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Published on: December 7, 2014
Evolution of Ritlecitinib Population Pharmacokinetic Models During Clinical Drug Development
Jessica Wojciechowski1, Vivek S Purohit2, Yeamin Huh2
1Pfizer Inc., 445 Eastern Point Road, Groton, CT, 06340, USA. jessica.wojciechowski@pfizer.com.
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.
Insights
This study developed a population pharmacokinetic model for ritlecitinib, an oral Janus kinase 3 inhibitor, to support clinical development for autoimmune diseases like alopecia areata and ulcerative colitis.
Area of Science:
- Pharmacokinetics and drug development
- Immunology and autoimmune diseases
- Computational modeling in medicine
Background:
- Ritlecitinib, an oral Janus kinase 3 inhibitor, is in clinical development for alopecia areata, vitiligo, ulcerative colitis, Crohn's disease, and rheumatoid arthritis.
- Simultaneous clinical trial readouts necessitate strategic planning for population pharmacokinetic (PopPK) model development.
Purpose of the Study:
- To develop and evaluate a robust PopPK model for ritlecitinib.
- To ensure timely decision-making throughout the drug's clinical development lifecycle.
- To address clinical questions regarding systemic exposure of ritlecitinib.
Main Methods:
- Utilized data from 12 clinical trials (Phase I, II, and III) involving healthy participants and patients with autoimmune conditions.
- Employed a stepwise PopPK modeling approach with three iterative updates, leveraging accumulating data.
- The final model was a two-compartment model with non-stationary clearance and bioavailability influenced by peripheral compartment concentrations.
Main Results:
- Three iterations of the ritlecitinib PopPK model were successfully developed, supporting study readouts for alopecia areata, vitiligo, and ulcerative colitis.
- The modeling process evolved from initial structural modeling to comprehensive covariate testing and evaluation.
- The final model accurately described ritlecitinib pharmacokinetics and informed clinical development decisions.
Conclusions:
- The iterative PopPK modeling approach effectively managed accumulating data throughout ritlecitinib's development.
- This strategy successfully addressed key clinical questions related to systemic exposure.
- The developed model informed the approved product label, demonstrating its utility in drug development.
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