Pharmacokinetics Of Fentanyl Research Articles

A low blood volume LC‐MS/MS assay for the quantification of fentanyl and its major metabolites norfentanyl and despropionyl fentanyl in children

Preterm and term neonates often require surgical procedures and analgesia. However, our knowledge about neonatal pharmacokinetics of fentanyl, the most commonly used drug for these procedures, and its metabolites is still incomplete. To facilitate pharmacokinetic studies of fentanyl and its metabolites in neonates and other children, we developed and validated an LC-MS/MS method based on minimally invasive, low blood volume sampling. LC-MS/MS was used for the simultaneous analysis of fentanyl, despropionyl fentanyl (DPF), and norfentanyl from dried blood samples (DBS) collected on filter paper. Positive ions were monitored using multiple reaction monitoring. Since the standard matrix for measuring fentanyl blood concentrations is plasma, the assay was developed and validated in plasma, whole blood, and then DBS. Our method was able to measure clinically relevant levels of fentanyl and its metabolites. In DBS, the lower limits of quantification were 100 pg/mL for fentanyl with a range of reliable response from 0.1 to 100 ng/mL (r(2)>0.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r(2)>0.99). In plasma and in DBS inter-day accuracy and precisions of fentanyl met predefined acceptance criteria and also indicated comparable assay performance in both matrices.

The Population Pharmacokinetics of Fentanyl in Patients Undergoing Living-Donor Liver Transplantation

Fentanyl, an opioid analgesic with a high hepatic extraction ratio, is frequently used to supplement general anesthesia during liver transplantation and is also continuously infused to provide postoperative analgesia. However, because fentanyl is metabolized mainly in the liver, the pharmacokinetics of fentanyl may vary widely during the different phases of the surgery, potentially leading to adverse events. Using nonlinear mixed-effects modeling, we characterized the pharmacokinetics of fentanyl in 15 patients (American Society of Anesthesiologists Physical Status Classification 2 or 3) undergoing living-donor liver transplantation (LDLT). Fentanyl was continuously infused at the rate of 200-400µg/h throughout the operation. The time course of the fentanyl plasma concentration levels was best described in terms of a two-compartment model. Estimates were made of the pharmacokinetic parameters during the preanhepatic, anhepatic, and neohepatic phases: central volume of distribution (V(1)) (l): 59.0 + hourly volume infused by rapid infusion system (RIS) × 42.5, 113.0, and 189.0, respectively, × (body weight/69)(1.3); peripheral volume of distribution (V(2)) (l): 94.3, 412.0, and 427.0, respectively; intercompartmental clearance (Q) (l/h): 96.4 × (cardiac output (CO)/6.7)(2.5), 22.6, and 28.2, respectively; metabolic clearance (Cl) (l/h): 21.7 during the preanhepatic and neohepatic phases, and 0 during the anhepatic phase. The preanhepatic central volume of distribution was found to be markedly influenced by the massive infusion of fluids and blood products. The more hyperdynamic the circulation was during the preanhepatic phase, the higher the distributional clearance.

Effect of fentanyl target-controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red-tailed hawks (Buteo jamaicensis)

