Juha Grönlund

Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied. WHAT THIS STUDY ADDS Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone. When both of CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially. AIM The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone. METHODS A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated. RESULTS Paroxetine alone reduced the area under concentration-time curve (AUC(0,0-48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,infinity) of oxycodone increased by 2.9-fold (P < 0.001), and its C(max) by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo. CONCLUSIONS Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.

Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

BackgroundThe aim of this study was to investigate the effects of the cytochrome P450 3A4 (CYP34A) inhibitor itraconazole on the pharmacokinetics and pharmacodynamics of orally and intravenously administered oxycodone.MethodsTwelve healthy subjects were administered 200 mg itraconazole or placebo orally for 5 days in a four-session paired cross-over study. On day 4, oxycodone was administered intravenously (0.1 mg/kg) in the first part of the study and orally (10 mg) in the second part. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacodynamic effects were evaluated.ResultsItraconazole decreased plasma clearance (Cl) and increased the area under the plasma concentration–time curve (AUC0–∞) of intravenous oxycodone by 32 and 51%, respectively (P < 0.001) and increased the AUC(0–∞) of orally administrated oxycodone by 144% (P < 0.001). Most of the pharmacokinetic changes in oral oxycodone were seen in the elimination phase, with modest effects by itraconazole on its peak concentration, which was increased by 45% (P = 0.009). The AUC(0–48) of noroxycodone was decreased by 49% (P < 0.001) and that of oxymorphone was increased by 359% (P < 0.001) after the administration of oral oxycodone. The pharmacologic effects of oxycodone were enhanced by itraconazole only modestly.ConclusionsItraconazole increased the exposure to oxycodone by inhibiting its CYP3A4-mediated N-demethylation. The clinical use of itraconazole in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid-associated adverse effects.

Feasibility and cardiac safety of inhaled xenon in combination with therapeutic hypothermia following out-of-hospital cardiac arrest.

Objectives:Preclinical studies reveal the neuroprotective properties of xenon, especially when combined with hypothermia. The purpose of this study was to investigate the feasibility and cardiac safety of inhaled xenon treatment combined with therapeutic hypothermia in out-of-hospital cardiac arrest patients. Design:An open controlled and randomized single-centre clinical drug trial (clinicaltrials.gov NCT00879892). Setting:A multipurpose ICU in university hospital. Patients:Thirty-six adult out-of-hospital cardiac arrest patients (18–80 years old) with ventricular fibrillation or pulseless ventricular tachycardia as initial cardiac rhythm. Interventions:Patients were randomly assigned to receive either mild therapeutic hypothermia treatment with target temperature of 33°C (mild therapeutic hypothermia group, n = 18) alone or in combination with xenon by inhalation, to achieve a target concentration of at least 40% (Xenon + mild therapeutic hypothermia group, n = 18) for 24 hours. Thirty-three patients were evaluable (mild therapeutic hypothermia group, n = 17; Xenon + mild therapeutic hypothermia group, n = 16). Measurements and Main Results:Patients were treated and monitored according to the Utstein protocol. The release of troponin-T was determined at arrival to hospital and at 24, 48, and 72 hours after out-of-hospital cardiac arrest. The median end-tidal xenon concentration was 47% and duration of the xenon inhalation was 25.5 hours. The frequency of serious adverse events, including inhospital mortality, status epilepticus, and acute kidney injury, was similar in both groups and there were no unexpected serious adverse reactions to xenon during hospital stay. In addition, xenon did not induce significant conduction, repolarization, or rhythm abnormalities. Median dose of norepinephrine during hypothermia was lower in xenon-treated patients (mild therapeutic hypothermia group = 5.30 mg vs Xenon + mild therapeutic hypothermia group = 2.95 mg, p = 0.06). Heart rate was significantly lower in Xenon + mild therapeutic hypothermia patients during hypothermia (p = 0.04). Postarrival incremental change in troponin-T at 72 hours was significantly less in the Xenon + mild therapeutic hypothermia group (p = 0.04). Conclusions:Xenon treatment in combination with hypothermia is feasible and has favorable cardiac features in survivors of out-of-hospital cardiac arrest.

