Date Published: June 8, 2018
Publisher: Public Library of Science
Author(s): Evelien J. M. Kuip, Wendy H. Oldenmenger, Martine F. Thijs—Visser, Peter de Bruijn, Astrid W. Oosten, Esther Oomen—de Hoop, Stijn L. W. Koolen, Carin C. D. Van der Rijt, Ron H. J. Mathijssen, D William Cameron.
The transdermal fentanyl patch is widely used to treat cancer-related pain despite its wide inter- and intrapatient variability in pharmacokinetics. The aim of this study was to investigate whether smoking and body size (i.e. body mass index) influence fentanyl exposure in patients with cancer. These are factors that typically change during treatment and disease trajectories. We performed an explorative cohort study in patients with cancer using transdermal fentanyl patches (Durogesic®), by taking a blood sample for pharmacokinetic analysis one day after applying a patch in patients with a stable fentanyl dose. A total of 88 patients were evaluable. Although no statistically significant difference was found, the plasma concentrations of non-smokers was 28% (95% CI [-14%; +89-%]) higher than those of smokers normalizing for a dose of 25μg/min. Patients with a low BMI (< 20 kg/m2) had almost similar (10% (95% CI [-39%; +97%]) higher) plasma concentrations compared to patients with a high BMI (> 25 kg/m2). A wider variation in fentanyl plasma concentrations was found in this study than anticipated. Due to this variation, studies in larger patient cohorts are needed to further investigate the effect of smoking on plasma concentration of fentanyl and thereby clarify the clinical significance of our findings.
Fentanyl is one of the most commonly used (strong acting) opioids to treat cancer-related pain [1–3] and it is often preferred over morphine, especially in patients with renal failure. Additionally, fentanyl usually results in less obstipation than other opioids [4–6]. The fentanyl transdermal patch has been used since decades to treat chronic pain. Fentanyl is also available in a liquid formulation for intravenous and subcutaneous administration and in various immediate release forms for oromucosal and nasal use [7, 8]. Fentanyl is highly lipophilic and is therefore rapidly absorbed by the subcutaneous fat-tissue. After placement of the patch fentanyl is absorbed by the skin. When the patch is removed systemic fentanyl concentration will slowly decrease as a result of fentanyl release from subcutaneous depots (formed below the patch) [7, 9, 10].
Our study was performed as a prospective single-center pharmacokinetic study at the Erasmus MC Cancer Institute. Patients were included from 1st of April 2014 until 27th of October 2015. Inclusion criteria were: patients with cancer ≥ 18 years, using a stable dose of a transdermal fentanyl (Durogesic®) for at least 8 days irrespective of the dose used and given written informed consent. Exclusion criteria were: use of fentanyl rescue medication (other opioids were allowed), the use of strong CYP inhibitors or inducers and serious psychiatric illness, confusion or intellectual disability. Smoking was defined as smoking tobacco daily. Non-smoking patients were defined as patients who had never smoked, or quit smoking at least one month before PK sampling. Patients were divided in three BMI groups; BMI <20 kg/m2 (low), BMI 20–25 kg/m2 (normal) and BMI >25 kg/m2 (high). Patients applied the patch to the upper arm. One venous blood sample was taken from the contralateral arm approximately 24 hours after application of a new patch. The blood samples were collected in potassium EDTA coated tubes. Patients were not evaluable when the appropriate blood samples were not taken. Lab results of levels of creatinine, estimated glomerular filtration rate (eGRF), calculated by Modification of Diet in Renal Disease (MDRD); [formula: eGFR (ml/min/1.73 m2) = 32788 x serum Creatinine (μmol/l) -1.154 x age (years) -0.203 x (0.742 when female) x (1.210 when of African descent)], aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin and alkaline phosphatase (ALP) were assessed. Protocol in S1 Protocol. Trend statement in S1 Trend.
In total, 104 patients were included. Eighty-eight patients (39 males (44%) and 49 females (56%)) with a median age of 59.5 years (interquartile range (IQR) 53.5–67.0) completed the study and were evaluable, Fig 1. The demographic data of these evaluable patients are presented in Table 1. Twenty-seven patients (30.7%) were defined as smokers and 61 patients (69.3%) as non-smokers. In total, 20 patients had a BMI < 20 kg/m2 (22.7%), 41 patients had a BMI between 20–25 kg/m2 (46.6%) and 27 patients had a BMI > 25 kg/m2(30.7%). Creatinine, eGFR, AST, ALT, bilirubin, albumin and ALP turned out to follow a log-normal distribution. Only AST levels were significantly lower in smokers compared to non-smokers (p = 0.026), although this is unlikely to be clinically relevant. All patients had normal or limited (CTCAE grade 1) toxicities of creatinine, eGFR, AST, ALT, bilirubin, albumin or ALP.
Interestingly, in this study, the interindividual variation in plasma fentanyl levels (geometric coefficient of variation = 87%) was much larger than our original assumption. Consequently, our study was underpowered to find a statistically significant difference in fentanyl plasma concentration. Nonetheless, based on our findings, the 27.7% higher normalized plasma concentrations of non-smokers compared to smokers, we cannot exclude an effect of smoking on fentanyl exposure. Smoking is a factor that frequently changes during phases of disease in patients with cancer. Together with the hypothesis that smoking leads to induction of CYP3A4 [20, 23] and that fentanyl metabolism might also be influenced by other (unknown) metabolic pathways [24, 25] it might be interesting to study smoking in a larger cohort of patients with cancer. Nevertheless, other strong inducers like rifampicin  and carbamazepine or phenobarbital  had highly relevant inductive effects on fentanyl PK. The combination of rifampicin and oral transmucosal fentanyl citrate led to a significant lower exposure to fentanyl compared to fentanyl alone (2.20 vs 5.87 ng/mL). A population pharmacokinetic analysis showed a significantly higher fentanyl clearance when patients used CYP3A4 inducers compared to patients who did not use CYP3A4 inducers .