Pharmacokinetic-pharmacodynamic modeling of the new steroid hypnotic eltanolone in healthy volunteers.

BACKGROUND: In the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of eltanolone or used electroencephalographic effect data for full pharmacodynamic modeling. Thus the authors conducted a study to evaluate the pharmacokinetic and pharmacodynamic properties of eltanolone after infusion in healthy volunteers. METHODS: Eltanolone emulsion was administered to 12 healthy men using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive infusions with an anticipated slope of 0.075 microgram.ml-1.min-1 and a targeted concentration of 2-2.5 micrograms/ml. During and after the infusion, electroencephalographic data were recorded as a continuous pharmacodynamic parameter to measure the hypnotic effect. In addition, blood pressure, heart rate, pulse oximetry, clinical signs of anesthesia, and any undesirable effects were recorded. The appearance of burst suppression periods in the raw electroencephalographic wave form was used as an end point for the infusion. Arterial blood samples were drawn frequently until 720 min after the cessation of the last infusion cycle. Eltanolone serum concentrations were measured using a specific gas chromatography-mass spectrometry assay. Nonlinear regression analysis was used to relate a power spectral parameter of the electroencephalograph (median frequency) to the serum concentration using a sigmoid Emax model, including an effect compartment to minimize possible hysteresis. Population pharmacokinetics were analyzed using an open three-compartment model. RESULTS: The pharmacokinetic model parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l/min), small volumes of distribution (Vc = 7.65 +/- 3.40 l; Vdss = 91.6 +/- 22 l), and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). With regard to the pharmacodynamic model parameters, eltanolone proved to be a potent hypnotic agent (Cp50 = 0.46 +/- 0.09 microgram/ml). The hypnotic effect coincided with a remarkable hysteresis between serum concentration and biophase, determined by an equilibration half-life of 8 min (ke0 = 0.087 +/- 0.013 min-1). All volunteers breathed spontaneously during the entire observation period and showed no clinically relevant hemodynamic changes. One volunteer experienced a convulsion while awakening. CONCLUSIONS: Eltanolone is a new potent steroid-type hypnotic agent with rapid elimination characteristics. Although it is short-acting, the remarkable hysteresis limits the control and might complicate administration of eltanolone if it is used as a component of a complete intravenous anesthesia regimen. Furthermore, it involves the potential disadvantage of drug accumulation and it prolongs recovery if larger-than-necessary doses are used to induce anesthesia rapidly.

[Concentration-effect relationship, hemodynamics and respiration after infusion of the steroid anesthetic eltanolone in healthy subjects]. / Konzentrations-wirkungsbeziehung, Hämodynamik und Respiration nach Infusion des Steroid-anästhetikums Eltanolon bei gesunden Probanden.

UNLABELLED: During the last five years several authors have reported largely satisfactory results, using the steroid intravenous anaesthetic eltanolone (pregnanolone) for induction of anaesthesia after administering a bolus dose. Until now, however, no investigations have been undertaken, dealing with the infusion pharmacokinetics of eltanolone after arterial blood sampling and using slow induction to quantify the concentration-effect relationship. Secondary objectives were to assess the haemodynamic and respiratory effects. MATERIAL AND METHODS: Eltanolone emulsion was administered to 12 healthy male volunteers using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive times with an anticipated slope of 0.075 microgram ml-1 min-1 and with a targeted concentration of 2 micrograms ml-1. During and following the infusion, EEG was recorded and clinical signs were assessed as measure of the hypnotic effect. Thus, the time intervals from start of infusion until the volunteers fell asleep, until they did no longer respond to loud verbal commands, until loss of the corneal reflex and until the appearance of burst suppression patterns in the EEG were recorded. The latter sign was used as endpoint for the infusion. After the cessation of the infusion the time intervals until the disappearance of burst suppression and the reappearance of the clinical signs were recorded until full orientation was regained. Arterial blood samples were frequently drawn up to 720 min following the cessation of the last infusion cycle. Eltanolone serum concentrations were measured by a specific GC-MS assay. Pharmacokinetics were analysed with NONMEM by an open three compartment model. The serum concentrations were correlated with the corresponding clinical signs to quantify the concentration-effect relationship. Blood pressure, heart rate and oxygen saturation were measured continuously and the arterial pCO2 was analysed every 6 min. RESULTS: The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l min-1), small volumes of distribution (Vc = 7.7 +/- 3.4 l; Vdss = 92 +/- 22 l and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). (Table 2). The clinical signs revealed a good hypnotic effect, resulting in burst suppression periods in the EEG after 19 min during the first and 15 min during the second infusion cycle. The slow induction enabled a thorough observation of the induction phase. During the first infusion cycle cessation of counting occurred after 7.7 +/- 1.3 min (mean +/- SD), reaction to verbal contact was lost after 10.4 +/- 1.3 min and the corneal reflex was lost only in about one half of the volunteers after 17.9 +/- 2.8. During recovery, the corneal reflex reappeared 9.4 +/- 2.4 min after stop of infusion, first reactions to loud verbal commands were recorded after 24.2 +/- 4.3 min and full orientation was regained after 34.7 +/- 6.2 min. During the second cycle all signs disappeared faster and were regained later. The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance. The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P < 0.05). Diastolic arterial blood pressure decreased of about 10%, while heart rate increased significantly of about 24% (P < 0.05). Oxygen saturation remained stable with values between 96 and 100% with the exception of one volunteer. Apnoea was not recorded during the entire observation period. The median value of all pCO2 analyses was 41 mmHg with a range of 25-60 mmHg. The only serious undesirable effect was a seizure during awakening in one volunteer which coincided with polyspike waves in his raw-EEG recordings. (ABSTRACT TR