ABSTRACT
BACKGROUND: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI. METHODS: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200â mg twice daily) or vancomycin (125â mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs. RESULTS: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (â¼3.5-fold), and increased the resistome. CONCLUSIONS: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.
Subject(s)
Anti-Bacterial Agents , Clostridioides difficile , Clostridium Infections , Gastrointestinal Microbiome , Vancomycin , Humans , Vancomycin/therapeutic use , Vancomycin/adverse effects , Clostridium Infections/drug therapy , Clostridium Infections/microbiology , Male , Female , Middle Aged , Double-Blind Method , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/adverse effects , Aged , Clostridioides difficile/drug effects , Gastrointestinal Microbiome/drug effects , Adult , Treatment Outcome , Metabolome/drug effects , Oxadiazoles/therapeutic use , Oxadiazoles/adverse effects , Dysbiosis/chemically induced , Benzimidazoles , PyridinesABSTRACT
Ibrutinib may inhibit intestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 µg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.
Subject(s)
Adenine/analogs & derivatives , Contraceptives, Oral/administration & dosage , Cytochrome P-450 CYP2B6/metabolism , Cytochrome P-450 CYP3A/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, B-Cell, Marginal Zone/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Piperidines/administration & dosage , Waldenstrom Macroglobulinemia/drug therapy , Adenine/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Area Under Curve , Bupropion/administration & dosage , Bupropion/pharmacokinetics , Contraceptives, Oral/pharmacokinetics , Drug Interactions , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/pharmacokinetics , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Levonorgestrel/administration & dosage , Levonorgestrel/pharmacokinetics , Lymphoma, B-Cell, Marginal Zone/blood , Lymphoma, B-Cell, Marginal Zone/metabolism , Lymphoma, Mantle-Cell/blood , Lymphoma, Mantle-Cell/metabolism , Metabolic Clearance Rate , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Middle Aged , Waldenstrom Macroglobulinemia/blood , Waldenstrom Macroglobulinemia/metabolismABSTRACT
Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is approved in the US and EU for the treatment of various B-cell malignancies. In clinical studies, BTK inhibitors have been associated with increased bleeding risk, which may result from BTK inhibition in platelets.Methods: To better understand the mechanism of ibrutinib in bleeding events, we isolated platelet-rich plasma from healthy donors (n = 8) and donors with conditions associated with impaired platelet function or with potentially increased bleeding risk (on hemodialysis, taking aspirin, or taking warfarin; n = 8 each cohort) and used light transmission aggregometry to assess platelet aggregation in vitro after exposure to escalating concentrations of ibrutinib, spanning and exceeding the pharmacologic range of clinical exposure.Results: Platelet aggregation was induced by agonists of 5 major platelet receptors: adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP6), ristocetin, collagen, or arachidonic acid (AA). Platelet aggregation induced by ADP, TRAP6, ristocetin, and AA was not meaningfully inhibited by the maximal concentrations of ibrutinib (10â µM). In contrast, collagen-induced platelet aggregation was dose-dependently inhibited by ibrutinib in all donor cohorts (maximum aggregation % with 10â µM ibrutinib, -64% to -83% of agonist activity compared to control agonist samples but without ibrutinib).Conclusion: These results confirm prior reports and support a mechanistic role for the inhibition of collagen-induced platelet aggregation in bleeding events among susceptible individuals receiving ibrutinib therapy.
