noroxycodone and Neoplasms

Oxycodone is a µ-opioid receptor agonist widely used in the treatment of cancer pain. The predominant metabolic pathway of oxycodone is CYP3A4-mediated N-demethylation to noroxycodone, while a minor proportion undergoes 3-O-demethylation to oxymorphone by CYP2D6. The aim of this study was to investigate the effects of the mild CYP3A4 inhibitor aprepitant on the pharmacokinetics of orally administered controlled-release (CR) oxycodone.. This study design was an open-label, single-sequence with two phases in cancer patients with pain who continued to be administered orally with multiple doses of CR oxycodone every 8 or 12 hours. Plasma concentration of oxycodone and its metabolites were measured up to 8 hours after administration as follows: on day 1, CR oxycodone was administered alone; on day 2, CR oxycodone was administered with aprepitant (125 mg, at the same time of oxycodone dosing in the morning). The steady-state trough concentrations (Css) were measured from day 1 to day 3.. Aprepitant increased the area under the plasma concentration-time curve (AUC0-8) of oxycodone by 25% (p<0.001) and of oxymorphone by 34% (p<0.001), as well as decreased the AUC0-8 of noroxycodone by 14% (p<0.001). Moreover, aprepitant increased Css of oxycodone by 57% (p = 0.001) and of oxymorphone by 36% (p<0.001) and decreased Css of noroxycodone by 24% (p = 0.02) at day 3 compared to day 1.. The clinical use of aprepitant in patients receiving multiple doses of CR oxycodone for cancer pain significantly altered plasma concentration levels, but would not appear to need modification of the CR oxycodone dose.. UMIN.ac.jp UMIN000003580.

Topics: Adult; Aged; Analgesics, Opioid; Aprepitant; Area Under Curve; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphinans; Morpholines; Neoplasms; Oxycodone; Oxymorphone; Pain

This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence.

Topics: Aged; Analgesics, Opioid; Cachexia; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain

Oxycodone is widely used for the treatment of cancer pain, but little is known of its pharmacokinetics in cancer pain patients. The aim of this study was to explore the relationships between ordinary patient characteristics and serum concentrations of oxycodone and the ratios noroxycodone or oxymorphone/oxycodone in cancer patients.. Four hundred and thirty-nine patients using oral oxycodone for cancer pain were included. The patients' characteristics (sex, age, body mass index [BMI], Karnofsky performance status, "time since starting opioids", "oxycodone total daily dose", "time from last oxycodone dose", use of CYP3A4 inducer/inhibitor, "use of systemic steroids", "number of medications taken in the last 24 h", glomerular filtration rate (GFR) and albumin serum concentrations) influence on oxycodone serum concentrations or metabolite/oxycodone ratios were explored by multiple regression analyses.. Sex, CYP3A4 inducers/inhibitors, total daily dose, and "time from last oxycodone dose" predicted oxycodone concentrations. CYP3A4 inducers, total daily dose, and "number of medications taken in the last 24 h" predicted the oxymorphone/oxycodone ratio. Total daily dose, "time from last dose to blood sample", albumin, sex, CYP3A4 inducers/inhibitors, steroids, BMI and GFR predicted the noroxycodone/oxycodone ratio.. Women had lower oxycodone serum concentrations than men. CYP3A4 inducers/inhibitors should be used with caution as these are predicted to have a significant impact on oxycodone pharmacokinetics. Other characteristics explained only minor parts of the variability of the outcomes.

Topics: Analgesics, Opioid; Cross-Sectional Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Linear Models; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Sex Factors

The aim of this study was to evaluate the plasma dispositions of oxycodone and its demethylates and dose escalation based on genetic polymorphisms of CYP2D6, CYP3A5, ABCB1, and OPRM1 in cancer patients receiving oxycodone. Sixty-two Japanese cancer patients receiving oxycodone extended-release tablets were enrolled. Predose plasma concentrations (C(12)) of oxycodone, noroxycodone, and oxymorphone were determined at the titrated dose. Daily oxycodone escalation rate was evaluated as the opioid escalation index (OEI). Genetic variants did not significantly alter oxycodone C(12). Oxymorphone C(12) and its ratio to oxycodone C(12) were significantly higher in CYP2D6 extensive metabolizers than in intermediate metabolizers but did not affect dose escalation. In contrast, noroxycodone C(12) and its ratio to oxycodone C(12) were significantly higher in the CYP3A5*1 carrier group than in the *3/*3 group. The OEI was significantly higher in the CYP3A5*3/*3 group than in the *1 carrier group. No significant difference was observed in the OEI in the other genetic variants. Noroxycodone C(12) was higher in the dose escalation group as compared to the nonescalation group and significantly affected the incidence of dose escalation. In conclusion, CYP3A5*3 altered the plasma disposition of noroxycodone, which was inversely affecting the dose escalation in cancer patients receiving oxycodone.