Effect of Inhibition of Cytochrome P450 Enzymes 2D6 and 3A4 on the Pharmacokinetics of Intravenous Oxycodone

Background and ObjectiveOxycodone is a μ-opioid receptor agonist that is mainly metabolized by hepatic cytochrome P450 (CYP) enzymes. Because CYP enzymes can be inhibited by other drugs, the pharmacokinetics of oxycodone are prone to drug interactions. The aim of this study was to determine whether inhibition of CYP2D6 alone by paroxetine or inhibition of both CYP2D6 and CYP3A4 by a combination of paroxetine and itraconazole alters the pharmacokinetics of and pharmacological response to intravenous oxycodone.MethodsWe used a randomized, three-phase, crossover, placebo-controlled study design in 12 healthy subjects. The subjects were given 0.1 mg/kg of intravenous oxycodone after pre-treatments with placebo, paroxetine or a combination of paroxetine and itraconazole for 4 days. Plasma concentrations of oxycodone and its oxidative metabolites were measured over 48 hours, and pharmacokinetic and pharmacodynamic parameters subsequently evaluated.ResultsThe effect of paroxetine on the plasma concentrations of oxycodone was negligible. The combination of paroxetine and itraconazole prolonged the mean elimination half-life of oxycodone from 3.8 to 6.6 hours (p<0.001), and increased the exposure to oxycodone 2-fold (p < 0.001). However, these changes were not reflected in pharmacological response.ConclusionThe results of this study indicate that there are no clinically relevant drug interactions with intravenous oxycodone and inhibitors of CYP2D6. If both oxidative metabolic pathways via CYP3A4 and 2D6 are inhibited the exposure to intravenous oxycodone increases substantially.

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00879892.

Effect of Telithromycin on the Pharmacokinetics and Pharmacodynamics of Oral Oxycodone

The aim of this study is to determine whether the inhibition of CYP2D6 and CYP3A4 enzyme activity with telithromycin affects the pharmacokinetics and pharmacodynamics of orally administered oxycodone in a randomized 2‐phase crossover study. Eleven healthy subjects were pretreated with 800 mg of oral telithromycin or placebo for 4 days. On day 3, they ingested 10 mg of immediate‐release oxycodone. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 hours, and pharmacodynamic effects were evaluated. Telithromycin increased the area under the plasma concentration‐time curve (AUC0‐∞) of oxycodone by 80% (P < .001) and reduced the AUC0‐∞ of noroxycodone by 46% (P < .001). Most of the pharmacokinetic changes were seen in the elimination phase, with little effect by telithromycin on the peak concentration of oxycodone. Pharmacodynamic effects of oxycodone were modestly enhanced by telithromycin. In conclusion, telithromycin clearly reduces the N‐demethylation of oxycodone to noroxycodone by inhibiting the CYP450 3A4 enzyme. The use of telithromycin in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid adverse effects. Reduction of oxycodone dose by 25% to 50% followed by readjustment according to the clinical response might be appropriate.

Miconazole Oral Gel Increases Exposure to Oral Oxycodone by Inhibition of CYP2D6 and CYP3A4

ABSTRACT Our aim was to assess the effect of miconazole oral gel on the pharmacokinetics of oral oxycodone. In an open crossover study with two phases, 12 healthy volunteers took a single oral dose of 10 mg of immediate-release oxycodone with or without thrice-daily 85-mg miconazole oral gel treatment. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h. Pharmacological effects of oxycodone were recorded for 12 h. Pharmacokinetic parameters were compared by use of the geometric mean ratios (GMRs) and their 90% confidence interval (CIs). Pretreatment with miconazole oral gel caused a strong inhibition of the CYP2D6-dependent metabolism and moderate inhibition of the CYP3A4-dependent metabolism of oxycodone. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC0-∞; GMR, 1.63; 90% CI, 1.48 to 1.79) and the peak concentration of oxycodone (GMR, 1.31; 90% CI, 1.19 to 1.44) were increased. The AUC of the CYP2D6-dependent metabolite oxymorphone was greatly decreased (GMR, 0.17; 90% CI, 0.09 to 0.31) by miconazole gel, whereas that of the CYP3A4-dependent metabolite noroxycodone was increased (GMR, 1.30; 90% CI, 1.15 to 1.47) by miconazole gel. Differences in the pharmacological response to oxycodone between phases were insignificant. Miconazole oral gel increases the exposure to oral oxycodone, but the clinical relevance of the interaction is moderate. Miconazole oral gel produces a rather strong inhibitory effect on CYP2D6, which deserves further study.

