Pharmacokinetics and sedative effects of alfaxalone with or without dexmedetomidine in rabbits.

This study aimed to investigate the specific pharmacokinetic profile and effects of alfaxalone after intravenous (IV) and intramuscular (IM) administration to rabbits and evaluate the potential interaction with dexmedetomidine. The study design was a blinded, randomized crossover with a washout period of 2 weeks. Five New Zealand white rabbits were used. Each animal received single IV and IM injections of alfaxalone at a single dose of 5 mg/kg, and single IV and IM injections of alfaxalone (5 mg/kg) combined with dexmedetomidine (100 µg/kg) administered intramuscularly. Blood samples were collected at predetermined times and analysed by high-performance liquid chromatography. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation/anaesthesia scores were evaluated by a modified numerical rating scale. At pre-determined time points heart and respiratory rates were measured. Times to sternal recumbency and standing position during the recovery were recorded. Concentrations of alfaxalone alone were very similar (slighty smaller) to concentrations when alfaxalone was combined with dexmedetomidine, after both routes of administration. Dexmedetomidine enhanced and increase the duration of the sedative effects of alfaxalone. In conclusion, alfaxalone administered in rabbits provides rapid and smooth onset of sedation. After IV and IM injections of alfaxalone combined with dexmedetomidine, a longer MRT and a deeper and extended sedation have been obtained compared to alfaxalone alone. Consequently, alfaxalone alone or in combination with dexmedetomidine could be useful to achieve respectively moderate to deep sedation in rabbits.

Pharmacokinetic and Pharmacodynamic Analysis of Alfaxalone Administered as a Bolus Intravenous Injection of Phaxan in a Phase 1 Randomized Trial.

BACKGROUND: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers. METHODS: A dose of 0.5 mg/kg (0.42-0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (EMAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t1/2keo). RESULTS: A 3-compartment model used to fit PK data with an additional compartment, linked by t1/2keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87-1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53-2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32-1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19-1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79-10.7 L (median; 95% CI) and V3: 19.1 L; 8.61-37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX: 0.94; 0.71-0.99 (median; 95% CI), a plasma concentration (Cp) for 50% effect (C50): 0.98 mg/L; 0.83-1.09 mg/L (median; 95% CI), and a Hill coefficient (γ): 12.1; 6.7-15 (median; 95% CI). The t1/2keo was 8 minutes; 4.70-12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes). CONCLUSIONS: After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of <60 are comparable to those previously reported in patients anesthetized with alfaxalone. The t1/2keo is relatively high, but the large Hill coefficient contributes to rapid onset and offset of action. This information can inform future studies of this formulation.

Pharmacokinetics and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos).

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross-over design with a washout period between doses. Mean (±SD) Cmax following IM injection was 1.6 (±0.8) µg/ml with Tmax at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (VD ) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min-1  kg-1 . Elimination half-lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.

Alfaxalone total intravenous anaesthesia in dogs: pharmacokinetics, cardiovascular data and recovery characteristics.

OBJECTIVE: To evaluate the cardiovascular effects, pharmacokinetic (PK) data and recovery characteristics of an alfaxalone constant rate infusion (CRI) of different duration in dogs at manufacturer's recommended dose rate. STUDY DESIGN: Experimental, prospective, randomized, crossover study. ANIMALS: Six intact female Beagles. METHODS: Following an intravenous alfaxalone bolus (3 mg kg-1), anaesthesia was maintained using an alfaxalone CRI at 0.15 mg kg-1 minute-1 for 90 (short CRI) or 180 minutes (long CRI). Venous blood samples were collected to determine the PK profile. Cardiovascular variables and recovery characteristics were evaluated. Recovery was scored on a scale ranging from 0, excellent to 4, bad. A mixed-model statistical approach was used to compare the cardiovascular parameters (global α = 0.05). An analysis of variance was performed to compare PK parameters and recovery times between treatments. RESULTS: No significant difference was noted between protocols for any PK parameter. Volume of distribution at steady state (935.74 ± 170.25 versus 1119.15 ± 190.65 mL kg-1), elimination half-life (12 ± 2 versus 13 ± 3 minutes), clearance from the central compartment (26.02 ± 4.41 versus 27.74 ± 5.65 mL kg-1 minute-1) and intercompartmental clearance (8.47 ± 4.06 versus 12.58 ± 7.03 mL kg-1 minute-1) were comparable for short CRI and long CRI. Cardiovascular variables remained within physiological limits. Mechanical ventilation was necessary (short CRI: n = 1, long CRI: n = 4). The manufacturer's recommended dose rate resulted in a light plane of anaesthesia. No significant differences in recovery times and scores were observed between treatments. The quality of recovery was scored as very poor with both protocols. CONCLUSIONS AND CLINICAL RELEVANCE: PK data were similar between long and short infusions of alfaxalone at the manufacturer's recommended dose, with acceptable cardiovascular conditions. Nevertheless, both protocols resulted in a superficial plane of general anaesthesia with poor recovery characteristics.

Hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats.

OBJECTIVE: To characterize the hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats. STUDY DESIGN: Experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with desflurane in oxygen for instrumentation. Catheters were placed in a medial saphenous vein for drug administration and in a carotid artery for arterial blood pressure measurement and blood collection. A thermodilution catheter was placed in the pulmonary artery via an introducer placed in a jugular vein for measurement of central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac output and core body temperature, and for sampling mixed venous blood. A lead II electrocardiogram was connected. Desflurane administration was discontinued and a target-controlled infusion system was used to administer alfaxalone to reach six plasma alfaxalone concentrations ranging from 1.0 to 30.4 mg L-1, with 7.6 mg L-1 considered a clinical concentration for anesthesia. Cardiovascular measurements were recorded, and arterial and mixed-venous blood samples were collected for blood-gas analysis and plasma alfaxalone concentration measurement at each target concentration. Data were analyzed using a repeated-measures analysis of variance and Dunnett's test for comparisons to the lowest target concentration. Significance was set at p < 0.05. RESULTS: Mean ± standard deviation plasma alfaxalone concentrations were 0.73 ± 0.32, 1.42 ± 0.41, 3.44 ± 0.40, 6.56 ± 0.43, 18.88 ± 6.81 and 49.47 ± 5.50 mg L-1 for the 1, 1.9, 3.8, 7.6, 15.2, and 30.4 mg L-1 target concentrations, respectively. PaCO2 increased with increasing target plasma alfaxalone concentrations and was 69.4 ± 14.2 mmHg (9.3 ± 1.9 kPa) at the 30.4 mg L-1 target. Some cardiovascular variables were statistically significantly affected by increasing target plasma alfaxalone concentrations. CONCLUSION AND CLINICAL RELEVANCE: Within the plasma concentration range studied, alfaxalone caused hypoventilation, but the cardiovascular effects were of small clinical significance.

Clinical pharmacokinetics and pharmacodynamics of intravenous alfaxalone in young Thoroughbred horses premedicated with medetomidine and midazolam.

To investigate the clinical pharmacokinetics and pharmacodynamics of intravenous alfaxalone in young Thoroughbred horses, seven Thoroughbred horses were randomly anaesthetised twice with either 1 or 2 mg/kg of intravenous alfaxalone after premedication with medetomidine (6 µg/kg intravenous) and midazolam (20 µg/kg intravenous). Blood samples were collected at predetermined time points up to two hours after administration. Plasma alfaxalone concentrations were quantified by a liquid chromatography tandem-mass spectrometry method and analysed by non-compartmental pharmacokinetic analysis. Induction and recovery qualities were good to excellent for both doses. Recovery time for the 2 mg/kg (median 90 minutes) was significantly longer than that for the 1 mg/kg (median 50 minutes). Respiratory rate for the 2 mg/kg was significantly lower than that for the 1 mg/kg, resulting in hypoxaemia. The median (range) elimination half-life, total clearance and volume of distribution were 58.2 (42.3-70.7) minutes, 11.6 (10.3-14.5) ml/minute/kg and 0.8 (0.7-0.9) l/kg for the 1 mg/kg and 59.8 (47.5-68.0) minutes, 14.7 (12.1-16.0) ml/minute/kg and 0.9 (0.9-1.2) l/kg for the 2 mg/kg, respectively. Alfaxalone is rapidly eliminated from the plasma in young Thoroughbred horses. Respiratory depression should be especially noted when alfaxalone is used in clinical practice.

Alfaxalone for total intravenous anaesthesia in horses.

