Alopecia areata (AA) is an autoimmune form of hair loss with limited treatments.
To evaluate the efficacy and safety of the Janus kinase inhibitors ritlecitinib and brepocitinib in patients who have ...AA with ≥ 50% scalp hair loss.
Patients were randomized to once-daily ritlecitinib, brepocitinib, or placebo. The primary efficacy endpoint was a 24-week change from baseline in the Severity of Alopecia Tool (SALT) score. The key secondary efficacy endpoint was the proportion of patients achieving 30% improvement in SALT score (SALT30).
The ritlecitinib, brepocitinib, and placebo groups included 48, 47, and 47 patients, respectively. At week 24, least-squares mean difference from placebo in SALT score change from baseline was 31.1 (95% confidence interval CI, 18.8-43.5) for ritlecitinib and 49.2 (95% CI, 36.6-61.7) for brepocitinib (P < .0001 for both comparisons with placebo). SALT30 was achieved by 50% (90% CI, 38%-62%) of patients receiving ritlecitinib, 64% (90% CI, 51%-75%) receiving brepocitinib, and 2% (90% CI, 0%-9%) receiving placebo. Two patients experienced a serious adverse event (rhabdomyolysis) in the brepocitinib group only.
Only a single-dosage regimen of each study drug was included.
Treatment with ritlecitinib or brepocitinib for 24 weeks was efficacious and generally well tolerated.
The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration–time profile of brepocitinib plasma concentration after single‐ and multiple‐oral administration ...in healthy volunteers (HVs) and patients with immuno‐inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed‐effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two‐compartment model with first‐order absorption and a lag time for tablet formulation, dose‐dependent bioavailability, and Box–Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70‐kg non‐Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well‐characterized by a two‐compartment model with first‐order absorption and dose‐dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.
The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for ...therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration-dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long-lasting hyperthermia with maximal body temperature surpassing 40
°C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517-induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1-selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.
The oral Janus kinase 1 (JAK1) inhibitor abrocitinib reduced signs and symptoms of atopic dermatitis (AD) in a placebo‐controlled, randomized, double‐blind, phase IIb trial (dose range 10–200 mg). A ...kinetic‐pharmacodynamic (K‐PD) model consisting of proliferation, maturation, and blood circulation compartments was developed to characterize platelet count changes during the study. The K‐PD model consisted of a drug elimination constant, four system parameters describing platelet dynamics, variance terms, correlation, and residual errors. Overall, these patients exhibited mean transit time from progenitor cells to platelets of 8.2 days (longer than the reported megakaryocyte life span), likely arising from JAK1‐induced perturbations of platelet progenitor homeostasis. The final model described dose‐related platelet count declines until nadir at treatment week 4 and return to baseline levels thereafter. The model was deemed suitable to support the design of subsequent abrocitinib AD trials and indicated limited clinically relevant platelet reductions in the range of doses studied.
Maintaining platelet homeostasis is important to avoid spontaneous bleeding and organ damage. Thrombopoietin, the primary regulator of platelet production, is affected by and acts in part via Janus ...kinase (JAK)‐signal transducer and activator of transcription (STAT)–mediated mechanisms. Interleukin‐6 is also partly responsible for inducing thrombopoietin production via the JAK‐STAT pathway. Although current understanding suggests that JAK2 is a primary mediator of platelet regulation, the emerging data show that a JAK1‐specific inhibitor resulted in the modulation of platelet numbers following dosing. To gain a mechanistic understanding, a model describing platelet regulation based on known physiology and JAK‐STAT pathways was built. The model provides a tool to coalesce biological understanding of platelet physiology and an in silico experimental platform to explore drug effects on platelet homeostasis. In this article, we explain the model construction and demonstrate the use of JAK‐inhibitor programs as informing probes of the physiology, gaining insights on dosing paradigms that avoid platelet‐related safety concerns.
Ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor, was evaluated in patients with ulcerative colitis (UC) in a phase 2b trial. Model-informed ...drug development strategies were applied to bridge observations from phase 2b to predictions for a proposed phase 3 study design to assess the probability of achieving the target efficacy outcome. A longitudinal exposure-response model of the time course of the 4 Mayo subscores (rectal bleeding, stool frequency, physician's global assessment, and endoscopic subscore) in patients with UC receiving placebo or ritlecitinib was developed using population modeling approaches and an item response theory framework. The quantitative relationships between the 4 Mayo subscores accommodated the prediction of composite endpoints such as total Mayo score and partial Mayo score (key endpoints from phase 2b), and modified clinical remission and endoscopic remission (proposed phase 3 endpoints). Clinical trial simulations using the final model assessed the probability of candidate ritlecitinib dosing regimens (including those tested in phase 2b and alternative) and phase 3 study designs for achieving target efficacy outcomes benchmarked against an approved treatment for moderate-to-severe UC. The probabilities of achieving target modified clinical remission and endoscopic improvement outcomes at both weeks 8 and 52 for ritlecitinib 100 mg once daily was 74.8%. Model-based assessment mitigated some of the risk associated with proceeding to pivotal phase 3 trials with dosing regimens of which there was limited clinical experience.
Aims
The aim of the studies was to characterize the pharmacokinetics of desloratadine in healthy children and to determine the appropriate dose for paediatric patients 2–11 years old.