ObjectiveTo determine the impact of three different target plasma concentrations of fentanyl on the minimum anaesthetic concentration (MAC) for isoflurane in the red-tailed hawk and the effects on the haemodynamic profile. Study designExperimental study. Animal populationSix healthy adult red-tailed hawks (Buteo jamaicensis) of unknown sex with body weights (mean ± SD) of 1.21 ± 0.15 kg. MethodsThis study was undertaken in two phases. In the first phase anaesthesia was induced with isoflurane in oxygen via facemask and maintained with isoflurane delivered in oxygen via a Bain circuit. Following instrumentation baseline determination of the MAC for isoflurane was made for each animal using the bracketing method and a supramaximal electrical stimulus. End-tidal isoflurane concentration (E′Iso) was then set at 0.75 × MAC and after an appropriate equilibration period a bolus of fentanyl (20 μg kg−1) was administered intravenously (IV) in order to determine the pharmacokinetics of fentanyl in the isoflurane-anaesthetized red-tailed hawk. During the second phase anaesthesia was induced in a similar manner and E′Iso was set at 0.75 × MAC for each individual. Fentanyl was infused IV to achieve target plasma concentrations between 8 and 32 ng mL−1. At each fentanyl plasma concentration, the MAC for isoflurane and cardiovascular variables were determined. Data were analyzed by use of repeated-measures anova. ResultsMean ± SD fentanyl plasma concentrations and isoflurane MACs were 0 ± 0, 8.51 ± 4, 14.85 ± 4.82 and 29.25 ± 11.52 ng mL−1, and 2.05 ± 0.45%, 1.42 ± 0.53%, 1.14 ± 0.31% and 0.93 ± 0.32% for the target concentrations of 0, 8, 16 and 32 ng mL−1, respectively. At these concentrations fentanyl significantly (p = 0.0016) decreased isoflurane MAC by 31%, 44% and 55%, respectively. Dose had no significant effect on heart rate, systolic, diastolic or mean arterial blood pressure. Conclusions and clinical relevanceFentanyl produced a dose-related decrease of isoflurane MAC with minimal effects on measured cardiovascular parameters in red-tailed hawks.

Pharmacokinetics of subcutaneous fentanyl in Greyhounds

The purpose of the study was to describe the pharmacokinetics of subcutaneous fentanyl (15μg/kg) in six healthy Greyhound dogs. Fentanyl plasma concentrations were determined by a liquid chromatography with mass spectrometry method. Non-compartmental pharmacokinetic analysis was used. Fentanyl was rapidly absorbed with a mean peak concentration (C(MAX)) of 3.56ng/mL at 0.24h. The mean terminal half-life, volume of distribution per bioavailability, and clearance per bioavailability were 2.97h, 7.09L/kg, 27.60mL/min/kg, respectively. Pain occurred on injection in all six dogs, but addition of 8.4% sodium bicarbonate (1mL per 20mL fentanyl) resulted in no pain on injection in 3/3 dogs but similar C(MAX) values. The subcutaneous route may be an alternative route of fentanyl administration if intravenous administration is not practical.

Impact of CYP3A4*1G polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery

Purpose This study aimed to investigate the impact of CYP3A4*1G genetic polymorphism on metabolism of fentanyl in Chinese patients undergoing lower abdominal surgery. Methods 176 patients receiving elective lower abdominal surgery under general anesthesia were recruited into this study. Genotyping of CYP3A4*1G was carried out by direct sequencing. The plasma fentanyl concentration was detected 30 min after anesthesia induction by high performance liquid chromatography–ultraviolet ray (HPLC–UV). The visual analog scale (VAS) was used for pain evaluation at rest during patient-controlled analgesia (PCA) treatment 0 h, 12 h and 24 h after operation. PCA fentanyl consumption and adverse effects were recorded during the first 24 h after surgery. Results The frequency of CYP3A4*1G variant allele was 0.227 (80/352, 95% CI 0.165, 0.289) in these patients. After grouping according to the genotype of CYP3A4*1G, plasma fentanyl concentration in the *1/*1 variant (wild-type) group (12.8 ± 6.5 ng/ml) was significantly lower than that in the *1/*1G group (16.8 ± 9.0 ng/ml, P < 0.01) and the *1G/*1G group (28.1 ± 9.5 ng/ml, P < 0.01). Patients in the *1G/*1G group (247.1 ± 73.2 μg) consumed significantly less fentanyl than that in either the wild-type group (395.0 ± 138.5 μg) or the *1/*1G group (359.8 ± 120.2 μg) ( P < 0.01). There was a significant correlation between plasma fentanyl concentration and PCA fentanyl consumption (r = −0.552, P < 0.001). Conclusions CYP3A4*1G polymorphism is related to the pharmacokinetics of fentanyl, and patients with CYP3A4*1G variant A allele have a lower metabolic rate of fentanyl. The specific CYP3A4*1G polymorphism may predict the individual requirement of fentanyl.