OBJECTIVE: To determine the suitability of alfaxalone total intravenous (IV) anaesthesia in horses and concurrently evaluate infusion rates, cardiovascular effects, pharmacokinetics and the quality of the anaesthetic recovery period. STUDY DESIGN: Prospective, experimental study. ANIMALS: Eight Standardbred horses. METHODS: Horses were premedicated with IV acepromazine (0.03 mg kg-1) and xylazine (1 mg kg-1) and anaesthesia was induced with guaifenesin (35 mg kg-1) and alfaxalone (1 mg kg-1). Anaesthesia was maintained for 180 minutes using an IV infusion of alfaxalone at a rate determined by a horse's response to a supramaximal electrical noxious stimulus. Venous blood samples were regularly collected to determine alfaxalone plasma concentrations and for pharmacokinetic analysis. Cardiopulmonary variables were monitored and the quality of the anaesthetic recovery period scored. RESULTS: The median (range) alfaxalone infusion rate was 3.1 (2.4-4.3) mg kg-1 hour-1. The mean ± standard deviation plasma elimination half-life, plasma clearance and volume of distribution for alfaxalone were 41 minutes, 25 ± 6.3 mL minute-1 kg-1 and 1.6 ± 0.5 L kg-1, respectively. During anaesthesia, mean arterial blood pressure was maintained above 70 mmHg in all horses. Cardiac index reached a minimum value (68% of baseline values) immediately after induction of anaesthesia and was maintained between 74% and 90% of baseline values for the remainder of the anaesthetic protocol. Following the cessation of the alfaxalone infusion, six of eight horses exhibited muscle tremors and paddling. All horses stood without incident on the first or second attempt with a median recovery score of 4.5 (good to excellent). CONCLUSIONS AND CLINICAL RELEVANCE: Anaesthesia in horses can be maintained with an infusion of alfaxalone at approximately 3 mg kg-1 hour-1. The alfaxalone infusion rates used resulted in minimal haemodynamic changes and good recovery quality. Mean alfaxalone plasma concentration was stable over the infusion period and clearance rates were similar to previously published single-dose alfaxalone studies in horses.

Effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone required to prevent movement in response to a noxious stimulus (MIRNM) in dogs. STUDY DESIGN: Experimental crossover design. ANIMALS: A group of six healthy, adult, intact female mixed-breed dogs, weighing 19.7 ± 1.3 kg. METHODS: Dogs were randomly administered one of three treatments at weekly intervals: premedication with 0.9% saline (treatment A), fentanyl 5 µg kg-1 (treatment ALF) or fentanyl 10 µg kg-1 (treatment AHF), administered intravenously over 5 minutes. Anesthesia was induced 5 minutes later with incremental doses of alfaxalone to achieve intubation and was maintained for 90 minutes in A with alfaxalone (0.12 mg kg-1 minute-1), in ALF with alfaxalone (0.09 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1) and in AHF with alfaxalone (0.06 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). The alfaxalone infusion was increased or decreased by 0.006 mg kg-1 minute-1 based on positive or negative response to antebrachium stimulation (50 V, 50 Hz, 10 ms). Data were analyzed using a mixed-model anova and presented as least squares means ± standard error. RESULTS: Alfaxalone induction doses were 3.50 ± 0.13 (A), 2.17 ± 0.10 (ALF) and 1.67 ± 0.10 mg kg-1 (AHF) and differed among treatments (p < 0.05). Alfaxalone MIRNM was 0.17 ± 0.01 (A), 0.10 ± 0.01 (ALF) and 0.07 ± 0.01 mg kg-1 minute-1 (AHF) and differed among treatments. ALF and AHF decreased the MIRNM by 44 ± 8% and 62 ± 5%, respectively (p < 0.05). Plasma alfaxalone concentrations at MIRNM were 5.82 ± 0.48 (A), 4.40 ± 0.34 (ALF) and 2.28 ± 0.09 µg mL-1 (AHF). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, significantly decreased the alfaxalone induction dose and MIRNM.

Pharmacokinetics of intramuscular alfaxalone and its echocardiographic, cardiopulmonary and sedative effects in healthy dogs.

