Voriconazole greatly increases the exposure to oral buprenorphine.

PURPOSE: Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine. METHODS: Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2-5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg. RESULTS: Voriconazole greatly increased the mean area under the plasma concentration-time curve (AUC0-18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0-18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases. CONCLUSIONS: Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.

Development and pilot testing of PHARAO-a decision support system for pharmacological risk assessment in the elderly.

PURPOSE: The aims of this study are to describe the development of PHARAO (Pharmacological Risk Assessment Online), a decision support system providing a risk profile for adverse events, associated with combined effects of multiple medicines, and to present data from a pilot study, testing the use, functionality, and acceptance of the PHARAO system in a clinical setting. METHODS: About 1400 substances were scored in relation to their risk to cause any of nine common and/or serious adverse effects. Algorithms for each adverse effect score were developed to create individual risk profiles from the patient's list of medication. The system was tested and integrated to the electronic medical record, during a 4-month period in two geriatric wards and three primary healthcare centers, and a questionnaire was answered by the users before and after the test period. RESULTS: A total of 732 substances were tagged with one or more of the nine risks, most commonly with the risk of sedation or seizures. During the pilot, the system was used 933 times in 871 patients. The most common signals generated by PHARAO in these patients were related to the risks of constipation, sedation, and bleeding. A majority of responders considered PHARAO easy to use and that it gives useful support in performing medication reviews. CONCLUSIONS: The PHARAO decision support system, designed as a complement to a database on drug-drug interactions used nationally, worked as intended and was appreciated by the users during a 4-month test period. Integration aspects need to be improved to minimize unnecessary signaling.

Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.

PURPOSE: This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. METHODS: We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. RESULTS: Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC0-∞) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (Cmax) 1.37-fold (P < 0.013) and half-life (t ½ ) 1.37-fold (P < 0.001). Posaconazole increased the AUC00-∞ of buprenorphine 1.25-fold (P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. CONCLUSIONS: Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.

Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects.

Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first-pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four-session paired cross-over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6-mg (placebo phase) or 0.8-mg (rifampicin phase) buprenorphine sublingually on day 7. In the second part of the study, subjects received 0.4-mg buprenorphine intravenously. Plasma concentrations of buprenorphine and urine concentrations of buprenorphine and its primary metabolite norbuprenorphine were measured over 18 h. Adverse effects were recorded. Rifampicin decreased the mean area under the dose-corrected plasma concentration-time curve (AUC 0-18) of sublingual buprenorphine by 25% (geometric mean ratio (GMR): 0.75; 90% confidence interval (CI) of GMR: 0.60, 0.93) and tended to decrease the bioavailability of sublingual buprenorphine, from 22% to 16% (P = 0.31). Plasma concentrations of intravenously administered buprenorphine were not influenced by rifampicin. The amount of norbuprenorphine excreted in the urine was decreased by 65% (P < 0.001) and 52% (P < 0.001) after sublingual and intravenous administration, respectively, by rifampicin. Adverse effects were frequent. Rifampicin decreases the exposure to sublingual but not intravenous buprenorphine. This can be mainly explained by an enhancement of CYP3A-mediated first-pass metabolism, which sublingual buprenorphine only partially bypasses. Concomitant use of rifampicin and low-dose sublingual buprenorphine may compromise the analgesic effect of buprenorphine.

Effects of terbinafine and itraconazole on the pharmacokinetics of orally administered tramadol.

BACKGROUND: Tramadol is widely used for acute, chronic, and neuropathic pain. Its primary active metabolite is O-desmethyltramadol (M1), which is mainly accountable for the µ-opioid receptor-related analgesic effect. Tramadol is metabolized to M1 mainly by cytochrome P450 (CYP)2D6 enzyme and to other metabolites by CYP3A4 and CYP2B6. We investigated the possible interaction of tramadol with the antifungal agents terbinafine (CYP2D6 inhibitor) and itraconazole (CYP3A4 inhibitor). METHODS: We used a randomized placebo-controlled crossover study design with 12 healthy subjects, of which 8 were extensive and 4 were ultrarapid CYP2D6 metabolizers. On the pretreatment day 4 with terbinafine (250 mg once daily), itraconazole (200 mg once daily) or placebo, subjects were given tramadol 50 mg orally. Plasma concentrations of tramadol and M1 were determined over 48 h and some pharmacodynamic effects over 12 h. Pharmacokinetic variables were calculated using standard non-compartmental methods. RESULTS: Terbinafine increased the area under plasma concentration-time curve (AUC0-∞) of tramadol by 115 % and decreased the AUC0-∞ of M1 by 64 % (P < 0.001). Terbinafine increased the peak concentration (C max) of tramadol by 53 % (P < 0.001) and decreased the C max of M1 by 79 % (P < 0.001). After terbinafine pretreatment the elimination half-life of tramadol and M1 were increased by 48 and 50 %, respectively (P < 0.001). Terbinafine reduced subjective drug effect of tramadol (P < 0.001). Itraconazole had minor effects on tramadol pharmacokinetics. CONCLUSIONS: Terbinafine may reduce the opioid effect of tramadol and increase the risk of its monoaminergic adverse effects. Itraconazole has no meaningful interaction with tramadol in subjects who have functional CYP2D6 enzyme.