Pharmacokinetics of fentanyl administered transdermally and intravenously in sheep

To investigate the pharmacokinetics of fentanyl administered transdermally and IV in sheep. 21 adult female sheep. Fentanyl was administered IV to 6 healthy sheep. Transdermal fentanyl patches (TFPs) were applied to 15 sheep 12 hours prior to general anesthesia and surgery. Seria blood samples were collected for 18 hours after IV injection and 84 hours after TFP application. Fentanyl concentrations were quantified via liquid chromatography-mass spectrometry, and pharmacokinetic values were estimated. All sheep completed the study without complications. Following a dose of 2.5 g/kg administered IV, the half-life was 3.08 hours (range, 2.20 to 3.36 hours), volume of distribution at steady state was 8.86 L/kg (range, 5.55 to 15.04 L/kg), and systemic clearance was 3.62 L/kg/h (range, 2.51 to 5.39 L/kg/h). The TFPs were applied at a mean dose of 2.05 g/kg/h. Time to maximum plasma concentration and maximal concentration were 12 hours (range, 4 to 24 hours) and 1.30 ng/mL (range, 0.62 to 2.73 ng/mL), respectively. Fentanyl concentrations were maintained at >0.5 ng/mL for 40 hours after TFP application. IV administration of fentanyl resulted in a short half-life. Application of a TFP resulted in stable blood fentanyl concentrations in sheep.

Evaluation of the Single‐ and Multiple‐Dose Pharmacokinetics of Fentanyl Buccal Soluble Film in Normal Healthy Volunteers

Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid-tolerant patients with cancer. This open-label, 3-period, sequential dose study evaluated the dose-to-dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600- or 1800-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg doses administered at 1-hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48-hour period after each single dose of FBSF and 72 hours after the 3-dose regimen. Peak plasma concentrations (mean C(max) = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC(0-12) = 6.3 and 6.2 h.ng/mL; mean AUC(inf) = 9.14 and 9.60 h.ng/mL) were nearly identical after the 2 single doses (P >or= .1, all comparisons). C(max) and overall fentanyl exposure (AUC(inf)) increased approximately 3-fold with the 3-dose regimen compared with the single-dose periods. Fentanyl plasma concentrations following single doses of FBSF were reproducible, and 3 doses administered 1 hour apart produced a tripling in exposure and maximal concentration compared with a single dose.

Pharmacokinetics of fentanyl after subcutaneous administration in volunteers

Pain relief using intermittent subcutaneous injections of an opioid (e.g. morphine) avoids the need for venous access and does not require complex or expensive pumps and devices. Although data on the pharmacokinetics of subcutaneous morphine exist, there are no comparable data for fentanyl in healthy volunteers. Therefore, the aim of this study was to characterize the pharmacokinetics of 200 microg fentanyl administered as a single bolus dose via the subcutaneous route in healthy opioid-naive volunteers. Nine healthy male volunteers were given 200 microg of subcutaneous fentanyl for more than 30 s. Opioid effects were blocked by administration of naltrexone. Venous blood samples taken at intervals from 5 min to 10 h after the dose were assayed using a liquid chromatography-mass spectrometry method. Pharmacokinetic data were analysed using a noncompartmental analysis approach. After subcutaneous bolus dose administration, the median maximum concentration of fentanyl was 0.55 ng ml(-1) (range 0.28-0.87 ng ml(-1)), reached at a median time of 15 min (range 10-30 min). The terminal half-life was 10.00 h (range 5.48-16.37 h). Absorption of subcutaneous fentanyl was relatively rapid and similar to the rate of absorption previously reported for subcutaneous morphine; the terminal half-life for fentanyl was substantially longer (10 h) than that of morphine (2.1 h), and blood concentrations were no more variable than that after administration by other nonintravenous routes.