The pharmacokinetics and the effects of a single intramuscular (IM) dose of alfaxalone on sedation and cardiopulmonary and echocardiographic variables was studied in dogs. Twelve healthy adult Beagles (3 females, 9 males) were used in this prospective controlled cross-over trial. Echocardiography was performed with and without 4 mg kg-1 alfaxalone IM with a week wash-out interval. Sedation (19-point scale; 0 = no sedation), cardiopulmonary parameters, blood gas analysis and plasma concentration of alfaxalone were assessed every 5 minutes following the injection (T0). The influence of the alfaxalone plasma concentration and time on physiological variables was tested using a linear model whereas echocardiographic measurements were compared between conscious and alfaxalone-administered dogs using paired t-tests. Compared to baseline, alfaxalone administration was followed by an increase in heart rate (HR) from T5 to T30 and a decrease in mean arterial pressure (MAP) at T10, T25 and T30, in stroke volume (SV; 15 ± 5 to 11 ± 3 ml; P<0.0001), and end-diastolic volume (EDV; 24.7 ± 5.7 to 19.4 ± 4.9 ml). Cardiac output (CO) and blood gas analysis did not change significantly throughout. Mean plasma half-life was 29 ± 8 minutes, volume of distribution was 1.94 ± 0.63 L kg-1, and plasma clearance was 47.7 ± 14.1 ml kg-1 minute-1. Moderate to deep sedation was observed from T5 to T35. Ten dogs showed paddling, trembling, nystagmus and strong reaction to sound during the procedure. Although there were no significant changes in CO and oxygenation, the impact of HR, MAP, SV, EDV alterations requires further investigations in dogs with cardiac disease.

Pharmacokinetics of alfaxalone infusions, context-sensitive half-time and recovery times in male neutered cats.

OBJECTIVES: To determine the context-sensitive half-time of alfaxalone following intravenous infusions of various durations. To estimate the time necessary for plasma concentration to decrease by up to 95%. STUDY DESIGN: Prospective randomized and simulation studies. ANIMALS: A group of six 1-year-old male castrated research cats. METHODS: Cats were instrumented with catheters in a jugular and a medial saphenous vein. Alfaxalone was administered using a target-controlled infusion system, to target a plasma alfaxalone concentration of 7.6 mg L-1. The infusion lasted 30 (n = 2), 60 (n = 2) or 240 (n = 2) minutes. Blood samples were collected prior to drug administration, and at several times during and up to 8 hours after the infusion, for the determination of plasma alfaxalone concentration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to each time-concentration profile, and a population model was fitted to data from all individuals. The context-sensitive half-time was determined from each individual model. In addition, times for plasma alfaxalone concentration to decrease by 50-95% following bolus administration and target-controlled infusions or continuous rate infusions of 0.5-8 hours were estimated by simulation using the population model. RESULTS: Context-sensitive half-times were 2 and 8, 6 and 9, and 18 and 20 minutes for the 30, 60 and 240 minutes, respectively. Time for plasma alfaxalone concentration to decrease by 90% was predicted to range from 7 to 120 or 113 minutes following a bolus to an 8 hour target-controlled or continuous rate infusion, respectively. CONCLUSION AND CLINICAL RELEVANCE: Recovery time from alfaxalone anesthesia in cats is predicted to be influenced by the duration of target-controlled infusion.

Pharmacokinetics and effects of alfaxalone after intravenous and intramuscular administration to cats.

AIMS: To determine the pharmacokinetics, and anaesthetic and sedative effects of alfaxalone after I/V and I/M administration to cats. METHODS: Six European shorthair cats, three males and three females, with a mean weight of 4.21 (SD 0.53) kg and aged 3.8 (SD 0.9) years were enrolled in this crossover, two-treatment, two-period study. Alfaxalone at a dose of 5 mg/kg was administered either I/V or I/M. Blood samples were collected between 2-480 minutes after drug administration and analysed for concentrations of alfaxalone by HPLC. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation scores were evaluated between 5-120 minutes after drug administration using a numerical rating scale (from 0-18). Intervals from drug administration to sit, sternal and lateral recumbency during the induction phase, and to head-lift, sternal recumbency and standing position during recovery were recorded. RESULTS: The mean half-life and mean residence time of alfaxalone were longer after I/M (1.28 (SD 0.21) and 2.09 (SD 0.36) hours, respectively) than after I/V (0.49 (SD 0.07) and 0.66 (SD 0.16) hours, respectively) administration (p<0.05). Bioavailability after I/M injection of alfaxalone was 94.7 (SD 19.8)%. The mean intervals to sternal and lateral recumbency were longer in the I/M (3.73 (SD 1.99) and 6.12 (SD 0.90) minutes, respectively) compared to I/V (0 minutes for all animals) treated cats (p<0.01). Sedation scores indicative of general anaesthesia (scores >15) were recorded from 5-15 minutes after I/V administration and deep sedation (scores 11-15) at 20 and 30 minutes. Deep sedation was observed from 10-45 minutes after I/M administration. One cat from each group showed hyperkinesia during recovery, and the remainder had an uneventful recovery. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone administered I/V in cats provides rapid and smooth induction of anaesthesia. After I/M administration, a longer exposure to the drug and an extended half life were obtained compared to I/V administration. Therefore I/M administration of alfaxalone could be a reliable, suitable and easy route in cats, taking into account that alfaxalone has a slower onset of sedation than when given I/V and achieves deep sedation rather than general anaesthesia.

