Influence of aprepitant and localization of the patch on fentanyl exposure in patients with cancer using transdermal fentanyl

Kuip, Evelien; Oldenmenger, Wendy H; Visser-Thijs, Martine F.; Bruijn, Peter de; Hoop, Esther Oomen–de; Mathijssen, Ron H.J.; Rijt, Carin C.D. van der; Koolen, Stijn L.W.

doi:10.18632/oncotarget.24812

Cited by 6 publications

(6 citation statements)

References 31 publications

(46 reference statements)

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“…This hypothesis is powered by findings of other groups, that revealed inconsistencies in respect to the metabolism of fentanyl. Concomitant administration of transdermal fentanyl and aprepitant, another CYP3A inhibitor that is extensively metabolized by the enzyme, showed no significant influence on the AUC of fentanyl as it was expected before 14 . However, norfentanyl was not quantified in that study.…”

Section: Discussionmentioning

confidence: 73%

Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients

Geist

Ziesenitz

Bardenheuer

et al. 2019

Sci Rep

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Transdermal fentanyl is widely used to control pain in cancer patients. The high pharmacokinetic variability of fentanyl is assumed to be due to cytochrome P450 3A-mediated (CYP3A) N-dealkylation to norfentanyl in humans. However, recently published clinical studies question the importance of the described metabolic pathway. In this small study in palliative cancer patients under real-life clinical conditions, the influence of CYP3A on fentanyl variability was investigated. In addition to the determination of midazolam plasma concentration to reveal CYP3A activity, plasma concentrations of fentanyl and its metabolite, norfentanyl, were measured in identical blood samples of 20 patients who participated in an ongoing trial and had been on transdermal fentanyl. Fentanyl, norfentanyl, midazolam, and 1′-OH-midazolam were quantified by liquid chromatography/tandem mass spectrometry. Plasma concentrations of fentanyl and norfentanyl exhibited a large variability. Mean estimated total clearance of fentanyl and mean metabolic clearance of midazolam (as a marker of CYP3A activity) were 75.5 and 36.3 L/h. Both clearances showed a weak correlation and hence a minimal influence of CYP3A on fentanyl elimination.

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Section: Discussionmentioning

confidence: 73%

Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients

Geist

Ziesenitz

Bardenheuer

et al. 2019

Sci Rep

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“…Condición que genera la disminución en la posibilidad de toxicidad y disminución de reacciones adversas. Se evidencia efectividad en el cambio de alternativas con opioides como es el caso de la buprenorfina y fentanilo, resultados similares como los presentados en diversos estudios 9,12,16,20,[24][25][26] dando mejoría en la calidad de vida, mejorando el patrón de sueño, el estado de ánimo y el manejo del dolor.…”

Section: Discussionunclassified

“…Influencia de aprepitanty localización de la exposición del parche de fentanilo en pacientes con cáncer que usan fentanilo transdérmico 12 .…”

Section: Kuip Et Al (2018)unclassified

“…Se encuentran entre los beneficios del uso medicamentos transdermicos la administración controlada de opioides, mayor adherencia al tratamiento paliativo por parte de los pacientes, mayor beneficio del uso de buprenorfina transdérmica en comparación al uso de buprenorfina intravenosa en pacientes con cáncer, disminución del riesgo de sobredosificación, se minimizan los efectos adversos de los medicamentos, efectividad del uso de fentanilo transdérmico en pacientes con cáncer, lo que ayuda a controlar la intensidad del dolor y a mejorar la calidad de vida. La administración transdérmica y de opioides tópicos también se asocia con un menor riesgo de adicción en comparación con las vías oral y parenteral de la administración de analgésicos opioides 12,13,[17][18][19][20][21][22] .…”

Section: Beneficios Y/o Ventajas Del Uso De La Analgesia En Pacientesunclassified

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Uso de analgesia transdérmica en pacientes con necesidades paliativas

