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: CL(fenta) (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.

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.

Background There is no nationwide data on polypharmacy in palliative care in Japan. In this study, the research committee of the Japanese Society for Pharmaceutical Palliative Care and Sciences conducted an online survey on polypharmacy and inappropriate prescriptions involving its members who worked as hospital pharmacists. Methods The online questionnaire included questions about hospital pharmacist interventions for cancer patients who regularly used six or more drugs during a two-month period from October to November 2017. Results Of 2618 hospital pharmacists, 359 responded (13.7%). With regard to cancer patients receiving opioids, 40.9 and 22.3% of the respondents replied that percentages of patients prescribed six or more regular medications were “40–69%” and “70–99%,” respectively. Regarding patients on polypharmacy, 73.0% of the respondents reported a low or moderate rate of inappropriate prescriptions, with responses such as “long-term administration of irresponsible or aimless medications”, “adverse drug reactions,” and “duplication of the pharmacological effect”. Furthermore, 24.2, 46.8, and 23.4% of respondents replied that the rates of drug reduction due to pharmacist recommendations were “0”, “1–39%”, and “more than 40%,” respectively. Pharmacist interventions decreased the use of inappropriate medications, including antiemetics, gastrointestinal medications, and hypnotic sedatives, and reduced or prevented adverse drug reactions such as extrapyramidal symptoms, delirium, and sleepiness. Similar results were obtained for cancer patients who did not use opioids. However, the rates of cancer patients on polypharmacy and with reduction of inappropriate medications by pharmacist interventions were significantly higher in cancer patients receiving opioids. Finally, recommendations of board-certified pharmacists in palliative pharmacy contributed to a decrease in the use of inappropriate medications in cancer patients on polypharmacy ( p = 0.06). Conclusion This nationwide survey clarified pharmacist interventions for polypharmacy in palliative care in Japan. Our data showed frequent polypharmacy in cancer patients receiving opioids, and benefits of pharmacist interventions, especially by board-certified pharmacists in palliative pharmacy, for reducing inappropriate medications and improving adverse drug reactions. Trial registration The study approval numbers in the institution; 0046. Registered November 6, 2017. Electronic supplementary material The online version of this article (10.1186/s40780-019-0143-5) contains supplementary material, which is available to authorized users.

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Compound injections of oxycodone and hydrocotarnine are currently used as one of the treatment options for some cases with cancer pain. However, there have been no reports examining the factors that influence oxycodone and hydrocotarnine clearance, so detailed examination is necessary. As for hydrocotarnine, there have been no reports examining the pharmacokinetics. Therefore in this study, we determined the pharmacokinetics of oxycodone and hydrocotarnine in patients with cancer pain. The study was conducted on 19 patients, in whom pain control was attempted by using the compound injections of oxycodone and hydrocotarnine. We used HPLCelectrochemical detector (ECD) to determine oxycodone and hydrocotarnine serum concentrations, and used the nonlinear least-squares method (MULTI) for calculation of the pharmacokinetic parameters. Furthermore, we examined the factors that influence the clearance of oxycodone and hydrocotarnine by multiple regression analysis (step wise method). The pharmacokinetic parameters were as follows: Oxycodone; V d ‫5.501؎7.622؍‬ l (mean؎S.D.), CL‫1.52؎9.73؍‬ l/h, t 1/2 ‫9.1؎1.4؍‬ h. Hydrocotarnine; V d ‫2.732؎8.672؍‬ l, CL‫3.46؎1.59؍‬ l/h, t 1/2 ‫7.0؎0.2؍‬ h. The clearance of oxycodone represented by a regression formula was significantly correlated to the age, the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance of hydrocotarnine represented by a regression formula was significantly correlated to the presence or absence of within 7 d on the death or liver metastasis, or of the heart failure of the patients. The clearance also indicated that oxycodone concentration in the blood was likely to be higher in patients having these factors. Oxycodone/hydrocotarnine compound injections should be used with caution and dose reduction may be necessary in such populations.

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); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 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.

No nationwide study on polypharmacy in palliative care among Japanese community pharmacies has yet been conducted. We conducted an online questionnaire survey for community pharmacist members of The Japanese Society for Pharmaceutical Palliative Care and Sciences regarding their contributions to cancer patients who regularly used six or more drugs, including opioids, in service during the two-month period from October to November 2017. Of 579 community pharmacists, 83 responded to the survey (14.3%). Among them, 47.0 and 27.7% of respondents replied that more than 40% of opioid-using and non-using cancer patients were prescribed six or more regular medications, respectively. The proportion of patients with polypharmacy was marginally higher among opioid-using than non-using patients. Additionally, 31.3 and 22.9% of respondents replied that a low or moderate rate of opioid-using and non-using patients with polypharmacy received inappropriate prescriptions, respectively, including "unnecessary medications," "adverse drug reactions" and "duplication of pharmacological effect." The proportion of patients who received inappropriate prescriptions was significantly higher among opioid-using than non-using patients. Furthermore, 37.3 and 19.3% of respondents replied that pharmacist's recommendations contributed to drug reduction in opioidusing and non-using patients with polypharmacy who received inappropriate prescriptions, respectively. The responders with higher confidence in palliative care showed more success rate for reducing inappropriate medications. Our findings suggest that opioid use can be associated with an increased risk of polypharmacy in cancer patients, and that recommendations by a population of community pharmacists can reduce inappropriate medications and improve adverse drug reactions in both opioid-using and non-using cancer patients with polypharmacy.

The population pharmacokinetics of panipenem was studied in 23 neonates. Their postconceptional age (PCA) was 24.7-42.6 weeks and their body weight was 530-4455 g at initiation of therapy. Panipenem was infused over a period of 60 min in a dose of 10.2-34.7 mg/kg bd in 21 patients, tid in one patient and four times daily in one patient for a mean of 10.7 days. Blood samples were obtained just before the infusion and 1-2 h after and again 6 h after the infusion. All the data for the 108 serum panipenem concentrations were evaluated with a non-linear mixed-effect model (NONMEM with first-order method), a computer program designed for population pharmacokinetic analysis. One- and two-compartment population pharmacokinetic parameters were measured. The two-compartment parameters were as follows: panipenem clearance CL = 0.150 L/h, central volume of distribution = 0.54 L, intercompartmental clearance = 0.014 L/h and peripheral volume of distribution = 0.28 L. The one-compartment parameters were CL = 0.175 L/h and volume of distribution = 0.55 L. In the fitting process using the one-compartment model, significantly fixed effects related to CL were PCA, postnatal age (PNA), gestational age (GA), body weight (BW) and serum creatinine, and that for the distribution volume (V) was BW. CL showed a logarithmic rise with PCA (CL = 0.00176 x exp(0.14 x PCA)). The CL levels in the patients with PCA < 33 weeks (0.098 L/h) were significantly lower (P < 0.001) than those with PCA > or = 33 weeks (0.25 L/h). The final formulae for the population pharmacokinetic parameters are as follows: CL = 0.0832 (PCA < 33 weeks), CL = 0.179 x BW (PCA > or = 33 weeks), V = 0.53 x BW (coefficient of variation; 23.9% for CL, 28.5% for V). Based on these data, a simulated time-concentration curve was compared with that for adult data in a clinical Phase I study. Our findings suggest that the panipenem dosage regimen of 10-20 mg/kg every 12 h should yield concentrations within the accepted therapeutic range.