RT Journal Article
SR Electronic
T1 Predicting transdermal fentanyl delivery using mechanistic simulations for tailored therapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.16.154195
DO 10.1101/2020.06.16.154195
A1 Thijs Defraeye
A1 Flora Bahrami
A1 Lu Ding
A1 Riccardo Innocenti Malini
A1 Alexandre Terrier
A1 René M. Rossi
YR 2020
UL http://biorxiv.org/content/early/2020/06/17/2020.06.16.154195.abstract
AB Transdermal drug delivery is a key technology for administering drugs. However, most devices are “one-size-fits-all”, even though drug diffusion through the skin varies significantly from person-to-person. For next-generation devices, personalization for optimal drug release would benefit from an augmented insight into the drug release and percutaneous uptake kinetics. Our objective was to quantify the changes in transdermal fentanyl uptake with regards to the patient’s age and the anatomical location where the patch was placed. We also explored to which extent the drug flux from the patch could be altered by miniaturizing the contact surface area of the patch reservoir with the skin. To this end, we used validated mechanistic modeling of fentanyl diffusion, storage, and partitioning in the epidermis to quantify drug release from the patch and the uptake within the skin. A superior spatiotemporal resolution compared to experimental methods enabled in-silico identification of peak concentrations and fluxes, and the amount of stored drug and bioavailability. The patients’ drug uptake showed a 36% difference between different anatomical locations after 72 h, but there was a strong interpatient variability. With aging, the drug uptake from the transdermal patch became slower and less potent. A 70-year-old patient received 26% less drug over the 72-h application period, compared to an 18-year-old patient. Additionally, a novel concept of using micron-sized drug reservoirs was explored in silico. These reservoirs induced a much higher local flux (µg cm-2 h-1) than conventional patches. Up to a 200-fold increase in the drug flux was obtained from these small reservoirs. This effect was mainly caused by transverse diffusion in the stratum corneum, which is not relevant for much larger conventional patches. These micron-sized drug reservoirs open new ways to individualize reservoir design and thus transdermal therapy. Such computer-aided engineering tools also have great potential for in-silico design and precise control of drug delivery systems. Here, the validated mechanistic models can serve as a key building block for developing digital twins for transdermal drug delivery systems.Competing Interest StatementThe authors have declared no competing interest.SymbolsAage [a]Aptactive area of the patch [m2]ciαdrug concentration of substance α in material i [kg m-3]csc,maxαmaximal concentration in the stratum corneum [kg m-3]cpt,iniαinitial concentration in the patch [kg m-3]dscthickness of stratum corneum [m]depthickness of epidermis [m]dvepthickness of viable epidermis [m]dptthickness of patch [m]Diαdiffusion coefficient/diffusivity of substance α in material i [m2 s-1]Gbl,up(t)uptake flow rate in blood at a specific point in time [kg s-1]Gpt,rel(t)release flow rate of patch at a specific point in time [kg s-1]gbl,up(t)uptake flux across the skin into the blood at a specific point in time [kg m-2 s-1]KA/Bαpartition coefficient between material A and B for substance αKo/wαpartition coefficient between octanol and water for substance αKiαdrug capacity of substance α in material i [-]Lptlength (or width) of patch (reservoir) [m]Lsklength (or width) of skin [m]mpt,iniinitial amount of drugs contained in the patch [kg]mpt,res(t)remaining (residual) amount of drugs contained in the patch at a specific point in time [kg]mep,stor(t)total amount of drugs stored in the epidermis at a specific point in time [kg]mpt,rel(t)cumulative amount of drugs released by the patch at a specific point in time [kg]mbl,up(t)cumulative amount of drugs taken up by the blood flow at a specific point in time [kg] R diffusive resistance of a material [s m-1]Ssαvolumetric source term for substance α [kg m-3s-1]SU,Xjrelative sensitivity of U to a change in Xjttime [s]t1/2half-uptake-time [s]Uprocess quantityXjmodel input parameterYbl,upfractional drug release of the patch [-]Greek symbolsαsubstance indicatorψαdrug potential of substance α [kg m-3]Subscriptsblbloodimaterial indicatoriniinitialscstratum corneumepepidermisvepviable epidermisiniinitialfinfinalupuptakerelreleasestorstoredskskinptpatchAbbreviationsHUThalf-uptake-timeTDDStransdermal drug delivery systems