmin,ss (0.280 μg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 μg/ml), even after adjustment for protein binding. The median amprenavir C min,sswas also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 μg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C max. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

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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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