Bibiana Cardozo, Eleni Karatza, Vangelis Karalis
1. National and Kapodistrian University of Athens. 2. Aix-Marseille University
Introduction: Risedronate is a potent antiresorptive agent that possesses high affinity for hydroxyapatite. It is indicated for Paget’s disease and for the treatment – prevention of osteoporosis [1]. Risedronate has been reported to be poorly absorbed (less than 0.7%). As all nitrogen-containing bisphosphonates, risedronate is distributed widely throughout the body, primarily in bones, but also in soft tissues such as liver, kidney, and spleen [2]. Risedronate is primarily cleared by the kidneys and 65% of an intravenously administered dose can be recovered in the urine within 24h [3]. Despite the fact that there are some non-compartmental analyses of risedronate in the literature, a population pharmacokinetic study hasn’t been published yet. Indeed, to our knowledge the present study is the first to investigate the pharmacokinetics of risedronate using population pharmacokinetic modeling.
Objectives: This study aimed to
- describe the pharmacokinetics of risedronate after oral administration and characterize its absorption
- explore the blood concentration of risedronate after administration of different dose regimens
Methods: Plasma concentration (C) – time (t) data were obtained from an open label, four period, two sequence, single dose, crossover bioequivalence study comparing two immediate release tablets containing 30mg of risedronate in 40 male volunteers. Risedronate was administered under fasted state.
Non-linear mixed-effect modeling was applied, and a variety of models were tested in order to explore different number and assembly of compartments, as well as different absorption and clearance kinetics.
The effects of several covariates on risedronate pharmacokinetic parameters were tested (Age, Weight, Height, BMI, Albumin, Creatinine, Creatinine Clearance, Alkaline phosphatase and calcium). Inter-occasion variability of the parameters was also explored, as well as the effect of two different treatments. Correlations between the random effects were also assessed. Models tested were evaluated in terms of their physiological relevance, goodness-of-fit criteria and goodness of fit plots. Several error models were tested. The entire computational work was implemented in Monolix 2019R2. Simulations were performed using simulx, i.e. a function included in the R package ‘mlxR’. Different dosing schemes were explored based on the posology indicated in Actonel® SmPC.
Results: Following oral administration, the pharmacokinetics of risedronate were best described by a two-compartment model with a lag time (attributed to its low permeability), first order absorption, and elimination. The estimated pharmacokinetic parameters were: the absorption rate constant in the central compartment (ka = 0.509 h-1), the absorption lag time (tlag=0.119 h), the apparent volume of distribution in the central compartment (V1/F = 275 L), the apparent volume of distribution in the peripheral compartment (V2/F = 8130 L), the apparent clearance from the central compartment (CL/F = 350 L/h), and the apparent inter-compartmental clearance (Q/F = 244 L/h). Random effects of clearance (CL) and inter-compartmental clearance (Q) were found to be correlated (cor(Cl,Q) = 0.952).
No statistically significant covariates explaining between-subject variability were found among those explored. Application of a proportional error model led to the most favorable description of residual variability. Using simulations, risedronate C-t profiles after multiple dosing were obtained for different doses and frequencies of administration.
Conclusions: Risedronate exhibits very low plasma levels and high residence time in the body. Through the development of a population pharmacokinetic model, the absorption and disposition kinetics for risedronate were characterized. To the best of our knowledge, this is the first population pharmacokinetic analysis for this biphosphonate compound.
References:
[1] FDA. (Rev 2009). Highlights of prescribing information Actonel®. United States.
[2] Cremers, C., & Papapoulos, S. (2011). Pharmacology of bisphosphonates. Bone, 49, 42-49.
[3] Mitchell, D. Y., Barr, W. H., Eusebio, R. A., Pallone Stevens, K. A., Duke, F. P., Russell, D. A., Thompson, G. A. (2001). Risedronate Pharmacokinetics and Intra- and Inter-Subject Variability upon Single-Dose Intravenous and Oral Administration. Pharmaceutical Research, 18(2), 166-170.
Reference: PAGE () Abstr 9464 [www.page-meeting.org/?abstract=9464]
Poster: Drug/Disease Modelling - Other Topics