The bioequivalence of a single intravenous administration of the anesthetic alfaxalone in cyclodextrin versus alfaxalone in cyclodextrin plus preservatives in cats.

To demonstrate the bioequivalence of alfaxalone in cyclodextrin (Reference Product) to a formulation of alfaxalone in cyclodextrin also containing the preservatives ethanol, chlorocresol, and benzethonium chloride (Test Product) when administered for the purpose of inducing anesthesia in the cat. Blinded, single-dose, randomized, two-period, two-sequence, cross-over bioequivalence study with a 7-day washout period between treatments. Twenty-four (12 neutered males and 12 intact females), healthy, adult cats weighing 4.1±0.9 kg. Cats were administered 5 mg/kg IV of alfaxalone in the Reference or Test Product using a randomized cross-over design. One-milliliter venous blood samples were collected at predetermined time points to 12 hr after drug administration to determine alfaxalone plasma concentration over time. Alfaxalone concentrations were determined by a validated analytical testing method using HPLC-MS/MS. Plasma profiles of alfaxalone concentration against time were analyzed by noncompartmental analysis. The pivotal variables for bioequivalence were AUClast and Cmax . Equivalence was achieved if the 90% confidence interval for AUClast and Cmax fell into the asymmetric ±20% interval (0.80-1.25). Physiological variables, quality of anesthesia visual analog scale (VAS) scoring and anesthetic event times were recorded. ANOVA or ANCOVA (single time point), RMANOVA or RMANCOVA (multiple time point) was used for normally distributed data. GLIMMIX was used for nonnormally distributed data. VAS scores were analyzed as for blood bioequivalence data. Variables were evaluated for safety and assessed at alpha = 0.10. Cmax and AUClast for Reference and Test Products were statistically bioequivalent. No physiological variables except for a drug by time interaction for respiratory rate differed between treatment groups, and this difference was not clinically relevant. No anesthetic event times or VAS scores for quality of anesthesia were different between treatment groups. Neither formulation caused pain upon injection. The Reference and Test Products are pharmaceutically bioequivalent formulations when administered as a single intravenous administration for the purpose of induction of anesthesia in cats.

Effects of the α2-adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs.

OBJECTIVE To assess the possible impact of medetomidine on concentrations of alfaxalone in plasma, when coadministered as a constant rate infusion (CRI) to dogs, and to determine the possible impact of medetomidine on the cardiopulmonary effects of alfaxalone during CRI. ANIMALS 8 healthy adult Beagles. PROCEDURES 3 treatments were administered in a randomized crossover design as follows: 1 = saline (0.9% NaCl) solution injection, followed in 10 minutes by induction of anesthesia with alfaxalone (loading dose, 2.4 mg/kg; CRI, 3.6 mg/kg/h, for 60 minutes); 2 = medetomidine premedication (loading dose, 4.0 µg/kg; CRI, 4.0 µg/kg/h), followed by alfaxalone (as in treatment 1); and, 3 = medetomidine (as in treatment 2) and MK-467 (loading dose, 150 µg/kg; CRI, 120 µg/kg/h), followed by alfaxalone (as in treatment 1). The peripherally acting α2-adrenoceptor antagonist MK-467 was used to distinguish between the peripheral and central effects of medetomidine. Drugs were administered IV via cephalic catheters, and there was a minimum of 14 days between treatments. Cardiopulmonary parameters were measured for 70 minutes, and jugular venous blood samples were collected until 130 minutes after premedication. Drug concentrations in plasma were analyzed with liquid chromatography-tandem mass spectrometry. RESULTS The characteristic cardiovascular effects of medetomidine, such as bradycardia, hypertension, and reduction in cardiac index, were obtunded by MK-467. The concentrations of alfaxalone in plasma were significantly increased in the presence of medetomidine, indicative of impaired drug distribution and clearance. This was counteracted by MK-467. CONCLUSIONS AND CLINICAL RELEVANCE The alteration in alfaxalone clearance when coadministered with medetomidine may be attributed to the systemic vasoconstrictive and bradycardic effects of the α2-adrenoceptor agonist. This could be clinically important because the use of α2-adrenoceptor agonists may increase the risk of adverse effects if standard doses of alfaxalone are used.

