POPULATION PHARMACOKINETICS OF CONTINUOUS INFUSION OF FACTOR VIII IN HEMOPHILIA-A PATIENTS UNDERGOING ORTHOPEDIC SURGERY

Objective: to develop a population pharmacokinetic model taking into account blood losses during and after orthopedic surgery in adult hemophilia A patients receiving infusion of coagulation factor VIII, and to evaluate the influence of potential covariates.Methods: Factor VIII pharmacokinetic parameters were calculated from 24 patients. Among them, 7 were HIV+. The observations were analyzed with the mixed-effects compartment pharmacokinetic package NONMEM and the first-order conditional estimation method. To evaluate the stability and robustness of the final model the bootstrap method was used.Results: During the model-building process, central volume of distribution (V1) was related to body weight (P = 0.0263) and viral status (P = 0.0078). Moreover, the peripheral volume of distribution was related to body weight (P=0.0362). In the final model, only the viral status was significant for V1 when compared with the base model. Posterior predictive checks and robustness analysis showed that the model adequately described the pharmacokinetic parameters. The HIV covariate accounted for 29.8% of the unexplained variation across patients for V1. V1 increased by 33.3% in HIV+ patients compared to HIV- patients.Conclusion: A population pharmacokinetic model taking into account blood losses during and after orthopedic surgery was developed. The 33.3% increase in V1 observed in HIV+ patients explained the need for higher doses in these patients.Â

Artificial intelligence approach for the analysis of placebo-controlled clinical trials in major depressive disorders accounting for individual propensity to respond to placebo

Abstract Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline individual propensity to respond non-specifically to any treatment or intervention can be considered as a major non-specific confounding effect. The greater is the baseline propensity, the lower will be the chance to detect any treatment-specific effect. The statistical methodologies currently applied for analyzing RCTs doesn’t account for potential unbalance in the allocation of subjects to treatment arms due to heterogenous distributions of propensity. Hence, the groups to be compared may be imbalanced, and thus incomparable. Propensity weighting methodology was used to reduce baseline imbalances between arms. A randomized, double-blind, placebo controlled, three arms, parallel group, 8-week, fixed-dose study to evaluate efficacy of paroxetine CR 12.5 and 25 mg/day is presented as a cases study. An artificial intelligence model was developed to predict placebo response at week 8 in subjects assigned to placebo arm using changes from screening to baseline of individual Hamilton Depression Rating Scale items. This model was used to predict the probability to respond to placebo in each subject. The inverse of the probability was used as weight in the mixed-effects model applied to assess treatment effect. The analysis with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect-size about twice larger than the non-weighted analysis. Propensity weighting provides an unbiased strategy to account for heterogeneous and uncontrolled placebo effect making patients’ data comparable across treatment arms

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H 4 receptor inhibitor SENS-111 using a modified caloric test in healthy subjects

International audienceAIM:A Phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H4 receptor antagonist SENS-111, an oral small molecule.METHODS:One hundred healthy subjects were randomized in a placebo-controlled, double-blind study evaluating single-ascending doses (SAD; 100-500 mg) and multiple-ascending doses (MAD; 50-150 mg day-1 , 4 days; 200-250 mg day-1 , 7 days). Effects of SENS-111 on nystagmus and vertigo induced by modified caloric tests were measured in the MAD studies. Population PK and PK/PD models were developed using a nonlinear mixed-effects approach.RESULTS:SENS-111 was well tolerated with mild to moderate events. No sedation was reported. A maximal tolerated dose was not reached. Dose-proportional increases in concentrations were seen up to 200 mg and more than dose-proportional thereafter, with mean half-life between 24 and 56 h. The caloric test induced mild but measurable vertigo and nystagmus with large intra/inter-individual variation for all parameters. SENS-111 did not significantly impact nystagmus but significantly improved latency of vertigo appearance/disappearance, duration and European Evaluation of Vertigo questionnaire parameters vs. baseline. A two-compartment model with first-order absorption, distribution and elimination best fit the data. PK/PD indirect modelling applied to vertigo duration and latency of appearance indicated maximum activity between 100 and 500 ng ml-1 plasma concentrations, corresponding to 100 and 200 mg day-1 , which are appropriate for clinical efficacy evaluations in vestibular diseases.CONCLUSIONS:SENS-111 is a well-tolerated first-in-class H4 receptor antagonist with acceptable PK for oral daily dosing. PK/PD modelling determined plasma concentrations and doses for efficacy studies in patients with vertigo symptoms