Fentanyl Pharmacodynamics Research Articles

The pharmacokinetics and pharmacodynamics of fentanyl administered via transdermal patch in horses.

Understanding the pharmacokinetics and pharmacodynamics of fentanyl in horses is crucial for optimizing pain management strategies in veterinary medicine. Six adult horses were enrolled in a randomized crossover design. Treatments included: placebo, two 100 mcg/h patches (LDF), four 100 mcg/h patches (MDF), and six 100 mcg/h patches (HDF). Patches were in place for 72 h. Blood was obtained for fentanyl plasma concentration determination, thermal threshold, mechanical threshold, heart rate, respiratory rate, and rectal temperature were obtained prior patch placement and at multiple time points following patch placement for the following 96 h. Fentanyl plasma concentration was determined using LC-MS/MS. Data were analyzed using a generalized mixed effects model. Mean (range) maximum plasma concentration (Cmax), time to Cmax, and area under the curve extrapolated to infinity were 1.39 (0.82-1.82), 2.64 (1.21-4.42), 4.11 (2.78-7.12) ng/ml, 12.7 (8.0-16.0), 12.7 (8.0-16.0), 12 (8.0-16.0) h, 42.37 (27.59-55.56), 77.24 (45.62-115.06), 120.34 (100.66-150.55) h ng/ml for LDF, MDF, and HDF, respectively. There was no significant effect of treatment or time on thermal threshold, mechanical threshold, respiratory rate, or temperature (p > 0.063). There was no significant effect of treatment on heart rate (p = 0.364). There was a significant effect of time (p = 0.003) on heart rate with overall heart rates being less than baseline at 64 h. Fentanyl administered via transdermal patch is well absorbed and well tolerated but does not result in an anti-nociceptive effect as measured by thermal and mechanical threshold at the doses studied.

O1 | Pharmacodynamics of fentanyl following transdermal patch application in horses

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 28-28 ORAL PRESENTATIONS O1 | Pharmacodynamics of fentanyl following transdermal patch application in horses First published: 11 June 2023 https://doi.org/10.1111/jvp.13167Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 28-28 RelatedInformation

Influence of St. John's Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects: A Randomized Clinical Trial.

Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb-drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood-brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John's wort. This investigation evaluated effects of St. John's wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects. Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John's wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic-pharmacodynamic modeling. St. John's wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John's wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John's wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John's wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John's wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John's wort had no influence on analgesia, cognitive performance, or somatic cognitive-affective effects of fentanyl. St. John's wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John's wort will likely not respond differently to IV fentanyl for anesthesia or analgesia.

Prolonged therapy with the anticonvulsant carbamazepine leads to increased plasma clearance of fentanyl.

Fentanyl is a potent analgesic that accounts for an increasing number of overdose deaths in the United States. This study tested whether altered pharmacokinetics plays a pivotal role in the increased fentanyl dose requirements in patients receiving the enzyme-inducing anticonvulsant, carbamazepine. Neurosurgical patients receiving carbamazepine for >6 weeks (N = 11) or no carbamazepine (N = 6, controls) received a single bolus dose of fentanyl (200 μg) intravenously. Plasma was collected before and for up to 9 h after the bolus. Fentanyl concentrations were measured using liquid chromatography-mass spectrometry. Pharmacokinetic variables were derived from plasma concentration-time curves best fitted to a two-compartment model. Fentanyl clearance was significantly higher in the carbamazepine group compared to controls (mean ± SD: 20.1 ± 6.8 vs 13.2 ± 4.8 ml/min per kg, P < 0.05), and area under the plasma concentration curve (AUC) was significantly lower (150 ± 65 vs 233 ± 70 ng/ml × min, P < 0.02). Volume of distribution was larger in the carbamazepine group, but the difference was not statistically significant (5.4 ± 3.1 vs 3.6 ± 1.2 l/kg, P > 0.15). The terminal elimination half-life did not differ between the two groups. Chronic carbamazepine therapy leads to increased fentanyl clearance and decreased AUC, which may result in decreased duration of therapeutic plasma concentrations of fentanyl and an increased dose requirement. Assuming that carbamazepine does not change fentanyl pharmacodynamics, patients on chronic carbamazepine therapy may require more frequent or higher fentanyl doses to maintain therapeutic plasma concentrations.