A clinical evaluation of the pharmacokinetics and pharmacodynamics of intravenous alfaxalone in cyclodextrin in male and female rats following a loading dose and constant rate infusion.

OBJECTIVE: To characterise, as a clinical study, the pharmacokinetics and pharmacodynamics and describe the hypnotic effect of the neurosteroid alfaxalone (3α-hydroxy-5 α-pregnane-11, 20-dione) formulated with 2-hydroxypropyl-ß-cyclodextrin in male and female rats. STUDY DESIGN: Prospective, experimental laboratory study. ANIMALS: A total of 12 (six male and six female) adult, aged-matched Sprague Dawley rats. METHODS: Surgery and instrumentation was performed under isoflurane anaesthesia in an oxygen/nitrous oxide mixture (1:2) and local anaesthetic infiltration. All animals received a loading dose (1.67 mg kg-1 minute-1) for 2.5 minutes followed by a constant rate infusion (0.75 mg kg-1 minute-1) for 120 minutes of alfaxalone. Isoflurane and nitrous oxide was discontinued 2.5 minutes after the alfaxalone infusion started. Cardiorespiratory variables (heart rate, respiratory rate, arterial blood pressure and end tidal carbon dioxide tension) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Carotid artery blood samples were collected at strategic time points for blood gas analysis, haematology, biochemistry, and plasma concentrations of alfaxalone. Plasma samples were assayed using liquid chromatography-mass spectrometry. RESULTS: There were significant differences between the sexes for plasma clearance (p=0.0008), half-life (p=0.0268) and mean residence time (p=0.027). Mean arterial blood pressure was significantly higher in the male rats (p=0.0255). CONCLUSIONS AND CLINICAL RELEVANCE: This study confirms that alfaxalone solubilised in 2-hydroxypropyl-ß-cyclodextrin provides excellent total intravenous anaesthesia in rats. Sex-based differences in pharmacokinetics and pharmacodynamics were demonstrated and must be considered when designing biomedical research models using alfaxalone.

The effects of intravenous alfaxalone with and without premedication on intraocular pressure in healthy dogs.

The objective of this study was to investigate the effects of intravenous alfaxalone with and without premedication on intraocular pressure (IOP) in healthy dogs. Thirty-three dogs were randomized to receive 1 of 3 treatments: acepromazine [0.03 mg/kg body weight (BW)] with butorphanol (0.2 mg/kg BW) intramuscularly (IM), followed by intravenous (IV) alfaxalone (1.5 mg/kg BW); dexmedetomidine (0.002 mg/kg BW) with hydromorphone (0.1 mg/kg BW) IM, followed by alfaxalone (1 mg/kg BW) IV; and saline 0.9% (0.02 mL/kg BW) IM, followed by alfaxalone (3 mg/kg BW) IV. Intraocular pressure (IOP) was measured at baseline, 15 min, and 30 min after premedication, after pre-oxygenation, after administration of alfaxalone, and after intubation. After induction and after intubation, the IOP was significantly increased in all groups compared to baseline. While premedication with acepromazine/butorphanol or dexmedetomidine/hydromorphone did not cause a significant increase in IOP, the risk of vomiting and the associated peak in IOP after dexmedetomidine/hydromorphone should be considered when selecting an anesthetic protocol for dogs with poor tolerance for transient increases in IOP.

L'objectif de la présente étude était d'examiner les effets de l'administration intraveineuse (IV) d'alfaxalone avec et sans prémédication sur la pression intraoculaire (PIO) chez des chiens en santé. Trente-trois chiens ont été randomisés pour recevoir un des trois traitements: acépromazine [0,03 mg/kg de poids corporel (PC)] avec du butorphanol (0,2 mg PC) par voie intramusculaire (IM), suivi d'alfaxalone (1,5 mg/kg PC) IV; dexmedetomidine (0,002 mg/kg PC) avec de l'hydromorphone (0,1 mg/kg PC) IM, suivi d'alfaxalone (1 mg/kg PC) IV; et saline 0,9 % (0,02 mL/kg PC) IM, suivi d'alfaxalone (3 mg/kg PC) IV. La PIO a été mesurée au départ, 15 min et 30 min après la prémédication, après pré-oxygénation, après administration d'alfaxalone, et après intubation. Suite à l'induction et après intubation, la PIO était augmentée de manière significative dans tous les groupes comparativement à la valeur de base. Bien que la prémédication avec les combinaisons acépromazine/butorphanol ou dexmedetomidine/hydromorphone n'a pas causée d'augmentation significative de la PIO, le risque de vomissements et le pic associé de la PIO suite à l'administration de dexmedetomidine/hydropmorphone devraient être pris en considération lors de la sélection d'un protocole d'anesthésie pour des chiens avec une faible tolérance à une augmentation transitoire de la PIO.(Traduit par Docteur Serge Messier).

