Pharmacokinetic/Pharmacodynamic Modelling to Describe the Cholesterol Lowering Effect of Rosuvastatin in People Living with HIV

Abstract

Background: Rosuvastatin is a lipid-lowering agent widely prescribed in people living with HIV, which is actively transported into the liver, making it a potential victim of drug-drug interactions with antiretroviral agents.

Objectives: The aims of this study were to characterise the pharmacokinetic profile of rosuvastatin and to describe the relationship between rosuvastatin concentrations and non-high-density lipoprotein (HDL)-cholesterol levels in people living with HIV.

Methods: A population pharmacokinetic model (NONMEM) was developed to quantify the influence of demographics, clinical characteristics and comedications on rosuvastatin pharmacokinetics. This model was combined with an indirect effect model to describe non-HDL-cholesterol measurements.

Results: A two-compartment model with sequential zero- and first-order absorption best fitted the 154 rosuvastatin concentrations provided by 65 people living with HIV. None of the tested covariates significantly influenced rosuvastatin pharmacokinetics. A total of 403 non-HDL cholesterol values were available for pharmacokinetic-pharmacodynamic modelling. Baseline non-HDL cholesterol decreased by 14% and increased by 12% with etravirine and antiretroviral drugs with a known impact on the lipid profile (i.e. protease inhibitors, efavirenz, cobicistat), respectively. The baseline value was surprisingly 43% lower in people living with HIV aged 80 years compared with those aged 40 years. Simulations based on the covariate-free model predicted that, under standard rosuvastatin dosages of 5 mg and 20 mg once daily, 31% and 64% of people living with HIV would achieve non-HDL-cholesterol targets, respectively.

Conclusions: The high between-subject variability that characterises both rosuvastatin pharmacokinetic and pharmacodynamic profiles remained unexplained after the inclusion of usual covariates. Considering its limited potential for drug-drug interactions with antiretroviral agents and its potent lipid-lowering effect, rosuvastatin prescription appears safe and effective in people living with HIV with hypercholesterolaemia.

Clinical trial registration no: NCT03515772.

Conflict of interest statement

Perrine Courlet, Laurent A. Decosterd, Susana Alves Saldanha, Felix Stader, Anna Traytel, Matthias Cavassini, Thierry Buclin, Chantal Csajka and Monia Guidi have no conflict of interest to declare. Marcel Stoeckle got fee’s for advisory boards from Gilead, MSD, ViiV, Janssen-Cilag, Sandoz and Mepha, as well as grants for conferences from Gilead and MSD, yet unrelated to the present study. Catia Marzolini received a research grant from Gilead and speaker honoraria for her institution from MSD.

Figures

Fig. 1

Compartmental model used to describe rosuvastatin pharmacokinetic (PK) and pharmacodynamic (PD) data. Cl apparent rosuvastatin clearance, Ct rosuvastatin plasma concentration predicted by the model, D1 duration of zero-order absorption, HDL high-density lipoprotein, IC50 rosuvastatin concentration that produced a 50% inhibition of non-HDL-cholesterol production, ka absorption rate constant, kin production rate of non-HDL-cholesterol, kout elimination rate of non-HDL-cholesterol, Q apparent inter-compartmental clearance, Vc apparent central volume of distribution, Vp apparent peripheral volume of distribution

Fig. 2

Standardized observed rosuvastatin plasma concentration–time profiles. Rosuvastatin plasma concentrations were standardized for a daily dose of 10 mg once daily and are presented in log-scale. Concentrations in people living with HIV receiving boosted protease inhibitors are presented in pink triangles while concentrations observed in people living with HIV receiving antiretroviral drugs devoid of interaction potential are shown in white circles. Rosuvastatin plasma concentrations observed in people living with HIV enrolled in the pharmacokinetic study with rich sampling are joined with black lines

Fig. 3

Prediction-corrected visual predictive check of the final pharmacokinetic/pharmacodynamic model. Open circles represent log transformed rosuvastatin plasma concentrations (left) and non-high-density lipoprotein (HDL) cholesterol values (right). The continuous line represents the median observed concentration and the dashed lines represent the observed 2.5% and 97.5% percentiles. Shaded areas represent the model-based 95% confidence interval for the median and the 2.5% and 97.5% percentiles

Fig. 4

Rosuvastatin simulated plasma concentrations (n = 1000) after administration of a standard dose of 10 mg once daily, alone (grey) or with boosted protease inhibitors [PIs] (pink). Continuous lines represent the population median prediction and shaded areas represent the 95% prediction interval for rosuvastatin alone (grey) or with boosted PIs (pink)

Fig. 5

Distribution of non-high-density lipoprotein (non-HDL)-cholesterol values, 24 h after administration of rosuvastatin dose at steady state, simulated in 1000 individuals using the base pharmacokinetic/pharmacodynamic model. The dashed line represents the non-HDL-cholesterol target according to European AIDS Clinical Society guidelines [23]