The degree of fetal metformin exposure does not influence fetal outcome in gestational diabetes mellitus.

The purpose of the study was to examine in vivo placental transfer of metformin, its association with neonatal outcome in metformin-treated gestational diabetes (GDM) patients, and influence of metformin exposure on maternal glycemic control and weight gain. Two hundred and seventeen GDM patients were randomized to metformin or insulin in Turku University Hospital, Finland. Metformin concentrations were determined by mass spectrometry in maternal serum at 36 gestational weeks (gw) and at birth, and in umbilical cord blood. Main outcome measures were birth weight, gw at birth, umbilical artery pH and neonatal hypoglycemia, maternal weight gain, HbA1c and fructosamine concentration. Median umbilical cord/maternal serum metformin concentration ratio was 0.73. There were no differences in birth weight measured in grams or SD units (p = 0.49), or gw at birth (p always ≥0.49) between insulin- and metformin-treated patients stratified by trough metformin concentration tertiles measured at 36 gw. Rate of neonatal hypoglycemia (p = 0.92) and umbilical artery pH value (p = 0.78) was similar in insulin- and metformin-treated patients stratified by cord metformin concentration tertiles. Maternal glycemic control was similar in metformin concentration tertiles at 36 gw. Maternal weight gain was 223 g greater per week (p = 0.038) in the lowest metformin tertile compared to other tertiles combined. Maternal and fetal exposure to metformin is similar. Maternal or fetal metformin concentrations do not predict maternal glycemic control or neonatal outcome, but low maternal exposure may lead to greater maternal weight gain.

Epidemiology of CYP3A4-mediated clopidogrel drug-drug interactions and their clinical consequences.

AIMS: Clopidogrel is a prodrug that needs to be activated to inhibit platelet aggregation. The objective of this study was to evaluate the prevalence and clinical consequences of potential drug-drug interactions of clopidogrel with drugs affecting CYP3A4 activity. METHODS: Co-administrations of clopidogrel together with well-established CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin were investigated in a population-based pharmacoepidemiological study utilizing data from the national healthcare registers and in more detail from a university hospital register in Finland. The main outcome measures were all-cause mortality and mortality and morbidity related to thrombosis or bleeding. RESULTS: In the nationwide analysis, 6.1%, 1.0%, and 20.8% of the clopidogrel-treated patients were exposed to concomitant use of CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 (P < 0.001) for CYP3A4 inducer users and 0.74 (P = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP3A4 inhibitor groups compared with controls. Thrombosis complications leading to hospitalizations were more often seen in the atorvastatin group than in the control group. CONCLUSIONS: No uniform untoward effect of concomitant CYP3A4 inhibitor use on the clinical efficacy of clopidogrel was found. In patients receiving concomitant atorvastatin and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality. CYP3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.

Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction.

PURPOSE: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. METHODS: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. RESULTS: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. CONCLUSIONS: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.

Rifampicin markedly decreases the exposure to oral and intravenous tramadol.

PURPOSE: Tramadol is mainly metabolized by the cytochrome P450 (CYP) 2D6, CYP2B6 and CYP3A4 enzymes. The aim of this study was to evaluate the effect of enzyme induction with rifampicin on the pharmacokinetics and pharmacodynamics of oral and intravenous tramadol. METHODS: This was a randomized placebo-controlled crossover study design with 12 healthy subjects. After pretreatment for 5 days with rifampicin (600 mg once daily) or placebo, subjects were given tramadol either 50 mg intravenously or 100 mg orally. Plasma concentrations of tramadol and its active main metabolite O-desmethyltramadol (M1) were determined over 48 h. Analgesic and behavioral effects and whole blood 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured. RESULTS: Rifampicin reduced the mean area under the time-concentration curve (AUC0-∞) of intravenously administered tramadol by 43 % and that of M1 by 58 % (P < 0.001); it reduced the AUC0-∞ of oral tramadol by 59 % and that of M1 by 54 % (P < 0.001). Rifampicin increased the clearance of intravenous tramadol by 67 % (P < 0.001). Bioavailability of oral tramadol was reduced by rifampicin from 66 to 49 % (P = 0.002). The pharmacological effects of tramadol or whole blood serotonin concentrations were not influenced by pretreatment with rifampicin. CONCLUSIONS: Rifampicin markedly decreased the exposure to tramadol and M1 after both oral and intravenous administration. Therefore, rifampicin and other potent enzyme inducers may have a clinically important interaction with tramadol regardless of the route of its administration.

