Miguel Allo 1, Christian Hocht 4, Diego Chiappetta 5, Iñaki Trocóniz 1,2,3
1 1: Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. (Pamplona, Spain), 2 Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. (Pamplona, Spain), 3 Institute of Data Science and Artificial Intelligence (DATAI), University of Navarra, Pamplona, Spain. (Pamplona, Spain), 4 Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina. (Buenos Aires, Argentina), 5 Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina. (Buenos Aires, Argentina)
Introduction/Objectives:
Hypertension (HTN) remains the most important modifiable risk factor for cardiovascular disease and cardiovascular mortality worldwide.(1) Reductions in systolic blood pressure (SBP) and blood pressure variability have been associated with decreased target organ damage (TOD) secondary to HTN and a lower incidence of major adverse cardiovascular events (MACE).(2) Carvedilol (CAR), a non-selective β-adrenergic blocker with vasodilatory properties, has proven effective in lowering SBP. However, its relatively short half-life limits the maintenance of stable plasma concentrations over a 24-hour period, thereby compromising sustained antihypertensive control. (3) To overcome this limitation, several controlled-release delivery systems have been developed as a technological approach to optimize its therapeutic performance.(4). The aim of this study was to describe the antihypertensive pharmacokinetics/pharmacodynamics (PK/PD) relationship of six different controlled-release formulations of carvedilol in a population of spontaneously hypertensive (SHR) male rats and to estimate population pharmacokinetic parameters. Additionally, the study sought to determine the time-dependent increase in baseline systolic blood pressure observed in this population through the development of a disease progression model. Furthermore, this work endeavored to quantitatively characterize the in vivo release capacity of the active ingredient from the delivery systems to establish a model-based in vitro–in vivo correlation (IVIVC) platform.
Methods:
The results of trials using intravascular solution (1mg/kg), nanomicellar formulations administered orally (10 mg/kg/QD) and subcutaneous drug delivery systems(100 mg/Q3W, 7.2 mg/BIW), were analyzed. Data were collected from acute (3 hours, 5 hours, 3 days, and 21 days duration, depending on the formulation) and chronic (63 days duration) studies, in which plasma carvedilol concentrations and systolic blood pressure(SBP) values were determined in 6 male SHR rats per study. The disease progression model was developed using SBP values obtained from control non-treated SHR rats during chronic experiments. The analyses were performed under the population pharmacokinetic/pharmacodynamic umbrella using NONMEM 7.5. Model building followed a sequential procedure where the pharmacokinetics was first characterized and the individual Bayesian PK parameters were then used in a second step to generate the PK profiles as drivers of the cardiovascular response. During the first step different absorption/release and disposition models were investigated. With respect to the time course of the blood pressure, non-stationary baseline, delayed response and the eventual influence of the rate of release/absorption were evaluated.
Results:
Absorption from subcutaneous drug delivery systems was best described by a combination of zero-order and first-order rate processes, whereas absorption after oral administration was characterized by a first-order rate model. Systemic disposition of carvedilol profiles was well captured by a two-compartment model. Clearance was 0.457 L/h (8.3%). Volumes of distribution were estimated as 0.243 L (11.7%) and 0.615 L (20.8%) for the central and peripheral compartments, respectively. Intercompartmental clearance was 0.543 L/h (20.8%). The pharmacodynamic profile was described using an effect-compartment sigmoid maximum effect model. Maximum drug effect was ΔSBP% relative to baseline = -42.3% (7.2%) and the drug concentration producing 50 percent of the maximum effect was 216 ng/mL (13.2%). The effect-site equilibration half-life was 7.2 min (7.7%). The Hill coefficient was estimated as 1.2 (6.9%). Pharmacodynamic parameters were independent of the route of administration and formulation. The time-dependent increase in baseline systolic blood pressure was described using a mono-exponential disease progression model. Baseline response was 168 mmHg (0.5%). Maximum fractional increase from baseline was estimated as 0.204 (3%). First-order disease progression rate constant was 0.0134 h⁻¹ (26%).
Conclusions:
Population parameters were estimated and the PK/PD relationship was characterized for the antihypertensive effect of different controlled-release formulations of carvedilol in male SHR rats. The in vivo release capacity of the active ingredient from the different carvedilol formulations was characterized, with release being faster in orally administered formulations compared to subcutaneous formulations. Disease progression dynamics were accurately described by the proposed model.
References:
References:
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Reference: PAGE 34 (2026) Abstr 12023 [www.page-meeting.org/?abstract=12023]
Poster: Drug/Disease Modelling - Other Topics