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%.

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.     

Effective plasma alfaxalone concentration to produce immobility in male neutered cats

Objective

To determine the effective plasma alfaxalone concentration for the production of immobility in cats.

Intramuscular injection of alfaxalone in combination with butorphanol for sedation in cats

Objective

To assess quality of sedation following intramuscular (IM) injection of two doses of alfaxalone in combination with butorphanol in cats.

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 AUC_last and C_max. Equivalence was achieved if the 90% confidence interval for AUC_last and C_max 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. C_max and AUC_last 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.     

The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats

ObjectiveTo determine the cardiorespiratory and anesthetic effects of 0, 5, 15, and 50 mg kg^?1 intravenous (IV) alfaxalone in hydroxypropyl beta cyclodextrin (Alfaxan; Jurox Pty Ltd, Rutherford, NSW, Australia) in cats.Study designFour treatments of alfaxalone were administered in sequential order.AnimalsEight healthy adult cats (four male; four female) weighing between 3.71 and 5.91 kg.MethodsCats were instrumented for hemodynamic measurements. Four (0, 5, 15, and 50 mg kg^?1) IV doses of alfaxalone were administered over one minute, with a 3-hour washout period between doses 0, 5, and 15 mg kg^?1 on Day 0. The 50 mg kg^?1 treatment was administered 24 hours later. Measurements of heart rate, aortic systolic, mean, and diastolic blood pressures, pulmonary arterial and right atrial mean pressures, cardiac output, respiratory rate, tidal and minute volumes, and arterial blood pH and blood gases (PaO₂, PaCO₂) were performed at pre-determined intervals. Systemic vascular resistance and rate pressure product were calculated. The quality of induction, maintenance, and recovery from anesthesia and the response to noxious stimulation were categorically scored.ResultsAlfaxalone administration resulted in dose-dependent cardiorespiratory depression. Decreases in arterial blood pressure and increases in heart rate occurred at higher doses. Most variables returned to baseline by 15-30 minutes. Respiratory rate, minute volume, and PaO₂ decreased. Apnea was the most common side effect. Induction and maintenance quality were judged to be good to excellent at all doses and quality of recovery good to excellent at all but the 50 mg kg^?1 dose. The duration of anesthesia and unresponsiveness to noxious stimulation increased with dose. The administration of the 50 mg kg^?1 dose produced marked cardiorespiratory depression and apnea.Conclusions and clinical relevanceAlfaxalone produced dose-dependent anesthesia, cardiorespiratory depression and unresponsiveness to noxious stimulation in unpremedicated cats. Hypoventilation and apnea were the most common side effects.     

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 (MIR_NM) in dogs.

The minimum infusion rate of alfaxalone during its co-administration with lidocaine at three different doses by constant rate infusion in goats

Objective

To determine the minimum infusion rate (MIR) of alfaxalone required to prevent purposeful movement in response to standardized stimulation while co-administered with lidocaine at three different doses by constant infusion rate infusion (CRI) in goats.

Minimum infusion rate of alfaxalone for total intravenous anaesthesia after sedation with acepromazine or medetomidine in cats undergoing ovariohysterectomy