Effects of OPRM1A118G and CYP3A4*18B genetic polymorphism and the interaction on postoperative analgesia with fentanyl in patients undergoing radical resection of lung cancer

Objective To evaluate the effects of OPRM1A118G and CYP3A4*18B genetic polymorphism and the interaction on postoperative analgesia with fentanyl in the patients undergoing radical resection of lung cancer. Methods One hundred and thirty-nine patients (native of Henan province), aged 40-64 yr, weighing 40-70 kg, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ, scheduled for elective radical resection of lung cancer under general anesthesia, were enrolled in this study.The polymorphic sites of the OPRM1A118G and CYP3A4*18B allele were analyzed by using polymerase chain reaction technique and ABI 3130 Genetic Analyzer.The patients were divided into wild homozygote group (group AA, group *1/*1), heterozygote group (group AG, group *1/*18B) and mutation homozygote group (group GG, group *18B/*18B) according to their genotypes.The patients were divided into 7 groups according to the interaction between the two genes: AA plus *1/*1 group (group Ⅰ), AA plus *1/*18B group (group Ⅱ), AG plus *1/*1 group (group Ⅲ), AG plus *1/*18B group (group Ⅳ), GG plus *1/*1 group (group Ⅴ), GG plus *1/*18B group (group Ⅵ) and *18B/*18B group (group Ⅶ). Patient-controlled intravenous analgesia with fentanyl was started at the end of surgery to maintain the visual analogue scale ≤3 points.The amount of fentanyl used within 24 and 48 h after surgery was recorded, and the occurrence of adverse reactions within 48 h after surgery was observed. Results The amount of fentanyl used within 24 and 48 h after surgery was significantly higher in group GG than in group AA (P 0.05). Conclusion OPRM1A118G and CYP3A4*18B genetic polymorphism and the interaction are the genetic factors contributing to individual variation in fentanyl pharmacodynamics in the patients undergoing radical resection of lung cancer. Key words: Polymorphism, single nucleotide; Fentanyl; Lung neoplasms; Analgesia, patient-controlled

TRANSDERMAL FENTANYL: PHARMACOLOGICAL ASPECTS OF THERAPY IN CANCER PATIENTS. PART 1. FROM THE DEVELOPMENT OF TRANSDERMAL FENTANYL FORMULATIONS TILL META-ANALYSES OF CLINICAL TRIALS

There was given a review of data on pharmacology of fentanyl with focus on transdermal formulation. In the first part of the article improvements in technology of fentanyl transdermal patches were reviewed and advantages of the membrane-matrix system that are of practical use were highlighted. The results obtained from bioequivalence and therapeutic equivalence studies of traditional and improved transdermal fentanyl systems were given. Clinical trials with fentanyl transdermal patches as well as systematic reviews and meta-analyses on the efficacy and safety of transdermal fentanyl were summarized. The second part of the article will focus on factors contributing to the variability in pharmacokinetics and pharmacodynamics of fentanyl including pharmacogenetics; the taking into account the whole spectrum of these factors would allow to escaped the majority of errors during the administration of the drug e.g. transdermally. A special attention will be paid to basic principles and issues of the application of fentanyl transdermal therapeutic systems.

Effect of OPRM1A118G genetic polymorphism on postoperative analgesia with fentanyl in patients undergoing radical resection of lung cancer

Objective To evaluate the effect of OPRM1A118G genetic polymorphism on postoperative analgesia with fentanyl in the patients undergoing radical resection of lung cancer. Methods One hundred and seventy-four patients(native of He'nan province), aged 40-64 yr, weighing 40-70 kg, with American Society of Anesthesiologists physical status Ⅰor Ⅱ, undergoing elective radical resection of lung cancer under general anesthesia, were enrolled in this study.OPRM1A118G genetic polymorphic sites were analyzed by using polymerase chain reaction technique and ABI 3130 Genetic Analyzer.The patients were divided into wild homozygote group, heterozygote group and mutation homozygote group according to their genotypes.The analgesia pump was connected at the end of operation.Patient-controlled intravenous analgesia solution contained fentanyl 30 μg/kg and ondansetron 8 mg in 200 ml of normal saline.The analgesia pump was programmed to deliver a 2 ml bolus dose with a 15-min lockout interval and background infusion at a rate of 2 ml/h, maintaining the visual analogue scale score ≤3 points.The amount of fentanyl consumed within 24 and 48 h after operation was recorded, and the occurrence of adverse reactions was recorded within 48 h after operation. Results Compared with wild homozygote group, the amount of fentanyl consumed within 24 and 48 h after operation was significantly increased in mutation homozygote group(P 0.05). There was no significant difference in the incidence of postoperative adverse reactions between the three groups(P>0.05). Conclusion OPRM1A118G genetic polymorphism is one of the genetic factors contributing to individual variation in fentanyl pharmacodynamics in the patients undergoing radical resection of lung cancer. Key words: Polymorphism, single Nucleotide; Fentanyl; Lung neoplasms; Analgesia, patient-controlled