Subject(s)
Blood Platelets/drug effects , Platelet Aggregation Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Adult , Aged , Female , Humans , Male , Middle Aged , Piperidines , Platelet Aggregation Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Tissue Donors , Young AdultABSTRACT
OBJECTIVES: Bruton's tyrosine kinase (BTK) and tyrosine kinase expressed in hepatocellular carcinoma (TEC) are expressed by human platelets. These kinases participate in platelet activation through the collagen receptor glycoprotein VI and may perform overlapping functions. In clinical studies, BTK inhibitors (ibrutinib, acalabrutinib, tirabrutinib, zanubrutinib) have been associated with increased bleeding risk, which may result from inhibition of BTK alone or of both BTK and TEC, although the role of TEC in bleeding risk remains unclear. METHODS: Here, in vitro catalytic and binding activities of ibrutinib and acalabrutinib were determined with four assay systems. Platelet aggregation assays determined inhibitor potency and its relationship to selectivity between BTK and TEC. RESULTS: Neither inhibitor was substantially more selective for BTK over TEC. The potencies at which BTK inhibitors suppressed platelet aggregation correlated with the potencies in on-target BTK assays, including those in cells. At clinically relevant plasma concentration, ibrutinib, acalabrutinib, and tirabrutinib inhibited collagen-induced platelet aggregation to a similar extent, despite differing in vitro IC50 s. CONCLUSIONS: Our results suggest BTK inhibition is the primary driver for inhibition of platelet aggregation. The subtle differences between these inhibitors suggest only randomized, double-blind, placebo-controlled clinical studies can fully address the bleeding risks of different BTK inhibitors.
ABSTRACT
PURPOSE: This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib's pharmacokinetics (PK) in healthy participants. METHODS: This open-label, sequential-design study included 20 healthy adults aged 18-55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3-6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib's PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model. RESULTS: AUC48h and AUClast of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1-116.3] and 92.5% [77.8-109.9], respectively); Cmax decreased by 62.5% (GMR [90% CI] 37.5% [26.4-53.4]), with delayed tmax (1-2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased Cmax on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study. CONCLUSIONS: The decrease in Cmax without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib's bioavailability. No dose adjustments are recommended during ibrutinib's co-administration with omeprazole or other pH-altering agents.
Subject(s)
Omeprazole/pharmacology , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Adult , Drug Interactions , Female , Humans , Hydrogen-Ion Concentration/drug effects , Male , Middle Aged , Models, Biological , Omeprazole/adverse effects , Omeprazole/blood , Piperidines , Proton Pump Inhibitors/blood , Proton Pump Inhibitors/pharmacology , Pyrazoles/adverse effects , Pyrazoles/blood , Pyrimidines/adverse effects , Pyrimidines/bloodABSTRACT
This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , B-Lymphocytes/pathology , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Hematologic Neoplasms/drug therapy , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Adenine/analogs & derivatives , Administration, Oral , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A Inhibitors/therapeutic use , Diarrhea/chemically induced , Diarrhea/epidemiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Erythromycin/pharmacology , Erythromycin/therapeutic use , Female , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Humans , Male , Middle Aged , Neutropenia/chemically induced , Neutropenia/epidemiology , Piperidines , Polymorphism, Single Nucleotide , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Voriconazole/pharmacology , Voriconazole/therapeutic useABSTRACT
The author would like to correct the affiliations and conflict of interest in the publication of the original article. The corrected details are given below for your reading.
ABSTRACT
PURPOSE: Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. METHODS: Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. RESULTS: No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max. Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. CONCLUSIONS: Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.
Subject(s)
Electrocardiography/drug effects , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Adolescent , Adult , Female , Healthy Volunteers , Humans , Male , Middle Aged , Piperidines , Young AdultABSTRACT
Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of â¼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or TP53 status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Antineoplastic Agents/administration & dosage , Disease-Free Survival , Dose-Response Relationship, Drug , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Mutation , Patient Compliance , Piperidines , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Tumor Suppressor Protein p53/geneticsABSTRACT
This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUClast; unbound) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child-Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).