Methods
Two ...open‐label, single‐dose studies were carried out in healthy children between 2–5 (n = 18) and 6–11 years old (n = 18). On day 1, subjects received a single oral dose of desloratadine syrup (1.25 mg for 2–5 year olds or 2.5 mg for 6–11 year olds). Subjects were followed for an additional 4 days during which vital signs were measured daily and blood samples were collected periodically.
Results
Plasma desloratadine Cmax occurred at a median of 2.0 h after dosing in both age groups. Median values for the younger (2–5 years old) and older (6–11 years old) groups were 2.28 and 2.05 ng ml−1, respectively. Arithmetic (and harmonic) mean t1/2 (h) values for each group, respectively, were 16.4 (13.9) and 19.4 (15.8). Exposure to desloratadine was similar in both the younger and older age groups, with a median AUC(last) of 38.8 and 38.2 ng ml−1 h, respectively. These data were similar to values in adults, who received 5 mg doses of desloratadine. No adverse events or clinically significant abnormal laboratory values were noted in either group.
Conclusions
Single doses of desloratadine syrup (1.25 and 2.5 mg) were well tolerated in children 2–5 and 6–11 years old. Desloratadine exposure in children appears to be similar to that observed in adults, in whom efficacy has been established.
What is already known about this subject
• According to recent literature, the pathophysiologies of allergic rhinitis and chronic idiopathic urticaria are thought to be similar in adults and ...children. In addition, the response to antihistamine treatment is similar in adults and children, suggesting a similar concentration‐response relationship.
• However, an appropriate dose selection and the pharmacokinetics of desloratadine in children of ≥6 months−≤2 years old have never been addressed in the literature.
What this study adds
• This study demonstrated that desloratadine syrup offers a safe treatment option for allergic conditions in young children.
• A suitable dose for children aged ≥6 months−<1 year is 1.0 mg, while the corresponding predicted dose for children aged ≥1 year−≤2 years is 1.25 mg. These paediatric doses yielded similar systemic desloratadine exposures (AUC) to those seen with a typical adult dose of 5.0 mg.
Aims
The aim of this study was to identify the dose of desloratadine in children aged ≥6 months−≤2 years that would yield a single‐dose target exposure (AUC) comparable with that in adults taking 5 mg desloratadine as syrup.
Methods
In a phase 1, single‐dose, open‐label, pharmacokinetic study in 58 children aged ≥6 months−<1 year and ≥1 year−≤2 years were randomly assigned to desloratadine syrup 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml), respectively. Because the volume of blood that could be collected from individual subjects was limited, a population pharmacokinetic approach was used to estimate the pharmacokinetics of desloratadine. Safety was assessed based on results of screening and postdose physical examinations, laboratory safety tests, vital signs, and adverse events.
Results
The apparent clearance (CL/F) of desloratadine, population estimate (%CV), in children aged ≥6 months−<1 year was 27.8 l h−1 (35) and corresponding values in children ≥1 year−≤2 years was 35.5 l h−1 (51), compared with 137 l h−1 (58) for adults. The CL/F ratios (children to adults) indicated that doses of 1 mg for ≥6 months−<1 year and 1.25 mg for ≥1 year−≤2 years would result in similar systemic exposure to that observed in adults receiving the recommended 5 mg dose. Desloratadine was well tolerated with no safety issues.
Conclusions
Doses of 1.0 and 1.25 mg in children aged ≥6 months−≤2 years should result in an exposure to desloratadine similar to that of adults receiving doses of 5 mg.
Background
Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor undergoing parallel clinical development for alopecia areata, vitiligo, ...ulcerative colitis, Crohn’s disease, and rheumatoid arthritis.
Objective
As studies read out simultaneously, strategic planning of population pharmacokinetic model development and evaluation is required to ensure timely decisions.
Methods
Data from healthy participants and patients from 12 clinical trials between December 2014 and July 2021 were included: seven phase I studies in healthy participants and organ impairment, five phase II/III studies in patients with rheumatoid arthritis, ulcerative colitis, alopecia areata, and vitiligo. Population pharmacokinetic models consisted of stepwise procedures to accommodate data availability and the model’s application to answering clinical development questions. At each iteration of the model update, parameters of the next model were re-estimated by leveraging previous information and new data.
Results
Three model development lifecycle iterations of the ritlecitinib population pharmacokinetic model were conducted to support alopecia areata, vitiligo, and ulcerative colitis study readouts. Initial structural modeling based on healthy participant data (and some rheumatoid arthritis and alopecia areata data) in iteration 1 provided a platform for comprehensive covariate testing during iteration 2, and model evaluation and implementation of the frequentist prior approach in iteration 3. The final model was a two-compartment model with first-order absorption and direct-response non-stationary clearance and bioavailability driven by concentrations in the peripheral compartment.
Conclusions
The present approach demonstrated the evolution of three population pharmacokinetic models with accumulating data, addressed clinical drug development questions related to systemic exposures of ritlecitinib, and informed the approved product label.
Clinical Trial Registration
NCT02309827, NCT02684760, NCT02958865, NCT02969044, NCT03232905, NCT03732807, NCT04016077, NCT03715829, NCT04037865, NCT04004663, NCT04634565, NCT02974868.
PDF
