Osteoporosis treatment with risedronate: a population pharmacokinetic model for the description of its absorption and low plasma levels.

UNLABELLED

To develop a population pharmacokinetic model that describes the absorption and low plasma levels of risedronate in the body. The impact of patients' characteristics on risedronate kinetics is investigated. Simulations revealed the high variability in the concentration levels after different dosage schemes. No dosage adjustment is required in renal impairment.

INTRODUCTION

Risedronate exhibits very low plasma levels and high residence time in the body. The aim of this study is to describe and explain the risedronate transit through the body. The impact of volunteers' characteristics on the kinetics of risedronate is also investigated. Simulations are used to compare the risedronate plasma levels after different dosage schemes and assess the need for dose adjustment in patients with impaired kidney functionality.

METHODS

Plasma concentration-time data were obtained from a four-period, two sequence, single-dose, crossover bioequivalence study. The effects of several covariates (e.g., weight, albumin, creatinine, alkaline phosphatase, and calcium) on model parameters were tested. Non-linear mixed-effect modeling was applied and a variety of models were evaluated placing emphasis on absorption and disposition properties. The modeling and simulation work was implemented in Monolix 2020R1.

RESULTS

Following oral administration, the kinetics of risedronate was best described by a two-compartment model with lag time, first-order absorption, and elimination. The extent of peripheral distribution (i.e., bones) was found to be remarkably high. No volunteer characteristics were identified to affect significantly the disposition of risedronate. Using simulations, risedronate plasma profiles were obtained for different doses and frequencies of administration.

CONCLUSION

The absorption and disposition kinetics of risedronate were successfully characterized. Simulations revealed the high discrepancy in the concentration levels observed after different dosage regimens, implying the safety profile of risedronate. In virtual patients with renal impairment, the blood levels of risedronate are increased, but not in an extent requiring dose adaptation.