Subject(s)
Liver Diseases/complications , Neoplasms/complications , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Adult , Aged , Area Under Curve , Biomarkers , Drug Monitoring , Female , Humans , Incidence , Liver Diseases/blood , Liver Diseases/diagnosis , Liver Diseases/epidemiology , Liver Function Tests , Male , Middle Aged , Neoplasms/blood , Piperidines , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines/adverse effects , Severity of Illness IndexABSTRACT
Ibrutinib is a potent, small-molecule Bruton tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nmol/L); in addition, the IC50s were lower than that of lapatinib and dacomitinib. Inhibition of cell growth by ibrutinib coincided with downregulation of phosphorylation on HER2 and EGFR and their downstream targets, AKT and ERK. Irreversible inhibition of HER2 and EGFR in breast cancer cells was established after 30-minute incubation above 100 nmol/L or following 2-hour incubation at lower concentrations. Furthermore, ibrutinib inhibited recombinant HER2 and EGFR activity that was resistant to dialysis and rapid dilution, suggesting an irreversible interaction. The dual activity toward TEC family (BTK and ITK) and ERBB family kinases was unique to ibrutinib, as ERBB inhibitors do not inhibit or covalently bind BTK or ITK. Xenograft studies with HER2+ MDA-MB-453 and BT-474 cells in mice in conjunction with determination of pharmacokinetics demonstrated significant exposure-dependent inhibition of growth and key signaling molecules at levels that are clinically achievable. Ibrutinib's unique dual spectrum of activity against both TEC family and ERBB kinases suggests broader applications of ibrutinib in oncology. Mol Cancer Ther; 15(12); 2835-44. ©2016 AACR.
Subject(s)
Antineoplastic Agents/pharmacology , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Adenine/analogs & derivatives , Animals , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Cycle , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , ErbB Receptors/metabolism , Female , Humans , Mice , Piperidines , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Tumor Burden , Xenograft Model Antitumor AssaysABSTRACT
AIMS: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. METHODS: All participants received treatment A [560 mg oral ibrutinib, under fasting conditions], B (560 mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140 mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100 µg (13) C6 -ibrutinib was administered 2 h after each oral dose. RESULTS: The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. CONCLUSION: The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30 min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Citrus paradisi/chemistry , Food-Drug Interactions , Fruit and Vegetable Juices , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Administration, Oral , Adolescent , Adult , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Area Under Curve , Biological Availability , Carbon Isotopes , Cross-Over Studies , Dose-Response Relationship, Drug , Fasting , Female , Healthy Volunteers , Humans , Injections, Intravenous , Male , Middle Aged , Piperidines , Pyrazoles/administration & dosage , Pyrazoles/blood , Pyrimidines/administration & dosage , Pyrimidines/blood , Time Factors , Young AdultABSTRACT
Ronald de Vries graduated in Organic and Analytical Chemistry at the Free University of Amsterdam, The Netherlands. After working in a Contract Laboratory (CRO) for 7 years, he joined Janssen R&D in 1998. At Janssen R&D, Belgium, Ronald worked in the bioanalytical department that supports both clinical and nonclinical bioanalysis. In this department he had several roles, such as providing the bioanalytical support for various drug development programs and leading the method establishment group. He has done numerous global assay transfers to/from Janssen from/to other laboratories and plays an important role in the introduction and application of new technologies and applied innovation in the department. In 2014 he started in the drug metabolism and pharmacokinetics department of Janssen R&D, where his main tasks are in vivo and in vitro metabolite identification using high resolution MS and Radiodetection.
Subject(s)
Blood Chemical Analysis/methods , Pyrazoles/blood , Pyrimidines/blood , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Bile Acids and Salts/chemistry , Blood Chemical Analysis/standards , Calibration , Chromatography, High Pressure Liquid/standards , Humans , Liver Diseases/metabolism , Liver Diseases/pathology , Piperidines , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Pyrazoles/metabolism , Pyrimidines/metabolism , Quality Control , Tandem Mass Spectrometry/standards , Taurocholic Acid/chemistryABSTRACT
Ibrutinib (PCI-32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B-cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose-normalized (DN) exposure [DN-AUClast: 24-fold; DN-C max: 29-fold], rifampin decreased ibrutinib exposure [C max: 13-fold; AUClast: 10-fold]. Under nonfasted condition, GFJ caused a moderate increase [DN-C max: 3.5-fold; DN-AUC: 2.2-fold], most likely through inhibition of intestinal CYP3A. Half-life was not affected by CYP perpetrators indicating the interaction was mainly on first-pass extraction. All treatments were well-tolerated.