Impact of CYP3A and ABCB1 polymorphisms on the pharmacokinetics and pharmacodynamics of fentanyl

Impact of CYP3A and ABCB1 polymorphisms on the pharmacokinetics and pharmacodynamics of fentanyl

Contrasting paired signals arising from the same physiological process

using CRISP-TDMn and STDMn0. Plasma and effect site concentrations (Cp/Ce) were simulated by the PKPD modeling module of the Artemis platform. Encinas' PKPD8 model for fentanyl was used in this retrospective analysis. HRV and RRV were analyzed using the estimated Cp/Ce at the specific point in time. Data from the periods of the infant's NICU hospital course were used for the analysis of the relationship between drug concentration, HRV, RRV, and PIPP score. Results: A fentanyl Ce of 0.02 μg/mL was correlated with a low HRV, statistical significance P = .01 (P b .05), and a PIPP score of 6. The infant's PIPP score was 9 before the increased fentanyl drug dose. There was no detectable effect on RRV for this infant whose respiratory failure was managed with high-frequency jet ventilation at 240 breaths per minute. Conclusions: This case study demonstrates that a high concentration of fentanyl in this critically ill premature infant is associated with a reduction in PIPP score and correlates with decreased HRV. The estimated effect site concentration correlations with low HRV suggests that high-fidelity cardiorespiratory physiological data could serve as an indicator for fentanyl's pharmacodynamics as well as controller variable for a novel pain profile index.

A Predictive Pharmacokinetic/Pharmacodynamic Model of Fentanyl for Analgesia/Sedation in Neonates Based on a Semi-Physiologic Approach

Fentanyl is a synthetic opioid commonly used as an anesthetic and also increasingly popular as a sedative agent in neonates. Initial dosage regimens in this population are often empirically derived from adults on a body weight basis. However, ontogenic maturation processes related to drug disposition are not necessarily always body weight correlates. We developed a predictive pharmacokinetic/pharmacodynamic model that includes growth and maturation physiologic changes for fentanyl in neonatal care. Key pharmacokinetic variables and principles (protein binding, clearance, distribution) as related to fentanyl pharmacokinetic/pharmacodynamic behavior in adults (tricompartmental model) and to neonatal physiologic data (organ weights and blood flows, body composition, renal and hepatic function, etc.) were used to guide the building of a semi-physiologic ontogenic model. The model applies to a normal-term neonate without any other intervention. Then, extension to a pharmacokinetic/pharmacodynamic link model for fentanyl was made. The final model was evaluated by predicting the time course of plasma concentrations and the effect of a standard regimen of 10.5 μg/kg over a 1-h period followed by 1.5 μg/kg/h for 48 h. Hepatic clearance was linked to ontogeny of unbound fraction and of α1-acid glycoprotein. All parameters were reduced in the neonate compared to adults but in a differing proportion due to qualitative changes in physiology that are analyzed and accounted for. Systemic clearance (CLS), volume of the central compartment (V1) and steady-state volume of distribution predicted by the model were 0.028 L/min, 1.26 L, and 22.04 L, respectively. Weight-corrected parameters generally decreased in adults compared with neonates, but differentially, e.g., CLS = 0.0093 versus 0.0088 L/min/kg, while V1 = 0.42 versus 0.18 L/kg (neonates vs. adults). Under such complexity a pharmacokinetic/pharmacodynamic model is the appropriate method for rational efficacy targeting. Fentanyl pharmacodynamics in neonates were considered to be similar to those in adults except for the equilibrium rate constant, which was also scaled on an ontogenic basis. The model adequately predicted the reported mean expected concentration-time profiles for the standard regimen. Integrated pharmacokinetic/pharmacodynamic modeling showed that the usually prescribed dosage regimens of fentanyl in neonates may not always provide the optimum degree of sedation. The model could be used in optimal design of clinical trials for this vulnerable population. Prospective clinical testing is the reasonable next step.

シミュレーションに基づいたIV-PCAメニューの設定と応用

フェンタニルの術後1日分の効果部位濃度を線形3コンパートメントモデルで推定して，それを基にIV-PCAメニューを作成し，その推定効果部位濃度と術後の鎮痛効果の関係を検討した．薬物動態シミュレーションの結果，手術終了2時間前までに，50kgの標準体重の患者では，フェンタニル300μgのプライミングとIV-PCA 25μg/hrの持続投与開始を基準とすることで，術後，1ng/mlの安定したフェンタニル効果部位濃度が維持できた．また，中等度の疼痛が予想される非開腹手術では，覚醒時のフェンタニル効果部位濃度を1.4ng/ml程度，術後は1.0ng/ml程度に維持することで，有用な疼痛管理が可能であった．

