Predicting transdermal fentanyl delivery using physics-based simulations for tailored therapy
Authors: Bahrami Flora , Rossi René Michel , Defraeye Thijs 
Published: January 2021

Transdermal fentanyl patches are an effective alternative to the sustained-release of oral morphine for chronic pain treatment. Due to the narrow therapeutic range of fentanyl, the fentanyl concentration in the blood needs to be controlled carefully. Only then, effective pain relief can be reached while avoiding adverse effects such as respiratory depression. In this study, a physics-based digital twin of the patient was developed by implementing mechanistic models for transdermal drug uptake and the patient’s pharmacokinetic and pharmacodynamics response. A digital twin is a virtual representation of the patient and the transdermal drug delivery system, which is linked to the real-world patient by patient feedback, sensor data of specific biomarkers, or customizing the twin to a particular patient characteristic, for example, based on the age. This digital twin can predict the transdermal drug delivery processesin-silico. Our twin is used first to predict conventional therapy’s effect for using fentanyl patches on a virtual patient at different ages. The results show that by aging, the maximum transdermal fentanyl flux and maximum concentration of fentanyl in the blood decrease by 11.4% and 7.0%, respectively. Nonetheless, by aging, the pain relief increases by 45.2% despite the lower concentration of fentanyl in the blood for older patients. As a next step, the digital twin was used to propose a tailored therapy, based on the patient’s age, to deliver fentanyl based on the patient’s needs to alleviate pain. This predesigned therapy consisted of customizing the duration of applying and changing the commercialized fentanyl patches based on the calculated pain intensity. According to this therapy, a patient of 20 years old needs to change the patch 2.1 times more frequently compared to conventional therapy, which led to 30% more pain relief and 315% more time without pain. In addition, the digital twin was updated by the patient’s pain intensity feedback. Such therapy led to an increase in the patient’s breathing rate while having effective pain relief, therefore providing a safer and more comfortable treatment for the patient. We quantified the added value of a patient’s physics-based digital twin and sketched the future roadmap for implementing such twin-assisted treatment into the clinics.NomenclatureSymbolsciThe concentration of fentanyl in layeri(in the drug uptake model) [ng ml-1]cpThe concentration of fentanyl in the central compartment [ng ml-1]crThe concentration of fentanyl in the rapid equilibrated compartment [ng ml-1]csThe concentration of fentanyl in the slow equilibrated compartment [ng ml-1]cgThe concentration of fentanyl in the gastrointestinal compartment [ng ml-1]clThe concentration of fentanyl in the hepatic compartment [ng ml-1]ceThe concentration of fentanyl in the effect compartment [ng ml-1]DiDiffusion coefficient of fentanyl in layeri(in the mechanistic model) [m2s-1]D0Base diffusion coefficient of fentanyl [m2s-1]DTDiffusion coefficient of fentanyl at temperature T [m2s-1]D306Diffusion coefficient of fentanyl at 306[K] [m2s-1]dptThe thickness of the transdermal patch [µm]dscThe thickness of the stratum corneum [µm]dvepThe thickness of the viable epidermis [µm]dEdmThe thickness of the equivalent dermis [µm]EiThe intensity of effectiThe baseline of effectiThe maximum effectiEC50,iThe concentration related to half-maximum effecti[ng ml-1]fuThe fraction of unbound fentanyl in plasmajiFentanyl flux in layeri(in the mechanistic model)Ki/jThe partition coefficient of fentanyl between layeritoj(in the mechanistic model)KiThe drug capacity in layeri(in the mechanistic model)kcsInter-compartmental first-order equilibrium rate constant (central to slow equilibrated) [min-1]kcrInter-compartmental first-order equilibrium rate constant (central to rapid equilibrated) [min-1]kcgInter-compartmental first-order equilibrium rate constant (central to gastrointestinal) [min-1]kchInter-compartmental first-order equilibrium rate constant (central to hepatic) [min-1]kscInter-compartmental first-order equilibrium rate constant (slow equilibrated to central) [min-1]krcInter-compartmental first-order equilibrium rate constant (rapid equilibrated to central) [min-1]khcInter-compartmental first-order equilibrium rate constant (hepatic to central) [min-1]kghInter-compartmental first-order equilibrium rate constant (gastrointestinal to hepatic) [min-1]kmetMetabolization rate constant [min-1]kreRenal clearance rate constant [min-1]keInter-compartmental first-order equilibrium rate constant (for effect compartment) [min-1]SISensitivity indextTime [h]tDTime lag [h]Dependent variable related toxifor sensitivity analysisVcThe apparent volume of the central compartment [L]VsThe apparent volume of the slow equilibrated compartment [L]VrThe apparent volume of the rapid equilibrated compartment [L]VgThe apparent volume of the gastrointestinal compartment [L]VhThe apparent volume of the hepatic compartment [L]xiThe independent variable which sensitivity analysis is done based on itγHill coefficientψiDrug potential in domaini[ng ml-1]