Formulation Selection and Pharmacokinetic Comparison of Fentanyl Buccal Soluble Film with Oral Transmucosal Fentanyl Citrate

BioErodible MucoAdhesive (BEMA) is a new transmucosal drug delivery system designed to improve and ease the administration of drugs by this route. The first product that uses this novel delivery system contains fentanyl and is intended for the treatment of breakthrough pain in opioid-tolerant patients with cancer. The generic name is fentanyl buccal soluble film (FBSF). The objectives of this study were to compare the pharmacokinetic profile of FBSF formulations at three different pHs (pH 6, pH 7.25 and pH 8.5) and to understand the differences in the pharmacokinetics of fentanyl from FBSF compared with that of oral transmucosal fentanyl citrate (OTFC). This was a randomized, open-label, single-dose, four-period, Latin-square crossover study consisting of a 9-day inpatient treatment period. The study was conducted at a phase 1 clinical research unit in Austin, TX, USA. Twelve healthy subjects were enrolled, nine males and three females, between the ages of 21 and 44 years. Each subject received four 800 microg doses of fentanyl: single doses of the three FBSF formulations (pH 6, pH 7.25 and pH 8.5) and OTFC, with concurrent naltrexone. Plasma fentanyl concentrations were measured over a 48-hour period after each study dose. Pharmacokinetic parameters were calculated and compared. Peak plasma fentanyl concentrations (Cmax) and overall fentanyl systemic exposure (area under the plasma concentration-time curve from time zero extrapolated to infinity [AUCinfinity]) for each of the three FBSF formulations were greater than for OTFC. The pH 7.25 FBSF formulation provided the earliest time to reach Cmax (tmax), the highest Cmax value and the greatest AUC(infinity) value. Compared with OTFC, peak plasma fentanyl concentrations with pH 7.25 FBSF were significantly higher (mean Cmax 1.67 vs 1.03 ng/mL; p<0.05). Overall exposure was also greater with pH 7.25 FBSF than with OTFC (mean AUCinfinity 14.5 vs 10.3 ng . h/mL). All three FBSF formulations produced greater peak plasma concentrations and overall exposure to fentanyl than OTFC. In particular, the pH 7.25 FBSF formulation showed the most favourable pharmacokinetic profile of the three FBSF formulations. In comparison with OTFC, the pH 7.25 FBSF formulation produced the fastest and most efficient fentanyl delivery and was selected for further clinical development.

The pharmacokinetics of ketoconazole and its effects on the pharmacokinetics of midazolam and fentanyl in dogs

Ketoconazole inhibits the Cytochrome P450 3A12 (CYP3A12) metabolizing enzyme as well as the p-glycoprotein efflux pump. The extent and clinical consequence of these effects are poorly understood in dogs. The objective was to assess the pharmacokinetics of ketoconazole after single and multiple doses and the effect of multiple doses of ketoconazole on midazolam (a known CYP3A12 substrate) and the opioid fentanyl. Six greyhound dogs were studied. The study consisted of three phases. Phase 1 consisted of i.v. midazolam (0.23 mg/kg base) and fentanyl (15.71 microg/kg base). Phase 2 consisted of a single oral dose of ketoconazole (mean dose 12.34 mg/kg). Phase 3 consisted of i.v. midazolam (0.23 mg/kg) and fentanyl (10 microg/kg) after 5 days of oral ketoconazole (12.25 mg/kg/day). Ketoconazole significantly inhibited its own elimination with the mean residence time (MRT) increasing from 6.24 h in Phase 1 to 12.54 h in Phase 3. Ketoconazole significantly decreased the elimination of midazolam, as expected, with the MRT increasing from 0.81 to 1.49 h. The elimination of fentanyl was not significantly altered by co-administration of ketoconazole with the MRT being 3.90 and 6.35 h. The MRT was the most robust estimate of decreased drug elimination.