Pharmacodynamics of fentanyl for inhibition of emergence agitation aftar sevoflurane-remifentanil anesthesia in children

Oblective To define the median effective dose (ED50) and 95%effective dose of fentanyl for inhibition of emergence agitation after sevoflurane-remifentanil anesthesia in children.Methods Twenty six ASA ⅠorⅡchildren aged 5-8 yr weighing 15-30 kg undergoing adenoidectomy under general anesthesia were studied.The patients were unpremedicated.Anesthesia was induced with inhalation of 8%sevoflurane (fresh gas flow=6 L/min)and iv remifentanil 1μg/kg.The patients were mechanically ventilated after tracheal intubation.Fentanyl was injected iv to inhibit emergence agitation.The dose of fentanyl was determined by using modified Dixon's upand-down method (increment or decrement of 0.5μg/kg).The initial dose of fentanyl was 4 μg/kg.Anesthesia Sevoflurane inhalation and remifentanil infusion were terminated at the end of operation.The patients were transferred to the PACU.No alteration in the ventilatory settings was made.Stimulation of the patients was avoided during emergence.The emergence time and the occurrence of agitation,nausea and vomiting and respiratory depression within 4h after operation were recorded.ED50,ED95 and 95%confidence interval (CI) of fentanyl for inhibition of emergence agitation were calculated.Results ED50 was 3.01μg/kg (95%CI 2.52-3.40μg/kg) and ED95 3.81μg/kg(95%CI 3.41-6.22μg/kg).No nsusea and vomiting and respiratory depression occurred within 4h after operation.The emergence time was (11.3±2.6) min.Conclusion The ED50 and ED95 of fentanyl for inhibition of emergence agitation after sevoflurane-remifentanyl anesthesia were 3.01 and 3.81μg/kg respectively in children. Key words: Fentanyl; Dose-response relationship,drug; Child; Psychomotor agitation

Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children

BackgroundThis study describes a pharmacodynamic model during general anaesthesia in children relating the bispectral index (BIS) response to the anaesthetic dosing of propofol, fentanyl, and remifentanil. MethodsBIS, heart rate, mean arterial pressure, sedation scores, and anaesthetic protocols from 59 children aged 1–16 yr undergoing general surgery were considered for the study. Anaesthesia was performed with propofol, fentanyl, and remifentanil. A sigmoid model assuming additive interaction of propofol, fentanyl, and remifentanil was fitted to individual BIS as effect variable. The pharmacodynamic parameters were estimated by non-linear regression analysis. The ability of BIS to predict anaesthetic drug effect was quantified by the prediction probability Pk. ResultsBIS started at a baseline of 90 (9), decreased during induction to 30 (14) and remained at 57 (10) during anaesthesia. BIS predicted the anaesthetic drug effect with a Pk of 0.79 (0.08). The EC50 Propofol and the ke0 Propofol were 5.2 (2.7) μg ml−1 and 0.60 (0.45) min−1, respectively. The ke0 Propofol decreased from approximately 0.91 min−1 at 1 yr to 0.15 min−1 at 16 yr. The EC50 Remifentanil, ke0 Remifentanil, EC50 Fentanyl, and the ke0 Fentanyl were 24.1 (13.0) ng ml−1, 0.71 (0.32) min−1, 8.6 (7.4) ng ml−1, and 0.28 (0.46) min−1, respectively. ConclusionsThe effect equilibration half-time of propofol in children was age dependent. The pharmacodynamics of fentanyl and remifentanil in children were similar to those reported in adults. The BIS showed a close relationship to the modelled effect-site concentration, and therefore, it may serve as a measure of anaesthetic drug effect in children older than 1 yr.

The influence ofABCB1andOPRM1genetic polymorphism on fentanyl requirements for postoperative pain control

