Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC‐0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor

Herman, Ann; Chinn, Leslie W.; Kotwal, Shweta G.; Murray, Elaine R.; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian; Hanze, Eva; Viberg, Anders; Morimoto, Alyssa; Winter, Helen; Katsumoto, Tamiko R.

doi:10.1002/cpt.1056

Cited by 58 publications

(59 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The pharmacokinetics (PK) of fenebrutinib was characterized previously in healthy subjects in a Phase 1 trial, and plasma concentrations peaked 1-3 h after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 h (22). In the Phase 1 trial, fenebrutinib plasma exposures were found to increase approximately doseproportionally with modest accumulation following twice daily dosing.…”

Section: Bruton's Tyrosine Kinase (Btk) and Fenebrutinibmentioning

confidence: 96%

“…Fenebrutinib (GDC-0853, RG7845) is an orally administered BTK inhibitor that is highly selective and noncovalent, leading to reversible binding, intended to block B cell proliferation and the resulting excessive immune response seen in autoimmune disorders (21). Fenebrutinib has previously been evaluated in healthy subjects (22) and patients with resistant B cell lymphoma or chronic lymphocytic leukemia (23).…”

Section: Bruton's Tyrosine Kinase (Btk) and Fenebrutinibmentioning

confidence: 99%

See 1 more Smart Citation

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Chan¹,

Yu²,

Chinn³

et al. 2020

Pharm Res

View full text Add to dashboard Cite

Purpose Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis (RA). Our aim was to apply a model-informed drug development (MIDD) approach to examine the totality of available clinical efficacy data. Methods Population pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based metaanalysis (MBMA) of fenebrutinib were performed based on the Phase 2 data. Results PopPK of fenebrutinib after oral administration was described using a 3-compartment model with linear elimination and a flexible absorption transit compartment model. Healthy subjects had a 52% higher apparent clearance than patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 (CRP) data modeled fenebrutinib effect with an E max function, and an efficacy plateau was achieved within the exposure range obtained in the Phase 2 clinical trial. Based on literature data, a summary-level clinical efficacy database was constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the placebo and adalimumab arms of the Phase 2 clinical trial were found to be consistent with historical data for these treatments. Conclusions Our multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial. KEY WORDS Bruton's tyrosine kinase (BTK) inhibitor. exposure-response. model-based meta-analysis. population pharmacokinetics. rheumatoid arthritis ABBREVIATIONS AUC Area under the concentration-time curve BTK Bruton's tyrosine kinase CL/F Apparent clearance C max Maximum concentration C min Trough concentration CRP C-reactive protein DAS28 Disease Activity Score with 28-joint counts EBE Empirical Bayes estimates E-R Exposure-response F1 Relative extent of absorption FOCE-I First order conditional estimation with interaction MBMA Model-based meta-analysis MIDD Model-informed drug development MTT Mean transit time MTX Methotrexate NLME Non-linear mixed effects NTR Number of transit compartments pcVPC Prediction-corrected visual predictive check PD Pharmacodynamic The original version of this article was revised: The article was published with an incomplete title. The complete title is "Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis".

show abstract

Section: Bruton's Tyrosine Kinase (Btk) and Fenebrutinibmentioning

confidence: 96%

Section: Bruton's Tyrosine Kinase (Btk) and Fenebrutinibmentioning

confidence: 99%

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Chan¹,

Yu²,

Chinn³

et al. 2020

Pharm Res

View full text Add to dashboard Cite

show abstract

“…The dosing regimens of fenebrutinib were selected based on pharmacokinetic/pharmacodynamic modeling of BTK inhibition based on results from ascending dose studies in healthy subjects (16) with the goal of achieving plasma concentrations reaching at least IC 70 , as this extent of inhibition was correlated with efficacy in a rat collagen-induced arthritis model (15).…”

Section: Methodsmentioning

confidence: 99%

“…Fenebrutinib appears unique due to its high selectivity (for BTK versus nontarget kinases) relative to other BTK inhibitors as well as its noncovalent binding mode (15). Phase I clinical studies have shown fenebrutinib to be well-tolerated with no safety signals precluding further clinical development (16,17).…”

Section: Introductionmentioning

confidence: 99%

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Tuckwell¹,

Katsumoto

Zhao³

et al. 2020

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

show abstract

“…The in vitro cellular potency of fenebrutinib was determined to be 11 nM for the inhibition of BTK autophosphorylation in human whole blood obtained from healthy subjects. Additionally, target engagement has been demonstrated in a multiple ascending dose study in healthy subjects, where a maximal inhibition above 90% was seen in BTK autophosphorylation and basophil assays (Herman et al, 2018).…”

Section: Introductionmentioning

confidence: 97%

Absence of Pharmacokinetic Interactions between the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate

Jones

Winter

Katsumoto

et al. 2019

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of Bruton's tyrosine kinase being investigated for treatment of rheumatoid arthritis in patients with inadequate responses to methotrexate (MTX). This study interrogated the potential for pharmacokinetic drug interactions between fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study. They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day washout period. Subsequently, on days 15-20 the participants received 200 mg of fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a 200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios of MTX area under the plasma concentration-time curve (AUC) and C max on day 21 relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05 (0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02 (0.90-1.15), respectively. The combination treatment was well tolerated, with an adverse event profile similar to that reported in other MTX trials. These results indicate that there is no clinically significant pharmacokinetic interaction between fenebrutinib and MTX.

show abstract

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC‐0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor

Cited by 58 publications

References 30 publications

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis

Fenebrutinib Versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double‐Blind, Phase II Trial

Absence of Pharmacokinetic Interactions between the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate

Contact Info

Product

Resources

About