Comparative population pharmacokinetics of fentanyl using non-linear mixed effect modeling: Burns vs. non-burns

Objective Fentanyl is a commonly used analgesic and sedative for the burned in the operating theater as well as the burn care units. The aim of this study was to characterize fentanyl population pharmacokinetics in burns and to identify clinically significant covariates. Method Twenty adults, aged 37 ± 3 years, with 49 ± 4% (mean ± S.E.) total body surface area burn, were enrolled at 17 ± 3 days after the injury. Twenty non-burn adults served as controls. After an intravenous bolus of 200 mcg fentanyl, the plasma concentrations were sequentially determined up to 4.5 h. Concentration–time profiles were subjected to non-linear mixed effect modeling. Cardiac indices were estimated with esophageal Doppler monitor. Results Burned patients have higher cardiac index than the non-burned. Three-compartment model was the best fit. The volumes of distribution were considerably expanded in all three compartments (27.9 L vs. 63.4 L, 64.7 L vs. 92.9 L, 153 L vs. 301 L, respectively) compared to the non-burned. BURN was the single most important covariate significantly improving the model. Conclusion The primary effect of burn trauma on fentanyl pharmacokinetics is substantially expanded volumes of distribution, i.e., dilutional. Difference in simulation, however, was insufficient to explain the augmented resistance to fentanyl, implying the importance of titrating analgesics to the clinical effect.

Comparison of Liquid Chromatography-Mass Spectrometry and Radioimmunoassay for Measurement of Fentanyl and Determination of Pharmacokinetics in Equine Plasma

This study evaluated the validity of measuring fentanyl concentrations in equine plasma using radioimmunoassay (RIA) by comparing it to the established technique of liquid chromatography-mass spectrometry (LC-MS). Equine plasma samples were analyzed using a solid-phase Coat-A-Count fentanyl RIA and a validated LC-MS method. The fentanyl concentrations derived by both methods were compared by linear regression and pharmacokinetic analysis. The cross-reactivity of the primary equine fentanyl metabolite, N-[1-(2-phenethyl-4-piperidinyl)]maloanilinic acid (PMA), with the RIA was determined. The binding potency of fentanyl and PMA were compared at three opioid receptor subtypes in equine cerebral cortex using a radioligand binding technique. Fentanyl concentrations determined by RIA and LC-MS correlated, but the RIA overestimated low fentanyl concentrations and underestimated high fentanyl concentrations. The overestimation of low fentanyl concentrations is most likely due to the 29% cross-reactivity of PMA with the RIA. As a result, pharmacokinetic variables determined from an intravenous fentanyl bolus to four anesthetized horses differed depending on the analytical method. Although fentanyl bound with nanomolar potency to the three receptor subtypes, PMA exhibited no binding activity even at micromolar concentrations. In conclusion, when compared with LC-MS, fentanyl concentrations determined by RIA in equine plasma are misleading, especially for the calculation of fentanyl pharmacokinetics.

Pharmacokinetics and Pharmacodynamics of Intranasal Versus Intravenous Fentanyl in Patients with Pain after Oral Surgery

Fentanyl, a short-acting synthetic opioid, has a pharmacokinetic profile suited to fast relief of brief episodic pain. To characterize the pharmacokinetic-pharmacodynamic correlation of intranasal and intravenous fentanyl in opioid-naïve patients undergoing third molar extraction. A double-blind, double-dummy, crossover design study was conducted, with patients randomized to receive 1 of 4 fentanyl doses (75, 100, 150, or 200 microg) by both the intravenous and intranasal routes. Venous fentanyl concentrations were determined for up to 180 minutes and pain scores were recorded up to 240 minutes postdose. Duration of effect and time to rescue medication were also recorded. The pharmacokinetics of intravenous fentanyl reflected a 2-compartment model with a clearance of approximately 1.5 L/min. There was moderate (<50%) between-subject variability (BSV; %CV [coefficient of variation]) in the systemic kinetics of fentanyl. Bioavailability of intranasal fentanyl was 89%, following first-order absorption, with a lag of approximately 5 minutes and a half-life of approximately 6.5 minutes. Interpatient absorption variability was approximately 30% BSV for all absorption parameters. Intranasal versus intravenous administration led to a delayed mean fentanyl time to maximum concentration (13 vs 6 min) and lower maximum concentration (1.2 vs 2.0 ng/mL). Analgesic effect lagged behind the venous fentanyl concentration, with a half-life of approximately 2.5 minutes as described by a fractional sigmoid maximum drug effect dynamic model. The concentration-analgesia relationship was steep, with a 50% effective concentration of 0.46 ng/mL (Hill coefficient 3.5). Intranasal onset and offset of analgesia were slightly delayed, principally due to the delay and lag in systemic absorption, with slightly lower peak analgesic effect, compared with intravenous fentanyl. Duration of effect was directly related to intranasal fentanyl dose, with pain scores returning to predose values at approximately 120 minutes (75 microg) to approximately 240 minutes (200 microg) after a single dose. Intranasal fentanyl showed kinetic and dynamic properties that are desirable for the management of acute, episodic (breakthrough) pain.