Rojas-Marin

Vargas-Martínez

Trujillo-Ramirez

et al. 2019

rcpi

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El tratamiento integral del dolor es multimodal, y la farmacoterapia desempeña un papel clave. Una terapia eficaz para el dolor depende de la intensidad y el tipo de dolor, las comorbilidades y la elección adecuada del analgésico, su dosis y la vía de administración. Se ha observado a través de los estudios analizados en diferentes artículos de revisión la importancia del uso de la analgesia transdérmica en pacientes con necesidades paliativas, esta revisión tiene como objetivo presentar la identificación de los beneficios y/o ventajas del uso de la analgesia en pacientes con necesidades paliativas, determinar las desventajas del uso de analgesia transdérmica y describir los principales factores que intervienen en la no adherencia del tratamiento con analgesia transdérmica. Se realizó una revisión desde el año 2010 a 2019, se analizaron 10 artículos como insumo final para la presente revisión. Los opioides administrados por vía transdérmica se absorben en los vasos ubicados en el tejido subcutáneo y, posteriormente, se transportan en la sangre a los receptores opioides localizados en el sistema nervioso central y periférico, lo que nos muestras una mejor adherencia en el tratamiento del paciente paliativo, la cual permitió evaluar los beneficios del uso de los parches de buprenorfina y fentanilo, mostrando como resultado el adecuado control del dolor y proporcionando así una mejor calidad de vida por otro lado los analgésicos administrados por vía tópica tienen un perfil mucho mejor para los efectos adversos debido a que se relacionan con efectos sistémicos mínimos. Se requiere mayor información y educación de los pacientes, para tener una óptima adherencia.

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“…By considering these side effects, it is important to keep the fentanyl concentration in the blood at such a level that sufficient analgesia is reached while avoiding adverse effects such as respiratory depression for each patient. The conventional therapy for using the transdermal fentanyl patch, which is being used in clinics, is applying a transdermal patch for 72 hours on the skin [13], [14]. Applying a similar therapy for all the patients, by ignoring the physiological states and differences in the therapeutic range for each patient, often fails to treat the pain effectively [15].…”

Section: Introductionmentioning

confidence: 99%

Predicting transdermal fentanyl delivery using physics-based simulations for tailored therapy

Bahrami

Defraeye

2021

Preprint

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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 processes in-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.NomenclatureSymbolsci The concentration of fentanyl in layer i (in the drug uptake model) [ng ml-1]cp The concentration of fentanyl in the central compartment [ng ml-1]cr The concentration of fentanyl in the rapid equilibrated compartment [ng ml-1]cs The concentration of fentanyl in the slow equilibrated compartment [ng ml-1]cg The concentration of fentanyl in the gastrointestinal compartment [ng ml-1]cl The concentration of fentanyl in the hepatic compartment [ng ml-1]ce The concentration of fentanyl in the effect compartment [ng ml-1]Di Diffusion coefficient of fentanyl in layer i (in the mechanistic model) [m2 s-1]D0 Base diffusion coefficient of fentanyl [m2 s-1]DT Diffusion coefficient of fentanyl at temperature T [m2 s-1]D306 Diffusion coefficient of fentanyl at 306[K] [m2 s-1]dpt The thickness of the transdermal patch [µm]dsc The thickness of the stratum corneum [µm]dvep The thickness of the viable epidermis [µm]dEdm The thickness of the equivalent dermis [µm]Ei The intensity of effect i The baseline of effect i The maximum effect iEC50,i The concentration related to half-maximum effect i [ng ml-1]fu The fraction of unbound fentanyl in plasmaji Fentanyl flux in layer i (in the mechanistic model)Ki/j The partition coefficient of fentanyl between layer i to j (in the mechanistic model)Ki The drug capacity in layer i (in the mechanistic model)kcs Inter-compartmental first-order equilibrium rate constant (central to slow equilibrated) [min-1]kcr Inter-compartmental first-order equilibrium rate constant (central to rapid equilibrated) [min-1]kcg Inter-compartmental first-order equilibrium rate constant (central to gastrointestinal) [min-1]kch Inter-compartmental first-order equilibrium rate constant (central to hepatic) [min-1]ksc Inter-compartmental first-order equilibrium rate constant (slow equilibrated to central) [min-1]krc Inter-compartmental first-order equilibrium rate constant (rapid equilibrated to central) [min-1]khc Inter-compartmental first-order equilibrium rate constant (hepatic to central) [min-1]kgh Inter-compartmental first-order equilibrium rate constant (gastrointestinal to hepatic) [min-1]kmet Metabolization rate constant [min-1]kre Renal clearance rate constant [min-1]ke Inter-compartmental first-order equilibrium rate constant (for effect compartment) [min-1]SI Sensitivity indext Time [h]tD Time lag [h] Dependent variable related to xi for sensitivity analysisVc The apparent volume of the central compartment [L]Vs The apparent volume of the slow equilibrated compartment [L]Vr The apparent volume of the rapid equilibrated compartment [L]Vg The apparent volume of the gastrointestinal compartment [L]Vh The apparent volume of the hepatic compartment [L]xi The independent variable which sensitivity analysis is done based on itγ Hill coefficientψi Drug potential in domain i [ng ml-1]

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Influence of aprepitant and localization of the patch on fentanyl exposure in patients with cancer using transdermal fentanyl

Cited by 6 publications

References 31 publications

Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients

Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients

Uso de analgesia transdérmica en pacientes con necesidades paliativas

Predicting transdermal fentanyl delivery using physics-based simulations for tailored therapy

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