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\begin{document}

\title{Evaluation of the Effect of Ritlecitinib on the Pharmacokinetics of
Caffeine in Healthy Participants}



\author[1]{Liu Jian}%
\author[1]{Rohit Solan}%
\author[2]{Robert Wolk}%
\author[2]{Anna Plotka}%
\author[2]{Melissa O’Gorman}%
\author[1]{Jennifer Winton}%
\author[1]{Julia Kaplan}%
\author[1]{Vivek Purohit}%
\affil[1]{Affiliation not available}%
\affil[2]{Pfizer Inc}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\begin{abstract}
Objective: This clinical study was conducted to evaluate the impact of
ritlecitinib on the pharmacokinetics (PK) of caffeine, a cytochrome P450
1A2 (CYP1A2) substrate. Methods: In this single-center, single-arm,
open-label, fixed-sequence study, healthy participants received a single
100-mg dose of caffeine on two separate occasions: on Day 1 of Period 1
as monotherapy and on Day 8 of Period 2 after oral administration of
ritlecitinib 200 mg once daily (QD) for 8 days. Serial blood samples
were collected and analyzed using a validated LC/MS assay. PK parameters
were estimated by using a non-compartmental method. Safety was monitored
by physical examination, vital signs, electrocardiograms, and laboratory
assessments. Results: Twelve participants were enrolled and completed
the study. Co-administration of caffeine 100 mg in the presence of
steady-state levels of ritlecitinib (200 mg QD) increased caffeine
exposure compared with caffeine given alone. Area under the curve
(AUCinf) and maximum concentration (Cmax) of caffeine increased by
approximately 165\% and 10\%, respectively, when co-administered with
ritlecitinib. The ratios of the adjusted geometric means (90\% CI) for
caffeine AUCinf and Cmax were 265.14\% (234.12\%-300.26\%) and 109.74\%
(103.90\%-15.91\%), respectively, when caffeine was co-administered with
steady-state ritlecitinib (test) compared with its administration alone
(reference). Multiple doses of ritlecitinib when co-administered with a
single dose of caffeine were generally safe and well tolerated in
healthy participants. Conclusion: Ritlecitinib is a moderate inhibitor
of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.%
\end{abstract}%



\sloppy


Effect of Ritlecitinib on PK of Caffeine

Jian Liu,\textsuperscript{1} Rohit Solan,\textsuperscript{2} Robert
Wolk,\textsuperscript{3} Anna Plotka,\textsuperscript{4} Melissa T.
O'Gorman,\textsuperscript{5} Jennifer A. Winton,\textsuperscript{5}Julia
Kaplan,\textsuperscript{6} Vivek S. Purohit\textsuperscript{5}

Affiliations: \textsuperscript{1}Clinical Pharmacology, Pfizer
Investment Co., LTD, Beijing, China; \textsuperscript{2}Pfizer Research
\& Development UK Limited, Hurley, UK; \textsuperscript{3}Pfizer Global
Research \& Development, Groton, CT,
USA;\textsuperscript{4}Biostatistics, Pfizer Inc, Collegeville, PA,
USA;\textsuperscript{5}Clinical Pharmacology, Pfizer Inc, Groton, CT,
USA;\textsuperscript{6}Pfizer Inc, La Jolla, CA, USA

Corresponding author:

Jian Liu

9/F, Tower B, Minmetals Plaza, Dongcheng District

Beijing, China 100010

Tel: + 8610-8516 7429

E-mail: jian.liu2@pfizer.com

\textbf{Key words:} ritlecitinib, drug interaction, CYP1A2, caffeine, PK

Target journal: \emph{British Journal of Pharmacology}

Character count for title (including spaces): 100/150

Character count for short title (including spaces): 40/40

Word count for article: 2689/4000

Word count for abstract: 233/250

References: 22/no limit

Figures/tables: 6/8

\textbf{Hosted file}

\verb`b What is already known and what this study adds.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`c Abstract.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`d Main text.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`e Acknowledgements.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`f Conflict of interest statement.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`g Funding information.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`h Data availability statement.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`i References.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`Table 1.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`Table 2.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`Table 3.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`Table 4.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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\verb`Figure 2.docx`  available at \url{https://authorea.com/users/516794/articles/591504-evaluation-of-the-effect-of-ritlecitinib-on-the-pharmacokinetics-of-caffeine-in-healthy-participants}

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