Topics: Aged; Asian People; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Delayed-Action Preparations; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Polymorphism, Genetic; Receptors, Opioid, mu

We prospectively investigated the efficacy of opioid rotation from oral morphine to oral oxycodone in cancer patients who had difficulty in continuing oral morphine treatment because of inadequate analgesia and/or intolerable side effects.. Twenty-seven patients were enrolled and 25 were evaluated. The rate of patients who achieved adequate pain control, which provided an indication of treatment success, was evaluated as primary endpoint. The acceptability and pharmacokinetics of oxycodone were evaluated in addition to the assessment of analgesic efficacy and safety during the study period.. In spite of intense pain, the morphine daily dose could not be increased in most patients before the study because of intolerable side effects. However, switching to oral oxycodone allowed approximately 1.7-fold increase as morphine equivalent dose. Consequently, 84.0% (21/25) of patients achieved adequate pain control. By the end of the study, all patients except one had tolerated the morphine-induced intolerable side effects (i.e. nausea, vomiting, constipation, drowsiness). Common side effects (>10%) that occurred during the study were typically known for strong opioid analgesics, and most were mild to moderate in severity. A significant negative correlation between creatinine clearance (CCr) value and the trough concentrations of the morphine metabolites was observed. On the other hand, no significant correlation was found between CCr value and the pharmacokinetic parameters of oxycodone or its metabolites.. For patients who had difficulty in continuing oral morphine treatment, regardless of renal function, opioid rotation to oral oxycodone may be an effective approach to alleviate intolerable side effects and pain.

Topics: Administration, Oral; Aged; Analgesics, Opioid; Constipation; Drug Administration Schedule; Female; Humans; Linear Models; Male; Middle Aged; Morphinans; Morphine; Morphine Derivatives; Nausea; Neoplasms; Oxycodone; Pain; Prospective Studies; Renal Insufficiency, Chronic; Sleep Stages; Treatment Outcome; Vomiting

Thirty patients with cancer pain completed a double-blind crossover study comparing controlled-release (CR) and immediate-release (IR) oxycodone. In open-label titration (2 to 21 days), these patients were stabilized on IR oxycodone qid. They were then randomized to double-blind treatment with CR oxycodone q12h or IR oxycodone qid for 3 to 7 days followed by crossover at the same daily dose. Mean (+/- SD) pain intensity (0 = none to 10 = severe) decreased from a baseline of 6.0 +/- 2.2 to 2.7 +/- 1.1 after titration with IR oxycodone dosed qid. Pain intensity remained stable throughout double-blind treatment: 2.7 +/- 1.9 with CR oxycodone and 2.8 +/- 1.9 with IR oxycodone. Acceptability of therapy and pain scores correlated with plasma oxycodone concentrations for each interval and were similar for both medications (IR and CR oxycodone). Adverse events were similar for both formulations. Following repeat dosing under double-blind conditions, oral CR oxycodone administered q12h provided analgesia comparable to IR oxycodone given qid.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Biological Availability; Chronic Disease; Cross-Over Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Oxymorphone; Pain; Pain Measurement; Therapeutic Equivalency; Vomiting

Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain.

Topics: Administration, Oral; Adult; Aged; Analgesics, Opioid; Cross-Over Studies; Cytochrome P-450 CYP2D6; Debrisoquin; Delayed-Action Preparations; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Morphine; Morphine Derivatives; Neoplasms; Oxycodone; Pain; Pain Measurement; Phenotype

Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to non-essential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple non-invasive test to investigate opioid PKs.. Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection.. One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day). Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9-269.4 μg/L, respectively. Salivary concentrations of oxycodone (range 0.93-3,620, mean 336 μg/L) were much higher than plasma concentrations (mean 38.2 μg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r (2) = 0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method.. High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Morphinans; Neoplasms; Oxycodone; Patient Preference; Saliva; Tandem Mass Spectrometry; Time Factors; Young Adult