Effect of Carbamazepine on the Pharmacokinetics of Erdafitinib in Healthy Participants.

Erdafitinib, a selective and potent oral pan-FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open-label, single-sequence, drug-drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co-administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co-administration decreased total and free maximum plasma concentrations of erdafitinib (C) by 35% (95% CI 30%-39%) and 22% (95% CI 17%-27%), respectively.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

Background And Objective: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs.

A phase 1 study of intravenous mitazalimab, a CD40 agonistic monoclonal antibody, in patients with advanced solid tumors.

Mitazalimab is an agonistic human monoclonal antibody targeting CD40, a target for anti-tumor immunotherapy. This phase 1, dose-escalation study evaluated the safety, dose-limiting toxicities (DLTs), pharmacokinetic and pharmacodynamic profile of mitazalimab. Adults with advanced solid malignancies received mitazalimab intravenously once every-2-weeks.

Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6.

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).

Pharmacokinetics, Safety, and Antitumor Effect of Apalutamide with Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer: Phase Ib Study.

Purpose: Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC).

Patients And Methods: Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles.

Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: Part 2 of the open-label, multicenter, dose-escalation phase 1b study (PAVO).

Intravenous daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumumab and rHuPH20 (DARA SC).

Pharmacokinetic Drug-Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer.

Background And Objectives: Two phase I studies assessed the drug-drug interaction potential of apalutamide as a substrate and perpetrator.

Methods: Study A randomized 45 healthy men to single-dose apalutamide 240 mg alone or with strong inhibitors of cytochrome P450 (CYP)3A4 (itraconazole) or CYP2C8 (gemfibrozil). In study B, 23 patients with castration-resistant prostate cancer received probes for CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2C8 (pioglitazone), and transporter substrates for P-glycoprotein (P-gp) (fexofenadine) and breast cancer resistance protein (BCRP)/organic anion transporting polypeptide (OATP) 1B1 (rosuvastatin) at baseline and after repeat once-daily administration of apalutamide 240 mg to steady state.

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

Background And Objectives: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated.

Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma.

Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM.

An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer.

Purpose: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed.

Methods: Patients received 240 mg oral apalutamide daily.

The pH-altering agent omeprazole affects rate but not the extent of ibrutinib exposure.

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.

A drug-drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies.

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.

Correction to: Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

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.

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

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.

Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment.

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.

Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome.

Background: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor.

Objectives: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL).

Methods: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles.

Quisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myeloma.

The maximum tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/week) plus subcutaneous bortezomib (1.3 mg/m(2)) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was determined.

Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults.

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.

Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants.

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.

The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.

Purpose: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor.

Experimental Design: We performed a phase I dose-escalation study according to the standard 3+3 design.

The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia.

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.

Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study.

Background: Present first-line therapy for diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Ibrutinib, a novel oral Bruton's tyrosine kinase inhibitor, has shown single-drug activity in relapsed or refractory B-cell malignancies. We investigated the safety and efficacy of ibrutinib in combination with R-CHOP for patients with previously untreated CD20-positive B-cell non-Hodgkin lymphoma.

A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors.

Purpose: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi).

Experimental Design: In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titration design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th).

Phase I and pharmacological study of the broad-spectrum tyrosine kinase inhibitor JNJ-26483327 in patients with advanced solid tumours.

Background: JNJ-26483327 is an oral, potent, multi-targeted tyrosine kinase inhibitor, inhibiting kinases of epidermal growth factor receptor (EGFR)-1, -2 and -4, rearranged during transfection (RET) receptor, vascular endothelial growth factor receptor (VEGFR)-3 and Src family (Lyn, Fyn, Yes) at low nanomolar concentrations. This phase I, accelerated titration study assessed maximum tolerated dose, safety, pharmacokinetics and pharmacodynamic effects of JNJ-26483327.

Methods: Nineteen patients with advanced cancers received JNJ-26483327 continuous twice daily (BID) in escalating dose cohorts ranging from 100 to 2100 mg.