Ketamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics... Show moreKetamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two oral thin films on separate occasions in a randomized crossover design. The oral thin films were placed sublingually (n = 15) or buccally (n = 5) and left to dissolve for 10 min in the mouth during which the subjects were not allowed to swallow. For 6 subsequent hours, pharmacokinetic blood samples were obtained after which 20 mg S-ketamine was infused intravenously and blood sampling continued for another 2-hours. A population pharmacokinetic analysis was performed in NONMEM pharmacokinetic model of S-ketamine and its metabolites S-norketamine and S-hydroxynorketamine; p < 0.01 were considered significant. S-ketamine bioavailability was 26 ± 1% (estimate ± standard error of the estimate) with a 20% lower bioavailability of the 100 mg oral thin film relative to the 50 mg film, although this difference did not reach the level of significance. Due to the large first pass-effect, 80% of S-ketamine was metabolized into S-norketamine leading to high plasma levels of S-norketamine following the oral thin film application with 56% of S-ketamine finally metabolized into S-hydroxynorketamine. No differences in pharmacokinetics were observed for the sublingual and buccal administration routes. The S-ketamine oral thin film is a safe and practical alternative to intravenous S-ketamine administration that results in relatively high plasma levels of S-ketamine and its two metabolites. Show less
Jonkman, K.; Duma, A.; Olofsen, E.; Henthorn, T.; Velzen, M. van; Mooren, R.; ... ; Dahan, A. 2017
BACKGROUND: In pharmacokinetic pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of... Show moreBACKGROUND: In pharmacokinetic pharmacodynamic modeling studies, venous plasma samples are sometimes used to derive pharmacodynamic model parameters. In the current study the extent of arteriovenous concentration differences of morphine-6-glucuronide (M6G) was quantified. We used simulation studies to estimate possible biases in pharmacodynamic model parameters when linking venous versus arterial concentrations to effect. METHODS: Seventeen healthy volunteers received an IV 90-second infusion of 0.3 mg/kg morphine-6-glucuronide (M6G). Arterial and venous blood samples, from the radial artery and cubital vein, respectively, were obtained. An extended pharmacokinetic model was constructed linking arterial and venous compartments. The extent of bias in pharmacodynamic model parameter estimates was explored in simulation studies with NONMEM, simulating M6G effect using first-order effect-compartment inhibitory sigmoid E-MAX models. M6G effect was simulated at various values for the arterial blood-effect-site equilibration half-lifes (t(1/2)k(EO)), ranging from 5 to 240 minutes. RESULTS: Arteriovenous concentration differences were apparent, with higher arterial plasma concentrations just after infusion, whereas at later times (>60 minutes) venous M6G concentrations exceeded arterial concentrations. The extended pharmacokinetic model adequately described the data and consisted of 3 arterial compartments, 1 central venous compartment, and 1 peripheral venous compartment. The simulation studies revealed large biases in model parameters derived from venous concentration data. The biases were dependent on the value of t(1/2)k(EO). Assuming that the true values of M6G t(1/2)k(EO) range from 120 to 240 minutes (depending on the end point measured), we would have underestimated t(1/2)k(EO) by 30%, whereas the potency parameter would have been overestimated by about 40%, when using venous plasma samples. CONCLUSIONS: Because of large arteriovenous differences in M6G plasma, concentration biases in pharmacodynamic model parameters will occur when linking venous concentration to effect, using a traditional effect-compartment model. (Anesth Analg 2010;111:626-32) Show less
Sigtermans, M.; Noppers, I.; Sarton, E.; Bauer, M.; Mooren, R.; Olofsen, E.; Dahan, A. 2010
Aims: The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex... Show moreAims: The aim of the study was to explore the analgesic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20-min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion. Results: CRPS pain: Ketamine produced potent analgesia with a significant VAS reduction from 6.2 +/- 0.2 to 0.4 +/- 0.3 cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS = 2.8 +/- 1.0 cm at 5-h), when measured plasma ketamine concentrations were low (< 100 ng/ml). Experimental pain: Ketamine had a dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion. Discussion: The data indicate that while ketamine's effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain. (C) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. Show less