A review of the pharmacology and clinical application of alfaxalone in cats.

Alfaxalone-2-hydroxpropyl-ß-cyclodextrin (alfaxalone-HPCD) was first marketed for veterinary use in Australia in 2001 and has since progressively became available throughout the world, including the USA, where in 2012 Food and Drug Administration (FDA) registration was granted. Despite the growing body of published works and increasing global availability of alfaxalone-HPCD, the accumulating evidence for its use in cats has not been thoroughly reviewed. The purpose of this review is: (1) to detail the pharmacokinetic properties of alfaxalone-HPCD in cats; (2) to assess the pharmacodynamic properties of alfaxalone-HPCD, including its cardiovascular, respiratory, central nervous system, neuromuscular, hepatic, renal, haematological, blood-biochemical, analgesic and endocrine effects; and (3) to consider the clinical application of alfaxalone-HPCD for sedation, induction and maintenance of anaesthesia in cats. Based on the published literature, alfaxalone-HPCD provides a good alternative to the existing intravenous anaesthetic options for healthy cats.

Maternal and foetal cardiovascular effects of the anaesthetic alfaxalone in 2-hydroxypropyl-ß-cyclodextrin in the pregnant ewe.

The objective of this study was to determine the pharmacodynamics effects of the anaesthetic alfaxalone in 2-hydroxypropyl- ß -cyclodextrin in pregnant sheep after the intravenous injection of a 2 mg/kg weight dose. Six pregnant Ripollesa sheep, weighing 47.1 ± 4.4 kg, were used. Twenty-four hours after instrumentation, sheep were anaesthetized with intravenous alfaxalone in cyclodextrin. Time to standing from anaesthesia was 30.0 ± 10.81 min. Foetal heart rate increased significantly during the first 5 min after alfaxalone administration. Significant differences were observed in maternal diastolic arterial blood pressure between minute 10 and minutes 90, 120, 150, 180, 210, and 240. Significant differences were observed for foetal systolic arterial blood pressure between 5 and 30 min after alfaxalone administration. Significant differences in foetal pH were detected during the entire study period, whereas maternal pH returned to baseline values by 60 min after alfaxalone administration. The present study indicated that alfaxalone in 2-hydroxypropyl- ß -cyclodextrin administered as an intravenous bolus at 2 mg/kg body weight produced minimal adverse effects and an uneventful recovery from anaesthesia in pregnant sheep and their foetus.

Plasma pharmacokinetics of alfaxalone after a single intraperitoneal or intravenous injection of Alfaxan(®) in rats.

Alfaxalone (3α-hydroxy-5α-pregnane-11, 20-dione) is a neuroactive steroid with anaesthetic properties and a wide margin of safety. The pharmacokinetic properties of alfaxalone administered intravenously and intraperitoneally in rats (n = 28) were investigated. Mean t(1/2elim) for 2 and 5 mg/kg i.v. was 16.2 and 17.6 min, respectively, but could not be estimated for IP dosing, due to sustained plasma levels for up to 60 min after injection. Clp for i.v. injection was calculated at 57.8 ± 23.6 and 54.3 ± 6.8 mL/min/kg, which were 24.5% and 23% of cardiac output, respectively. The observed C(max) was 3.0 mg/L for IP administration, and 2.2 ± 0.9 and 5.2 ± 1.3 mg/L for 2 and 5 mg/kg i.v. administration, respectively. AUC(0-60) was 96.2 min.mg/L for IP dosing. The relative bioavailability for IP dosing was 26% and 28% compared to i.v. dosing. Differences in t(1/2elim) and Cl(p) from previous pharmacokinetic studies in rats are likely due to variations in alfaxalone formulation rather than sex differences. Alfaxan® given IP caused sustained levels of alfaxalone, no apnoea and longer sleep times than i.v. dosing, although immobilization was not induced in 30% of rats given Alfaxan® IP. A pharmacodynamic study of the effects of combining IP injection of Alfaxan® with other premedication agents is worthwhile, to determine whether improved anaesthesia induction could ultimately provide an alternative anaesthetic regimen for rats.