Development of a GC-MS assay for the determination of fentanyl pharmacokinetics in rabbit plasma after sublingual spray delivery.

Development of a GC-MS assay for the determination of fentanyl pharmacokinetics in rabbit plasma after sublingual spray delivery.

Pharmacokinetics and tolerance of transdermal fentanyl administration in foals

ObjectiveTo characterize the pharmacokinetics of fentanyl and the tolerance of foals to the drug following a single application of a commercially available transdermal system (TS). Study designProspective experimental study. AnimalsSix (two male, four female) foals aged 4–8 days, weighing 56–74 kg. MethodsAfter placement of a jugular sampling catheter, one fentanyl TS (FTS) containing 10.2 mg fentanyl, released at 100 μg hour−1, was applied for 72 hours. Blood samples were withdrawn over the course of 90 hours for fentanyl plasma analysis. Before and after the study, weight, complete blood count and blood chemistry values were obtained. During the study, tolerance and safety were monitored by physical examination and assessment of behavior. ResultsFentanyl was detected as early as 20 minutes after FTS placement. Peak plasma concentrations were variable (0.1–28.7 ng mL−1), were reached after 14.3 ± 7.6 hours (mean ± SD), and returned to baseline concentrations 12 hours after FTS removal. All foals satisfactorily tolerated the FTS application and no significant adverse effects were observed. Rectal temperature increased above 38.5 °C (max. 39.0 °C) in all foals, although this did not correlate with fentanyl plasma concentrations. Results of hematological and biochemical analyses were within reference ranges.Conclusion and clinical relevance Our data show that 100 μg hour−1 fentanyl administered by an FTS results in time-related but variable plasma concentrations in foals. The FTS was easy to apply and was well tolerated.

Pharmacokinetics and tolerance of transdermal fentanyl administration in foals

Objective To characterize the pharmacokinetics of fentanyl and the tolerance of foals to the drug following a single application of a commercially available transdermal system (TS). Study design Prospective experimental study. Animals Six (two male, four female) foals aged 4–8 days, weighing 56–74 kg. Methods After placement of a jugular sampling catheter, one fentanyl TS (FTS) containing 10.2 mg fentanyl, released at 100 μg hour−1, was applied for 72 hours. Blood samples were withdrawn over the course of 90 hours for fentanyl plasma analysis. Before and after the study, weight, complete blood count and blood chemistry values were obtained. During the study, tolerance and safety were monitored by physical examination and assessment of behavior. Results Fentanyl was detected as early as 20 minutes after FTS placement. Peak plasma concentrations were variable (0.1–28.7 ng mL−1), were reached after 14.3 ± 7.6 hours (mean ± SD), and returned to baseline concentrations 12 hours after FTS removal. All foals satisfactorily tolerated the FTS application and no significant adverse effects were observed. Rectal temperature increased above 38.5 °C (max. 39.0 °C) in all foals, although this did not correlate with fentanyl plasma concentrations. Results of hematological and biochemical analyses were within reference ranges. Conclusion and clinical relevance Our data show that 100 μg hour−1 fentanyl administered by an FTS results in time-related but variable plasma concentrations in foals. The FTS was easy to apply and was well tolerated.

Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference?

