Hideya Kokubun

Population Pharmacokinetics of Transdermal Fentanyl in Patients With Cancer-Related Pain

ABSTRACT Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CLfenta (L/h) = 3.53 × (15 − Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Population Pharmacokinetics of Oxycodone in Patients With Cancer-Related Pain

ABSTRACT Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 − Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); Vd (L) = 193; ka (h−1) = 0.336; Tlag (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, Vd: 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

Investigation of methicillin-resistant Staphylococcus aureus showing reduced vancomycin susceptibility isolated from a patient with infective endocarditis

A patient with infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) was treated with vancomycin (VAN). VAN was ineffective, although therapeutic drug monitoring (TDM) indicated that the recommended trough level was maintained. Five MRSA isolates obtained at various times were analyzed to determine the minimum inhibitory concentration (MIC) and were subjected to population analysis, simulation analysis pulsed-field gel electrophoresis (PFGE). MRSA susceptible to VAN was isolated before and during the early stage of treatment, while an MRSA strain showing reduced VAN MIC was isolated during treatment. Simulation analysis indicated that the viable bacterial count only decreased to 10(-3) to 10(-4) cells after 72 h of incubation. The five MRSA strains isolated at various times were identical by PFGE.

Pharmacokinetics of oxycodone after intravenous and subcutaneous administration in Japanese patients with cancer pain.

ABSTRACT In Japan, Oxycodone hydrochloride injection formulation has been approved in 2012. However, its pharmacokinetics has been poorly studied. The aim of this study is to evaluate the pharmacokinetics of oxycodone after intravenous and subcutaneous administration of oxycodone hydrochloride injection in Japanese patients with cancer pain. Noncompartmental analysis and population pharmacokinetic analysis were performed. We conducted a multicenter open-label study of oxycodone hydrochloride administered as constant infusion with the dose titrated individually according to the pain intensity in patients with cancer pain. Pharmacokinetic parameters for plasma oxycodone and its metabolites were estimated using pharmacokinetics of oxycodone was evaluated using a total of 344 plasma concentrations obtained from 89 patients. The estimated geometric mean clearance (CL) of oxycodone was 24.3 L per hour after constant intravenous infusion and 29.5 L per hour after constant subcutaneous infusion, respectively. Population pharmacokinetic analysis indicated that body surface area was the influencing factor on CL and there were no pharmacokinetic differences for CL between intravenous and subcutaneous infusion. These results provide important information for the clinical use of oxycodone injection.

Plasma Concentration of Oxycodone and Pain during Hemodialysis in a Patient with Cancer

Pain is one of the most common problems in palliative medicine, and opioid therapy should be used adequately. Clinically, many cancer patients with severe renal dysfunction receive opioids for pain control. However, the pharmacokinetics of opioids during hemodialysis are not completely understood. We investigated the time course of the plasma concentration of oxycodone and pain during hemodialysis in a 55-year-old man using oxycodone for cancer pain. The patient’s plasma concentration of oxycodone decreased during hemodialysis, and increased after it ended. Conversely, his pain increased after the beginning of hemodialysis, and improved after it was finished. Additionally, our results did not show a relationship between the plasma concentration of oxycodone and his pain. Breakthrough pain occurred several times during hemodialysis irrespective of the plasma concentration of oxycodone. The decrease in plasma oxycodone during hemodialysis appeared to be caused by the removal of oxycodone by hemodialysis, and the later increase after hemodialysis appeared to be related to the redistribution of oxycodone. On the other hand, breakthrough pain during hemodialysis may be caused by hemodialysis itself, rather than due to the decrease of the plasma concentration of oxycodone, given that no relationship between the plasma concentration of oxycodone and pain could be identified. When building a strategy of pain management during hemodialysis, both the possibilities of a decrease in the plasma concentration of oxycodone by hemodialysis and the increase of pain by hemodialysis itself should be considered.

Evaluation of Detachment and Clinical Usability of Transdermal Fentanyl Patches in Healthy Volunteers

The dose of a transdermal fentanyl patch is proportional to its application site area. Therefore, the absorption of fentanyl may decrease if the patch detaches, leading to insufficient analgesia. Sixteen healthy volunteers were enrolled in a study to investigate the appropriate application sites and clinical utility of three transdermal fentanyl patches available in Japan. Three placebos, Fentanyl 1-day (Fentos; Fen), Fentanyl 3-day (Durotep; Dur), and Generic Fentanyl 3-day (HMT) were administered using a crossover study design. The placebos were applied to 11 different sites, including both sides of the upper arm, abdomen, back, thigh, chest, and the middle of the chest. We determined the patch detachment area and incidence of patch-induced itching every 24 h and evaluated differences between each application site using the Wilcoxon signed-rank test. Significant patch detachment was observed on the abdomen and upper arms with Fen, on the abdomen and chest with Dur, and on the chest with HMT compared with that at other sites (p<0.005). Although no significant difference in itching was observed between regions when administering Fen, itching significantly increased on the chest and back when using Dur and on the abdomen when using HMT as compared with that at other sites (p<0.05). Our results indicate that the three transdermal Fen patches exhibit different adhesive properties and local adverse events, indicating that the application site should be cautiously selected for each patch type.