Plasma pharmacokinetics and pharmacodynamics of alfaxalone in neonatal foals after an intravenous bolus of alfaxalone following premedication with butorphanol tartrate.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neurosteroid anaesthetic, alfaxalone, in neonatal foals after a single intravenous (IV) injection of alfaxalone following premedication with butorphanol tartrate. STUDY DESIGN: Prospective experimental study. ANIMALS: Five clinically healthy Australian Stock Horse foals of mean ± SD age of 12 ± 3 days and weighing 67.3 ± 12.4 kg. METHODS: Foals were premedicated with butorphanol (0.05 mg kg(-1) IV) and anaesthesia was induced 10 minutes later by IV injection with alfaxalone 3 mg kg(-1) . Cardiorespiratory variables (pulse rate, respiratory rate, direct arterial blood pressure, arterial blood gases) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Venous blood samples were collected at strategic time points and alfaxalone plasma concentrations were assayed using liquid chromatography-mass spectrometry (LC/MS) and analysed by noncompartmental pharmacokinetic analysis. RESULTS: The harmonic, mean ± SD plasma elimination half life (t½) for alfaxalone was 22.8 ± 5.2 minutes. The observed mean plasma clearance (Cl(p) ) and volume of distribution (Vd) were 19.9 ± 5.9 mL minute kg(-1) and 0.6 ± 0.2 L kg(-1) , respectively. Overall, the quality of the anaesthetic inductions and recoveries was good and most monitored physiological variables were clinically acceptable in all foals, although some foals became hypoxaemic for a short period following recumbency. The mean durations of anaesthesia from induction to first movement and from induction to standing were 18.7 ± 7 and 37.2 ± 4.7 minutes, respectively. CONCLUSIONS: The anaesthetic protocol used provided a predictable and consistent plane of anaesthesia in the five foals studied, with minimal cardiovascular depression. In foals, as in the adult horse, alfaxalone has a short elimination half life. CLINICAL RELEVANCE: Alfaxalone appears to be an adequate anaesthetic induction agent in foals and the pharmacokinetics suggest that, with continuous infusion, it might be suitable to provide more prolonged anaesthesia. Oxygen supplementation is recommended.

The pharmacokinetics and pharmacodynamics of the injectable anaesthetic alfaxalone in the horse.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neurosteroidal anaesthetic, alfaxalone, in horses after a single intravenous (IV) injection of alfaxalone, following premedication with acepromazine, xylazine and guaiphenesin. STUDY DESIGN: Prospective experimental study. ANIMALS: Ten (five male and five female), adult, healthy, Standardbred horses. METHODS: Horses were premedicated with acepromazine (0.03 mg kg(-1) IV). Twenty minutes later they received xylazine (1 mg kg(-1) IV), then after 5 minutes, guaiphenesin (35 mg kg(-1) IV) followed immediately by IV induction of anaesthesia with alfaxalone (1 mg kg(-1) ). Cardiorespiratory variables (pulse rate, respiratory rate, pulse oximetry) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Venous blood samples were collected at strategic time points and plasma concentrations of alfaxalone were assayed using liquid chromatography-mass spectrometry (LC/MS) and analysed by noncompartmental pharmacokinetic analysis. The quality of anaesthetic induction and recovery was scored on a scale of 1-5 (1 very poor, 5 excellent). RESULTS: The median (range) induction and recovery scores were 4 (3-5) (good: horse slowly and moderately gently attained recumbency with minimal or no rigidity or paddling) and 4 (1-5) (good: horse stood on first attempt with some knuckling and ataxia) respectively. The monitored cardiopulmonary variables were within the range expected for clinical equine anaesthesia. The mean ± SD durations of anaesthesia from induction to sternal recumbency and from induction to standing were 42.7 ± 8.4 and 47 ± 9.6 minutes, respectively. The mean ± SD plasma elimination half life (t(1/2) ), plasma clearance (Clp) and volume of distribution (V(d) ) for alfaxalone were 33.4 minutes, 37.1 ± 11.1 mL minute(-1) kg(-1) and 1.6 ± 0.4 L kg(-1) , respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone, in a 2-hydroxypropyl-beta-cyclodextrin formulation, provides anaesthesia with a short duration of recumbency that is characterised by a smooth induction and satisfactory recovery in the horse. As in other species, alfaxalone is rapidly cleared from the plasma in the horse.