ObjectiveTo determine the induction doses, then minimum infusion rates of alfaxalone for total intravenous anaesthesia (TIVA), and subsequent, cardiopulmonary effects, recovery characteristics and alfaxalone plasma concentrations in cats undergoing ovariohysterectomy after premedication with butorphanol-acepromazine or butorphanol-medetomidine.Study designProspective randomized blinded clinical study.AnimalsTwenty-eight healthy cats.MethodsCats undergoing ovariohysterectomy were assigned into two groups: together with butorphanol [0.2 mg kg^?1 intramuscularly (IM)], group AA (n = 14) received acepromazine (0.1 mg kg^?1 IM) and group MA (n = 14) medetomidine (20 μg kg^?1 IM). Anaesthesia was induced with alfaxalone to effect [0.2 mg kg^?1 intravenously (IV) every 20 seconds], initially maintained with 8 mg kg^?1 hour^?1 alfaxalone IV and infusion adjusted (±0.5 mg kg^?1 hour^?1) every five minutes according to alterations in heart rate (HR), respiratory rate (f_R), Doppler blood pressure (DBP) and presence of palpebral reflex. Additional alfaxalone boli were administered IV if cats moved/swallowed (0.5 mg kg^?1) or if f_R >40 breaths minute^?1 (0.25 mg kg^?1). Venous blood samples were obtained to determine plasma alfaxalone concentrations. Meloxicam (0.2 mg kg^?1 IV) was administered postoperatively. Data were analysed using linear mixed models, Chi-squared, Fishers exact and t-tests.ResultsAlfaxalone anaesthesia induction dose (mean ± SD), was lower in group MA (1.87 ± 0.5; group AA: 2.57 ± 0.41 mg kg^?1). No cats became apnoeic. Intraoperative bolus requirements and TIVA rates (group AA: 11.62 ± 1.37, group MA: 10.76 ± 0.96 mg kg^?1 hour^?1) did not differ significantly between groups. Plasma concentrations ranged between 0.69 and 10.76 μg mL^?1. In group MA, f_R, end-tidal carbon dioxide, temperature and DBP were significantly higher and HR lower.Conclusion and clinical relevanceAlfaxalone TIVA in cats after medetomidine or acepromazine sedation provided suitable anaesthesia with no need for ventilatory support. After these premedications, the authors recommend initial alfaxalone TIVA rates of 10 mg kg^?1 hour^?1.     

Effects of two fentanyl constant rate infusions on thermal thresholds and plasma fentanyl concentrations in awake cats

Objective

To determine the pharmacokinetics and effects on thermal thresholds (TT) of two fentanyl constant rate infusions in awake cats.

Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs

ObjectiveTo compare the anaesthetic and cardiopulmonary effects of alfaxalone with propofol when used for total intravenous anaesthesia (TIVA) during ovariohysterectomy in dogs.Study designA prospective non-blinded randomized clinical study.AnimalsFourteen healthy female crossbred bitches, aged 0.5–5 years and weight 16–42 kg.MethodsDogs were premedicated with acepromazine 0.01 mg kg^?1 and morphine 0.4 mg kg^?1. Anaesthesia was induced and maintained with either propofol or alfaxalone to effect for tracheal intubation followed by an infusion of the same agent. Dogs breathed spontaneously via a ‘circle’ circuit, with oxygen supplementation. Cardiopulmonary parameters (respiratory and heart rates, end-tidal carbon dioxide, tidal volume, and invasive blood pressures) were measured continuously and recorded at intervals related to the surgical procedure. Arterial blood samples were analysed for blood gas values. Quality of induction and recovery, and recovery times were determined. Non-parametric data were tested for significant differences between groups using the Mann–Whitney U-test and repeatedly measured data (normally distributed) for significant differences between and within groups by anova.ResultsBoth propofol and alphaxalone injection and subsequent infusions resulted in smooth, rapid induction and satisfactory maintenance of anaesthesia. Doses for induction (mean ± SD) were 5.8 ± 0.30 and 1.9 ± 0.07 mg kg^?1 and for the CRIs, 0.37 ± 0.09 and 0.11 ± 0.01 mg kg^?1 per minute for propofol and alfaxalone respectively. Median (IQR) recovery times were to sternal 45 (33–69) and 60 (46–61) and to standing 74 (69–76) and 90 (85–107) for propofol and alphaxalone respectively. Recovery quality was good. Cardiopulmonary effects did not differ between groups. Hypoventilation occurred in both groups.Conclusions and clinical relevanceFollowing premedication with acepromazine and morphine, both propofol and alphaxalone produce good quality anaesthesia adequate for ovariohysterectomy. Hypoventilation occurs suggesting a need for ventilatory support during prolonged infusion periods with either anaesthetic agent.     

Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs

ObjectiveTo determine the cardiorespiratory and anesthetic effects of 2, 6, and 20 mg kg⁻¹ IV alfaxalone in hydroxypropyl beta cyclodextrin (Alfaxan) in dogs.Study designBlinded four-way crossover randomized by dose.AnimalsEight healthy adult purpose-bred mixed breed dogs (four male, four female) weighing between 12 and 28 kg.MethodsFour (0, 2, 6, 20 mg kg⁻¹) IV treatments of alfaxalone were administered to each dog with a 3-hour washout period between doses. Measurements of heart rate, aortic systolic, mean, and diastolic blood pressures, pulmonary arterial and right atrial mean pressures, cardiac output, respiratory rate, tidal and minute volumes, and arterial blood pH, blood gases (PaO₂, PaCO₂) were performed prior to and at predetermined intervals after drug administration. Systemic vascular resistance and rate pressure product were calculated. The quality of induction, maintenance, and recovery from anesthesia were categorically scored as was the response to noxious stimulation.ResultsThe administration of alfaxalone resulted in dose-dependent changes in cardiovascular and respiratory parameters. Decreases in arterial blood pressure and increases in heart rate occurred at higher doses with most variables returning to baseline in 15–30 minutes. Respiratory rate, minute volume, and PaO₂ decreased and apnea was the most common side effect. The duration of anesthesia increased with dose, and induction, maintenance, and recovery were judged to be good to excellent with all doses studied.Conclusions and clinical relevanceAlfaxalone produced good to excellent short-term anesthesia in unpremedicated dogs. Cardiorespiratory effects were minimal at lower doses. Anesthesia was judged to be good to excellent and associated with unresponsiveness to noxious stimulation for the majority of anesthesia. Hypoventilation and apnea were the most prominent and dose-dependent effects.     

Comparison of two formulations of alfaxalone for immersion anaesthesia in laboratory zebrafish (Danio rerio)

ObjectiveTo compare two commercial formulations of alfaxalone for immersion anaesthesia in laboratory zebrafish.Study designProspective, blinded, randomized study.AnimalsA total of 20 adult Danio rerio (Tuebingen strain).MethodsZebrafish were divided into two groups of 10 (five female, five male) and placed in individual immersion baths containing 10 mg L^–1 of unpreserved alfaxalone (group 1) or preserved alfaxalone (group 2). Anaesthetists blinded to treatment used a composite score scale (CSS) (range 0–12) to assess fish every 30 seconds until induction of anaesthesia. Anaesthetic induction occurred when equilibrium and response to stimulus were lost. Fish were then placed in a clean water bath and scored every 60 seconds. Recovery from anaesthesia was defined as a CSS of ≤ 1. Time variables recorded were anaesthetic induction time (AIT), anaesthetic recovery time (ART) and total procedure time (TPT). Fish were observed for evidence of roupgross external pathology during the procedure. Following anaesthesia, four fish from each group were randomly chosen and euthanized for gill histopathology analysis immediately after recovery criteria were met. Data are presented as mean ± standard deviation. An independent t test was used to compare the difference in average anaesthetic time variables between groups (α = 0.05).ResultsThere were no statistical differences between groups in reported variables. TPT, AIT and ART were 10.2 ± 1.2, 1.9 ± 0.9 and 8.3 ± 1.2 minutes for group 1 and 10.8 ± 2.9, 2.4 ± 1.2 and 8.4 ± 2.7 minutes for group 2. No gross external pathology was evident, and no fish died during the experimental period. Histopathology showed normal gill pathology and no difference between the groups.Conclusions and clinical relevanceImmersion anaesthesia using 10 mg L^–1 of either formulation of alfaxalone resulted in anaesthesia of similar quality and duration.     

Comparison of the brainstem auditory evoked responses during sevoflurane or alfaxalone anaesthesia in adult cats

Objective

To compare the effects of general anaesthesia using sevoflurane or alfaxalone on the brainstem auditory evoked response (BAER) test in adult healthy cats.