Fentanyl transdermal therapy is a suitable treatment for moderate-to-severe cancer-related pain. Patients show inter-individual drug uptake behavior, which leads to a different response to the therapy. This study aims to determine the effect of different physiological features of the patients on the pain relief achieved with the therapy. Therefore, a set of virtual patients was developed by using Markov Chain Monte Carlo (MCMC), based on actual patient data. The members of this virtual population differ by age, weight, gender, and height. Tailored digital twins were developed using these correlated, individualized parameters to propose a personalized therapy for each patient. It was shown that the patients of different ages, weights, and gender have significantly different fentanyl blood uptake, plasma fentanyl concentration, pain relief, and ventilation rate, which means the same therapy will not reach the same result for the patients. Therefore, we included the virtual patients' response to the treatment, namely pain relief, in the digital twins. We enabled these digital twins of each patient to adjust in-silico the therapy in real-time to have more efficient pain relief. By implementing digital-twin-assisted therapy, the average pain intensity decreased by 16% compared to conventional therapy. The median of time without pain increased by 23 hours over a 72-hour period. Therefore, the digital twin can be successfully used to assist in individual control of the transdermal therapy to reach higher pain relief and maintain a steady pain relief throughout the therapy.

The authors have declared no competing interest.

This work was financially supported by the Novartis Research Foundation (Virtual twinning for intelligent, personalized transdermal drug delivery) and OPO Foundation (Digital human avatars help tailor transdermal pain management (TREATME)). The funders were not involved in the study design, collection, analysis, and interpretation of data, the writing of this article, or the decision to submit it for publication.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used ONLY openly available human data that were published by Zech et al. study at 1992: Zech, D.F., Grond, S.U., Lynch, J., Dauer, H.G., Stollenwerk, B. and Lehmann, K.A., 1992. Transdermal fentanyl and initial dose-finding with patient-controlled analgesia in cancer pain. A pilot study with 20 terminally ill cancer patients. Pain, 50(3), pp.293-301.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

The human data is from the published study of Zech et al. in 1992: https://doi.org/10.1016/0304-3959(92)90034-9 The simulated data of the study are available upon reasonable request to the authors

https://doi.org/10.1016/0304-3959(92)90034-9