Background Alirocumab, a human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to significantly reduce low-density lipoprotein cholesterol levels; pharmacokinetics (PK) are governed by non-linear, target-mediated drug disposition (TMDD). Objectives We aimed to develop and qualify a population PK (PopPK) model to characterize the PK profile of alirocumab, evaluate the impact of covariates on alirocumab PK and on individual patient exposures, and estimate individual predicted concentrations for a subsequent PK/ pharmacodynamic (PD) analysis. Methods Data from 13 phase I-III trials of 2799 healthy volunteers or patients with hypercholesterolemia treated with intravenous or subcutaneous alirocumab (13,717 alirocumab concentrations) were included; a MichaelisMenten approximation of the TMDD model was used to estimate PK parameters and exposures. The final model comprised two compartments with first-order absorption. Elimination from the central compartment was described by linear (CLL) and non-linear Michaelis-Menten clearance (Vm and Km). The model was validated using visual predictive check and bootstrap methods. Patient exposures to alirocumab were computed using individual PK parameters. ResultsThe PopPK model was well-qualified, with the majority of observed alirocumab concentrations in the 2.5th-97.5th predicted percentiles. Covariates responsible for interindividual variability were identified. Body weight and concomitant statin administration impacted CLL, whereas time-varying free PCSK9 concentrations and age affected Km and peripheral distribution volume (V3), respectively. No covariates were clinically meaningful, therefore no dose adjustments were needed. Conclusions The model explained the between-subject variability, quantified the impact of covariates, and, finally, predicted alirocumab concentrations (subsequently used in a PopPK/PD model, see Part II) and individual exposures. Key PointsThe population pharmacokinetic model successfully allowed the prediction of the pharmacokinetic properties of alirocumab in the target population, as well as individual exposures.Covariates that impacted on the interindividual variability of alirocumab were identified, with the most important effect being the impact of body weight and coadministration of statins on the linear clearance rate.The impact of covariates did not have any clinically significant effect.

Background Alirocumab, a human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly lowers low-density lipoprotein cholesterol levels. Objective This analysis aimed to develop and qualify a population pharmacokinetic/pharmacodynamic model for alirocumab based on pooled data obtained from 13 phase I/II/III clinical trials. Methods From a dataset of 2799 individuals (14,346 lowdensity lipoprotein-cholesterol values), individual pharmacokinetic parameters from the population pharmacokinetic model presented in Part I of this series were used to estimate alirocumab concentrations. As a second step, we then developed the current population pharmacokinetic/ pharmacodynamic model using an indirect response model with a Hill coefficient, parameterized with increasing lowdensity lipoprotein cholesterol elimination, to relate alirocumab concentrations to low-density lipoprotein cholesterol values. Results The population pharmacokinetic/pharmacodynamic model allowed the characterization of the pharmacokinetic/pharmacodynamic properties of alirocumab in the target population and estimation of individual lowdensity lipoprotein cholesterol levels and derived pharmacodynamic parameters (the maximum decrease in lowdensity lipoprotein cholesterol values from baseline and the difference between baseline low-density lipoprotein cholesterol and the pre-dose value before the next alirocumab dose). Significant parameter-covariate relationships were retained in the model, with a total of ten covariates (sex, age, weight, free baseline PCSK9, total time-varying PCSK9, concomitant statin administration, total baseline PCSK9, co-administration of high-dose statins, disease status) included in the final population pharmacokinetic/pharmacodynamic model to explain betweensubject variability. Nevertheless, the high number of covariates included in the model did not have a clinically meaningful impact on model-derived pharmacodynamic parameters. Conclusions This model successfully allowed the characterization of the population pharmacokinetic/pharmacodynamic properties of alirocumab in its target population and the estimation of individual low-density lipoprotein cholesterol levels. Key PointsThe population pharmacokinetic/pharmacodynamic model of alirocumab successfully described the relationship between alirocumab concentrations and low-density lipoprotein cholesterol (LDL-C) levels in the target population of 2799 healthy volunteers or patients from 13 phase I/II/III clinical studies.The population pharmacokinetic/pharmacodynamic model allowed the estimation of individual LDL-C levels and derived pharmacodynamic parameters (the maximum decrease in LDL-C values from baseline and the difference between baseline LDL-C and the pre-dose value before the next alirocumab dose).Ten covariates were included in the final model, all exhibiting moderate to strong effects on the model parameters; however, although some covariates were associated with more frequent dose increases to accommodate for the...

A population pharmacokinetic analysis was conducted to characterize the pharmacokinetics of fexofenadine in Japanese pediatric patients (6 months through 16 years) with perennial allergic rhinitis or atopic dermatitis. The dataset was composed of 515 patients (including 109 adults), for a total of 1,080 concentration-time points. The analysis was performed with NONMEM using the SAEM method. Several structural models and residual error models were evaluated. The relationship between the individual estimates and the potential covariates was then investigated: demographic and pathophysiologic characteristics were tested as potential model covariates (forward selection method). The qualification of the model was performed using visual predictive check and bootstrap. A two-compartment disposition model with first-order absorption best fitted the data. The inter-individual variability was modeled through an exponential error model for all parameters (except for ka for which no inter-individual term could be estimated), while a proportional error model was used to model the residual variability. The final model included two covariates on elimination clearance and one on the intercompartmental clearance. CL/F was related to BSA and patient's age (expressed in months) Q/F was also related to BSA. Once the model was correctly qualified, exposure parameters such as Cmax and AUCτ were computed and compared between each age sub-group and between Japanese and Caucasians patients. These comparisons did not reveal any major difference (less than 50 %) between subgroups.

The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC(0-infinity) were 1.46, 1.47, and 1.44, respectively. The t(1/2z) was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once-daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.

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