This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two‐part phase I study (http://anzctr.org.au ACTRN12618001036202). Part A was a randomized, open‐label, three‐period, single‐dose crossover study (n = 12) with rilzabrutinib 100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized, double‐blind, placebo‐controlled, four‐way, single‐dose crossover study (n = 39) with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin (positive control). Primary objectives: part A – pharmacokinetics (PK) of rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B – effect of rilzabrutinib therapeutic and supratherapeutic concentration on electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded before and post‐dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17‐fold area under the concentration–time curve (AUC0–∞) and 7‐fold maximum plasma concentration (Cmax) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg was discontinued due to mild‐to‐moderate gastrointestinal intolerance. In Part B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC0–∞ from 454 to 3800 ng h/mL and Cmax from 144 to 712 ng/mL. The concentration–QTc relationship was slightly negative, shallow (−0.01 ms/ng/mL [90% CI −0.016 to −0.001]), and an effect >10 ms on QTcF could be excluded within the observed range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic doses, had no clinically relevant effects on ECG parameters, including the QTc interval.
The expression of Bruton tyrosine kinase (BTK) in B cells and innate immune cells provides essential downstream signaling for BCR, Fc receptors, and other innate immune cell pathways. The topical covalent BTK inhibitor PRN473 has shown durable, reversible BTK occupancy with rapid on-rate and slow off-rate binding kinetics and long residence time, resulting in prolonged, localized efficacy with low systemic exposure in vivo. Mechanisms of PRN473 include inhibition of IgE (FceR)-mediated activation of mast cells and basophils, IgG (FcgR)-mediated activation of monocytes, and neutrophil migration. In vivo, oral PRN473 was efficacious and well tolerated in the treatment of canine pemphigus foliaceus. In this study, we evaluated in vitro selectivity and functionality, in vivo skin Ab inflammatory responses, and systemic pharmacology with topically administered PRN473. Significant dose-dependent inhibition of IgG-mediated passive Arthus reaction in rats was observed with topical PRN473 and was maintained when given 16 h prior to challenge, reinforcing extended activity with once-daily administration. Similarly, topical PRN473 resulted in significant dosedependent inhibition of the mouse passive cutaneous anaphylaxis IgE-mediated reaction. Multiday treatment with topical PRN473 in rodents resulted in low-to-no systemic accumulation, suggesting that efficacy was mainly due to localized exposure. Reduced skin Ab inflammatory activity was also confirmed with oral PRN473. These preclinical studies provide a strong biologic basis for targeting innate immune cell responses locally in the skin, with rapid onset of action following once-daily topical PRN473 administration and minimal systemic exposure. Dose-dependent inhibition in these preclinical models of immune-mediated skin diseases support future clinical studies.
This single-center, open-label, non-randomized, two-part, phase I study was conducted (1) to evaluate the absolute oral bioavailability of rilzabrutinib 400 mg tablet following an i.v. microtracer dose of ~100 μg [14C]-rilzabrutinib (~1 μCi) and single oral dose of 400 mg rilzabrutinib tablet (part 1), and (2) to characterize the absorption, metabolism, and excretion (AME) of 14C-radiolabeled rilzabrutinib following single oral dose (300 mg) of [14C]-rilzabrutinib (~1000 μCi; administered as a liquid) in healthy male participants (part 2). A total of 18 subjects were enrolled (n = 8 in part 1; n = 10 in part 2). The absolute bioavailability of 400 mg rilzabrutinib oral tablet was low (<5%). In part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) time to maximum concentration (T max ) value of 2.03 h (1.83-2.50 h). The geometric mean (coefficient of variation) terminal half-life following the oral dose and i.v. microtracer dose of ~100 μg [14C]-rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) h, respectively. In part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]-rilzabrutinib solution with a median (range) T max value of 1.00 h (1.00-2.00 h). The majority of total radioactivity was in the feces for both non-bile collection subjects (92.9%) and bile collection subjects (87.6%), and ~5% of radioactivity was recovered in urine after oral administration. Urinary excretion of unchanged rilzabrutinib was low (3.02%). The results of this study advance the understanding of the absolute bioavailability and AME of rilzabrutinib and can help inform its further investigation. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Rilzabrutinib is a potent, oral, and reversible covalent Bruton's tyrosine kinase inhibitor being developed to treat autoimmune diseases. Rilzabrutinib is currentlyThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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