Evolution of Ritlecitinib Population Pharmacokinetic Models During Clinical Drug Development

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.

 

Comments:

This abstract highlights the iterative development of a population pharmacokinetic model for ritlecitinib, a compound with therapeutic potential across various conditions. The research integrates data from healthy participants and patients across multiple clinical trials to establish a robust model reflecting drug behavior in different populations and conditions.

Key points:

1. **Data Integration:** Data from 12 clinical trials conducted between December 2014 and July 2021 were utilized. These trials encompassed phases I, II, and III, involving healthy individuals and patients with conditions like rheumatoid arthritis, ulcerative colitis, alopecia areata, and vitiligo.

2. **Model Evolution:** The development process spanned three iterations. The initial iteration relied on data from healthy participants, gradually incorporating information from different patient populations in subsequent iterations. Each iteration updated the model parameters based on the accumulating dataset.

3. **Model Characteristics:** The final model adopted a two-compartment structure with first-order absorption. It also considered direct-response non-stationary clearance and bioavailability, which were influenced by concentrations in the peripheral compartment.

4. **Clinical Relevance:** The refined population pharmacokinetic model was instrumental in addressing specific clinical development queries related to ritlecitinib. It provided insights into systemic drug exposure, contributing to informed decisions during the studies and likely influencing the product's label.

This meticulous approach showcases how population pharmacokinetics can evolve and adapt with accumulating data, aiding in answering critical questions about drug behavior across different patient populations and clinical conditions.

Related Products

Cat.No.	Product Name	Information
S8538	Ritlecitinib (PF-06651600)	Ritlecitinib (PF-06651600) is a potent and irreversible JAK3-selective inhibitor with an IC50 of 33.1 nM but without activity (IC50 > 10 000 nM) against JAK1, JAK2, and TYK2.

Related Targets

JAK