ABSTRACT
PURPOSE: To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. METHODS: Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participants. RESULTS: Administration of single-dose ibrutinib under fasting conditions (study 1) resulted in approximately 60 % of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (≥30 min before or 2 h after), exposures were slightly (≈30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied. CONCLUSIONS: Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib.
Subject(s)
Food-Drug Interactions , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Administration, Oral , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cross-Over Studies , Fasting/metabolism , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Male , Middle Aged , Piperidines , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/blood , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/bloodABSTRACT
PURPOSE: Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients. METHODS: Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling. RESULTS: A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively. CONCLUSIONS: The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Models, Biological , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Adult , Agammaglobulinaemia Tyrosine Kinase , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Biological Availability , Cohort Studies , Cross-Over Studies , Dose-Response Relationship, Drug , Female , Food-Drug Interactions , Half-Life , Humans , Intestinal Absorption , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Lymphoma, Mantle-Cell/blood , Lymphoma, Mantle-Cell/metabolism , Male , Middle Aged , Piperidines , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/administration & dosage , Pyrazoles/blood , Pyrazoles/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/blood , Pyrimidines/therapeutic useABSTRACT
The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of ¹4C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At Cmax of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC(0-24 h) and AUC(0-72 h), respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Intestinal Absorption , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Adenine/analogs & derivatives , Adenine/analysis , Adenine/blood , Adenine/urine , Administration, Oral , Adult , Agammaglobulinaemia Tyrosine Kinase , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/analysis , Biotransformation , Carbon Radioisotopes , Feces/chemistry , Half-Life , Humans , Hydrolysis , Hydroxylation , Intestinal Elimination , Male , Metabolic Clearance Rate , Middle Aged , Oxidation-Reduction , Piperidines , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/analysis , Protein-Tyrosine Kinases/metabolism , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrazoles/analysis , Pyrazoles/blood , Pyrazoles/urine , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/analysis , Renal EliminationABSTRACT
BACKGROUND: The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells. METHODS: We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg. RESULTS: Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%. CONCLUSIONS: Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).
Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Adult , Agammaglobulinaemia Tyrosine Kinase , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Disease-Free Survival , Female , Humans , Male , Middle Aged , Piperidines , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/adverse effects , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Recurrence , Remission Induction , Treatment OutcomeABSTRACT
Gabapentin enacarbil (GEn) is an actively transported prodrug of gabapentin that provides sustained dose-proportional exposure to gabapentin and predictable bioavailability. Gabapentin enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages.
Subject(s)
Amines/pharmacokinetics , Carbamates/pharmacokinetics , Cyclohexanecarboxylic Acids/pharmacokinetics , Models, Biological , Prodrugs/pharmacokinetics , gamma-Aminobutyric Acid/analogs & derivatives , Adolescent , Adult , Aged , Aged, 80 and over , Amines/administration & dosage , Amines/adverse effects , Carbamates/administration & dosage , Carbamates/adverse effects , Cyclohexanecarboxylic Acids/administration & dosage , Cyclohexanecarboxylic Acids/adverse effects , Female , Gabapentin , Humans , Male , Middle Aged , Prodrugs/administration & dosage , Prodrugs/adverse effects , Restless Legs Syndrome/blood , Restless Legs Syndrome/drug therapy , Sleep Initiation and Maintenance Disorders/blood , Sleep Initiation and Maintenance Disorders/drug therapy , Sleep Initiation and Maintenance Disorders/metabolism , Young Adult , gamma-Aminobutyric Acid/administration & dosage , gamma-Aminobutyric Acid/adverse effects , gamma-Aminobutyric Acid/pharmacokineticsABSTRACT
PURPOSE: Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. RESULTS: Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. CONCLUSION: Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.