We have investigated the arterio-venous difference in the pharmacokinetics of 50 microg fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naïve middle-aged to elderly patients. Twelve male patients (range in age 47-84 years) scheduled for transurethral resection of the prostate gland received a 100-microl dose of 50 microg fentanyl base as a fentanyl citrate formulation in one nostril. Simultaneous arterial and venous blood samples for analyses of fentanyl were drawn at baseline and at 1, 3, 5, 7, 9, 13, 15, 20, 25, 35, 45 and 60 min after drug administration. Vital signs, sedation and symptoms of local irritation were recorded. The arterial C(max) (maximum serum concentration) of 0.83 ng/ml was nearly twofold higher than the venous C(max) of 0.47 ng/ml, and the arterial T(max) (time to maximum serum concentration) of 7.0 min was about 5 min shorter than the venous T(max) of 11.6 min. The arterial AUC(0-60) (area under the curve from 0 to 60 min after administration) of 21 min*ng/ml was approximately 30% larger than the venous AUC(0-60) of 15 min*ng/ml (all p values < or = 0.005). Venous T(max) and C(max) did not predict the corresponding arterial values. No significant adverse events were observed. A significant arterio-venous difference was present after intranasal administration of fentanyl. The short arterial T(max) complies with its rapid onset of action. The use of venous concentrations for the prediction of onset time of analgesia should be discouraged. A 50-microg dose of nasal fentanyl was well tolerated by opioid-naïve middle-aged to elderly male patients.

Pharmacokinetic–Pharmacodynamic Modeling of the Effectiveness and Safety of Buprenorphine and Fentanyl in Rats

ObjectiveRespiratory depression is a serious and potentially life-threatening side-effect of opioid therapy. The objective of this investigation was to characterize the relationship between buprenorphine or fentanyl exposure and the effectiveness and safety outcome in rats.MethodsData on the time course of the antinociceptive and respiratory depressant effect were analyzed on the basis of population logistic regression PK–PD models using non-linear mixed effects modeling software (NONMEM). The pharmacokinetics of buprenorphine and fentanyl were described by a three- and two-compartment model, respectively. A logistic regression model (linear logit model) was used to characterize the relationship between drug exposure and the binary effectiveness and safety outcome.ResultsFor buprenorphine, the odds ratios (OR) were 28.5 (95% CI, 6.9–50.1) and 2.10 (95% CI, 0.71–3.49) for the antinociceptive and respiratory depressant effect, respectively. For fentanyl these odds ratios were 3.03 (95% CI, 1.87–4.21) and 2.54 (95% CI, 1.26–3.82), respectively.ConclusionThe calculated safety index (ORantinociception/ORrespiratory depression) for fentanyl of 1.20 suggests that fentanyl has a low safety margin, implicating that fentanyl needs to be titrated with caution. For buprenorphine the safety index is 13.54 suggesting that buprenorphine is a relatively safe opioid.

Fentanyl pharmacokinetics are altered in patients with major burns,

Fentanyl pharmacokinetics are altered in patients with major burns,

Fentanyl Clearance and Volume of Distribution Are Increased in Patients With Major Burns

This study examined the pharmacokinetics of fentanyl in burned patients during the hyperdynamic phase. Twenty adults, aged 37 +/- 2 years (mean +/- SE), with 49 +/- 3% total body surface area burn, were studied at 17 +/- 2 days after the injury and compared to demographically matched controls. After a 200-microg IV bolus of fentanyl, blood samples (n = 20) were collected for 4.5 hours. Concentration-time curves were fitted to a 2-compartment model. Burned patients had a higher cardiac index. Median fentanyl clearance (CL, 21.0 vs 29.4 mL/kg/min), central compartment volume (V(1), 0.37 vs 0.61 L/kg), and total volume of distribution (V(area), 3.6 vs 5.8 L/kg) were higher in burned patients. Cardiac index was unrelated to CL. The increased V(1) and V(area) are likely due to large intravenous fluid replacement and tissue edema. Higher CL and larger V(1) and V(area) leading to a lower fentanyl plasma concentration may partially explain the increased opiate requirement previously observed after burn injury.