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 estimatesCL1.08 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 Q30.46 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 V319.1 L; 8.61–37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX0.94; 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