Re: Pergolizzi et al. 2011: Exposure to potential CYP450 pharmacokinetic drug–drug interactions

below. Depending on the body habitus, an appropriate frequency transducer is chosen. A preliminary scout scan is performed to locate the vessels in the vicinity. Subsequently, the scanning sequence is started anteriorly from the mid-thigh level. In a transverse view, the shaft of the femur appears as a curved hyperechoic crescent (Figure 1A). Keeping the shaft in the center of the field, the scanning is continued cephalad (more proximal on the femur) when the hyperechoic crescent straightens as it reaches the area of the trochanters (Figure 1B). Further advancement may show the peak formed by the greater trochanter (Figure 1C). A trochanteric bursa injection may be performed at this site. The transducer is then brought down to the level of the trochanters when it again appears as a hyperechoic straight line. The transducer at the level of the trochanters is then moved medial such that the trochanteric image is on the lateral end of the screen. The outline of the neck may then be visualized medially, sometimes, as an oblique line continuing from the straight hyperechoic line formed by the trochanteric level. By rotating just the medial end of the transducer cephalad and keeping the lateral end stationary, the rounded hyperechoic femoral head and straight hyperechoic line denoting the neck come into view (Figure 1D). The transducer is then adjusted to optimally visualize the head, neck, and the acetabulum with the iliofemoral ligament that will also appear hyperechoic (Figure 2 and Video S1). The image optimization may require adjusting the transducer tilt or obliquity. The target for injection is the anterior synovial recess located at the junction of the head and neck. This simple technique in the author’s experience offers continued visualization of the femur and permits comprehension of the change in the sonographic appearance of the femur from the shaft to the neck and head. In addition, it may also prevent novices from wrongly identifying the curved bony structures of the pelvis as part of the hip joint as is seen when scanning over the sciatic notch (Figure 3).

Surviving out-of-hospital cardiac arrest: The neurological and functional outcome and health-related quality of life one year later

BACKGROUND Data on long-term functional outcome and quality of life (QoL) after out-of-hospital cardiac arrest (OHCA) are limited. We assessed long-term functional outcome and health-related QoL of OHCA survivors regardless of arrest aetiology. METHODS All adult unconscious OHCA patients treated in 21 Finnish ICUs between March 2010 and February 2011 were followed. Barthel Index (BI), activities of daily living (ADL), accommodation, help needed and received, working status, car driving and self-experienced cognitive deficits were assessed in 1-year survivors (N = 206, 40.9% of the original FINNRESUSCI cohort) with a structured telephone interview. Health-related QoL and more complex ADL-functions were evaluated by EQ-5D and instrumental ADL questionnaires. RESULTS Good outcome, defined as Cerebral Performance Categories 1 or 2, had been reached by 90.3% of survivors. The median BI score was 100, and 91.3% of survivors were independent in basic ADL-functions. The great majority of survivors were living at home, only 8.7% lived in a sheltered home or needed institutionalized care. Of home-living survivors 71.4% scored high in instrumental ADL assessment. The majority (72.6%) of survivors who were working previously had returned to work. Health-related QoL was similar as in age- and gender-adjusted Finnish population. CONCLUSIONS Long-term functional outcome was good in over 90% of patients surviving OHCA, with health-related quality of life similar to that of an age and gender matched population.