Rifampicin has a profound effect on the pharmacokinetics of oral S-ketamine and less on intravenous S-ketamine.

Low-dose ketamine is currently used in several acute and chronic pain conditions as an analgesic. Ketamine undergoes extensive metabolism and is thus susceptible to drug-drug interactions. We examined the effect rifampicin, a well-known inducer of many cytochrome P450 (CYP) enzymes and transporters, on the pharmacokinetics of intravenous and oral S-ketamine in healthy volunteers. Eleven healthy volunteers were administered in randomized order 600 mg rifampicin or placebo orally for 6 days in a four-session paired cross-over study. On day 6, S-ketamine was administered intravenously (0.1 mg/kg) in the first part of the study and orally (0.3 mg/kg) in the second part. Plasma concentrations of ketamine and norketamine were measured up to 24 hr and behavioural and analgesic effects up to 12 hr. Rifampicin treatment decreased the mean area under the plasma ketamine concentration-time curve extrapolated to infinity (AUC (0-∞)) of intravenous and oral S-ketamine by 14% (p = 0.005) and 86% (p < 0.001), respectively. Rifampicin decreased greatly the peak plasma concentration of oral S-ketamine by 81% (p < 0.001), but shortened only moderately the elimination half-life of intravenous and oral S-ketamine. Rifampicin decreased the ratio of norketamine AUC (0-∞) to ketamine AUC (0-∞) after intravenous S-ketamine by 66%, (p < 0.001) but increased the ratio by 147% (p < 0.001) after the oral administration of S-ketamine. Rifampicin profoundly reduces the plasma concentrations of ketamine and norketamine after oral administration of S-ketamine, by inducing mainly its first-pass metabolism.

S-ketamine concentrations are greatly increased by grapefruit juice.

PURPOSE: We examined the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral S-ketamine. METHODS: A randomized crossover open-label study design with two phases at an interval of 4 weeks was conducted in 12 healthy volunteers. Grapefruit juice or water was ingested 200 ml t.i.d. for 5 days. An oral dose of 0.2 mg/kg of S-ketamine was ingested on day 5 with 150 ml grapefruit juice or water. Plasma concentrations of ketamine and norketamine were determined for 24 h, and pharmacodynamic variables were recorded for 12 h. Noncompartmental methods were used to calculate pharmacokinetic parameters. RESULTS: Grapefruit juice increased the geometric mean value of the area under the plasma ketamine concentration-time curve(AUC0-∞) by 3.0-fold (range 2.4- to 3.6-fold; P<0.001), the peak plasma concentration (Cmax) by 2.1-fold (range 1.8- to 2.6-fold; P<0.001), and the elimination half-life by 24% (P<0.05) as compared to the water phase. The ratio of main metabolite norketamine to ketamine (AUCm/AUCp) was decreased by 57% (P<0.001) during the grapefruit phase.Self-rated relaxation was decreased (P<0.05) and the performance in the digit symbol substitution test was increased (P<0.05) after grapefruit juice, but other behavioral or analgesic effects were not affected. CONCLUSIONS: Grapefruit juice significantly increased the plasma concentrations of oral ketamine in healthy volunteers.Dose reductions of ketamine should be considered when using oral ketamine concomitantly with grapefruit juice.

Decreased frost hardiness of Vaccinium vitis-idaea in reponse to UV-A radiation.

The aim of this study was to investigate plant frost hardiness responses to ultraviolet (UV) radiation, since the few results reported are largely contradictory. It was hypothesized that functional adaptation of life forms could explain these contradictions. Dwarf shrubs and tree seedlings, representing both evergreen and deciduous forms, were tested (Vaccinium vitis-idaea, Vaccinium myrtillus, Pinus sylvestris, Betula pubescens and its red form f. rubra). The research was performed in Sodankylä, Northern Finland (67°N), with enhanced UV-B- and UV-A-radiation treatments between 2002 and 2009. Plant frost hardiness was determined using the freeze-induced electrolyte leakage method in early autumn, during the onset of the frost hardening process. Additional physiological variables (malondialdehyde, glutathione, total phenols, C and N contents) were analyzed in V. vitis-idaea to explain the possible responses. These variables did not respond significantly to UV-radiation treatments, but explained the frost hardiness well (r² = 0.678). The main finding was that frost hardiness decreased in the evergreen shrub V. vitis-idaea, particularly with enhanced UV-A radiation. No significant responses were observed with the other plants. Therefore, this study does not support the idea that enhanced UV radiation could increase plant frost hardiness.