Background: Fentanyl, which is a potent synthetic μ-opioid receptor agonist, is one of the most widely used opioids in anes- thesia and pain control. However, the pharmacodynamics of fentanyl show wide inter-individual variability. Therefore, this study was conducted to evaluate the influence of the blood-brain barrier transporter protein, p-glycoprotein, and μ-opioid receptor genetic polymorphism on fentanyl pharmacodynamics. Methods: Seventy-nine patients who underwent posterior lumbar interbody fusion (PLIF) were included in this study. Postoperatively, the patients received fentanyl via an intravenous patient controlled analgesia device. The cumulative fentanyl doses and other pharmacodynamic data were then recorded at 2 h, 6 h, 12 h, 24 h and 48 h after the operation. In addition, genomic DNA was isolated from the patient's peripheral leukocytes and then evaluated for the presence of OPRM1 A118G and ABCB1 C3435T genetic polymorphism using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The results of this study indicated that ABCB1 C3435T genetic polymorphism may be related to the cumulative fentanyl requirement for postoperative pain control. However, these findings were not statistically significant (P = 0.09). In addition, no relationship was observed between OPRM1 A118G and the cumulative postoperative fentanyl requirement. However, the cumu- lative postoperative fentanyl requirement was lower in the TTAA group (ABCB1 3435 TT, OPRM1 118 AA) than in the CCGG group (ABCB13435 CC, OPRM1 118 GG). Conclusions: The ABCB1 C3435T polymorphism may affect fentanyl pharmacodynamics. However, further studies are required to confirm the relationship between p-glycoprotein and fentanyl. (Korean J Anesthesiol 2008; 55: 332~7)

Relationship between plasma concentrations and analgesia after intravenous fentanyl and disposition after other routes of administration in cats1

Data allowing rational use of analgesics in cats are limited. Pharmacokinetics and pharmacodynamics of fentanyl were studied in cats. Plasma fentanyl concentrations were measured using radioimmunoassay in a crossover study in six cats after 10 microg/kg (i.v.) or by application of fentanyl in pluronic lecithin organogel (PLO) to the inner ear pinna. On a separate occasion thermal thresholds were measured after i.v. fentanyl (10 microg/kg) or saline. Plasma fentanyl concentrations reached 4.7-8.31 ng/mL 2 min after i.v. administration and were undetectable after 95 min. Fentanyl was not detected in plasma at any time after PLO use. Thermal thresholds did not change following saline administration but were increased above baseline from 5 to 110 min after i.v. fentanyl. In this model a plasma concentration of >1.07 ng/mL was required to provide analgesia. Plasma concentrations were measured in additional cats after intranasal or oral dosing (2 microg/kg) and after 30 microg/kg in PLO gel. After oral and nasal dosing, Cmax values were 0.96 and 1.48 ng/mL at 5 and 2 min, respectively. Plasma fentanyl was not detected after application of the higher dose of fentanyl in PLO.

Pharmacokinetics of fentanyl following intravenous and transdermal administration in horses.

Although fentanyl has been reported to cause CNS excitation in horses, a transdermal therapeutic system (TTS) containing this mu agonist has recently been used empirically in equine medicine to treat moderate to severe pain. A better understanding of the disposition of fentanyl following transdermal administration would facilitate the clinical use of TTS fentanyl to obtain analgesia in horses. To determine the pharmacokinetics of fentanyl following i.v. and TTS patch administration in healthy, mature horses and to evaluate the tolerance of horses to TTS fentanyl administration. The pharmacokinetics of fentanyl in serum were assessed following a single i.v. dose, a single TTS dose, and multiple TTS doses in 6 healthy horses. Physical examinations, haematology and serum biochemistry analyses during transdermal fentanyl application were then performed to determine tolerance of continuous fentanyl administration. Fentanyl was very rapidly and completely absorbed following a single TTS dose. Mean serum fentanyl concentrations consistent with analgesia in other species were reached by 1 h and maintained until 32 h after patch application. Similar steady state serum concentrations were obtained when multiple doses of TTS fentanyl were administered every 48 or 72 h over 8 or 9 days, with less fluctuation in serum concentrations during the 48 h dosing interval. Three horses exhibited brief (< 12 h) episodes of increased body temperature; however, transdermal fentanyl administrations were not associated with other significant changes in haematology and biochemistry panels or physical examination findings. Although the pharmacodynamics of fentanyl have not been investigated fully in horses, transdermally-administered fentanyl exhibited a favourable pharmacokinetic profile without clinically relevant side effects and may be a useful analgesic in equine patients.

The CYP 3A4 inhibitor itraconazole has no effect on the pharmacokinetics of i.v. fentanyl

We studied 10 healthy volunteers given itraconazole 200 mg orally, once daily or placebo for 4 days in a crossover study. i.v. fentanyl 3 micrograms kg-1 was given on day 4. Plasma concentrations of fentanyl were measured by radioimmunoassay and ventilatory frequency and peripheral arteriolar oxygen saturation were also measured. Fentanyl-induced subjective effects (drowsiness, itching, nausea, performance, feeling of drug effect) were measured by visual analogue scales. The pharmacokinetics and pharmacodynamics of fentanyl were similar after both itraconazole and placebo. Thus although itraconazole is a strong inhibitor of the cytochrome 3A enzymes responsible for metabolism of fentanyl in vitro, it did not affect the i.v. pharmacokinetics of fentanyl in humans.

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively. This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.