Population Pharmacokinetics of Levobupivacaine During Transversus Abdominis Plane Block in Children.

BACKGROUND: Levobupivacaine is commonly used during transversus abdominis plane (TAP) block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided TAP block were evaluated to optimize dosing regimen, regarding the between-subject variability (BSV) and the volume of levobupivacaine injected. METHOD: The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1-5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 minutes after the block injection. The population pharmacokinetic analysis was performed using the NONMEM software. RESULTS: From the pharmacokinetic parameters obtained, median Cmax, tmax,, and area under the concentration versus time curve were 0.315 mg/L, 17 minutes, and 41 mg/L·min, respectively. BSV of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, TAP block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%. CONCLUSIONS: For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity.

Combined Semi-mechanistic Target-Mediated Drug Disposition and Pharmacokinetic-Pharmacodynamic Models of Alirocumab, PCSK9, and Low-Density Lipoprotein Cholesterol in a Pooled Analysis of Randomized Phase I/II/III Studies.

BACKGROUND AND OBJECTIVES: Alirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations. METHODS: Using data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A "full fixed effects modeling" strategy was implemented to quantify parameter-covariate relationships. RESULTS: The model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter-covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6 L versus 3.2 L) and allow for a 14% greater maximum lipid-lowering effect (88% versus 74%), highlighting the synergy of action between anti-PCSK9 therapeutic antibodies and statins toward lowering LDL-C plasma levels. Baseline levels of PCSK9 were found to be related to the amplitude of LDL-C variations by increasing the concentration of free PCSK9 necessary to reach half its capacity of inhibition of LDL-C degradation. CONCLUSION: The maximum effect of alirocumab is achieved when free PCSK9 concentration is close to zero, as seen mostly after 150 mg every 2 weeks (Q2W) or 300 mg every 4 weeks (Q4W), indicating that there would be no additional clinical benefit of increasing the dose higher than these recommended dosing regimens.

Differential Binding of Sarilumab and Tocilizumab to IL-6Rα and Effects of Receptor Occupancy on Clinical Parameters.

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.