St John's wort greatly decreases the plasma concentrations of oral S-ketamine.

Ketamine is an intravenous anaesthetic and analgesic agent but it can also be used orally as an adjuvant in the treatment of chronic pain. This study investigated the effect of the herbal antidepressant St John's wort, an inducer of cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics and pharmacodynamics of oral S-ketamine. In a randomized cross-over study with two phases, 12 healthy subjects were pretreated with oral St John's wort or placebo for 14 days. On day 14, they were given an oral dose of 0.3 mg/kg of S-ketamine. Plasma concentrations of ketamine and norketamine were measured for 24 h and pharmacodynamic variables for 12 h. St John's wort decreased the mean area under the plasma concentration-time curve (AUC(0-∞)) of ketamine by 58% (P < 0.001) and decreased the peak plasma concentration (C(max)) of ketamine by 66% (P < 0.001) when compared with placebo. Mean C(max) of norketamine (the major metabolite of ketamine) was decreased by 23% (P = 0.002) and mean AUC(0-∞) of norketamine by 18% (P < 0.001) by St John's wort. There was a statistically significant linear correlation between the self-reported drug effect and C(max) of ketamine (r = 0.55; P < 0.01). St John's wort greatly decreased the exposure to oral S-ketamine in healthy volunteers. Although this decrease was not associated with significant changes in the analgesic or behavioural effects of ketamine in the present study, usual doses of S-ketamine may become ineffective if used concomitantly with St John's wort.

Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs).

OBJECTIVES: Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs. STUDY DESIGN: Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas. RESULTS: Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to-fetal transfer (P<0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism. CONCLUSIONS: The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP-transporters may be an important factor in fetal exposure to repaglinide.

Effect of inhibition of cytochrome P450 enzymes 2D6 and 3A4 on the pharmacokinetics of intravenous oxycodone: a randomized, three-phase, crossover, placebo-controlled study.

BACKGROUND AND OBJECTIVE: Oxycodone 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: The 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.

NCT01110291: induction of CYP3A activity and lowered exposure to docetaxel in patients with primary breast cancer.

PURPOSE: To study the CYP3A activity before and after docetaxel administration. Furthermore, it was investigated whether peroral midazolam could predict docetaxel exposure and adverse events. METHODS: Twenty patients with primary high risk breast cancer were given docetaxel as a 1-h infusion 80 mg/m(2) in a 21-day cycle in 3 cycles followed by 3 cycles of cyclophosphamide, epirubicin and fluorouracil. CYP3A activity was assessed a day before and a day after docetaxel by 7.5 mg oral midazolam. All patients were given peroral dexamethasone a total dose of 45 mg, of which 15 mg was given before docetaxel infusion and 30 mg before the latter assessment of CYP3A activity. All except one patient were given 11-19 mg of intravenous dexamethasone before docetaxel infusion. RESULTS: CYP3A activity was clearly induced when assessed a day after docetaxel administration as shown by lower midazolam AUC (P < 0.0001) and higher AUC ratio (1-OH-midazolam/midazolam, P = 0.018). The mean docetaxel AUC was about a half of that previously reported in the literature. Incidence of febrile neutropenia was smaller (15%) than reported in literature with comparable docetaxel doses and seemed to associate with slower metabolism. No correlation between pharmacokinetics of midazolam and docetaxel was found at baseline. CONCLUSIONS: We show here a markedly reduced docetaxel exposure followed by CYP3A induction by, most likely, dexamethasone. Peroral midazolam seemed not to predict docetaxel exposure. Slow CYP3A-mediated metabolism might predispose patients to adverse events of docetaxel.

Miconazole oral gel increases exposure to oral oxycodone by inhibition of CYP2D6 and CYP3A4.

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 (AUC(0-∞); 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.

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir.

PURPOSE: this study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain. METHODS: a randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis. RESULTS: ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (± SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P <0.001) and 5.7 ± 0.9 h (P <0.001), respectively. Both ritonavir (P <0.001) and lopinavir/ritonavir (P <0.05) increased the self-reported drug effect of oxycodone. CONCLUSIONS: ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

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.