Population pharmacokinetics of budesonide (BDS) and its two main metabolites 6β-hydroxy-budesonide(6OH-BDS) and 16α-hydroxy-prednisolone(16OH-PREDN) with and without hyperhydration effect
Eleni Alexopoulou, Evangelos Karakitsios, Ioanna Athanasiadou, Kostas Georgakopoulos, Georgia Valsami, Aristeidis Dokoumetzidis
Department of Pharmacy, National and Kapodistrian University of Athens
Introduction: Budesonide is a corticosteroid drug commonly used to treat asthma and rhinitis [2], but also it appears to be one of the drugs that athletes misuse in order to benefit from its anabolic effect [1]. There is an extensive first pass effect thus the systemic availability is very low. The main metabolites of budesonide are the 6β-hydroxy-budesonide(6OH-BDS) and 16α-hydroxy-prednisolone(16OH-PREDN). Note that the metabolites have very low pharmacological activity.[2]
Objectives: The development of a population pharmacokinetic model for budesonide and its two main metabolites considering 2 different occasions of oral administration with and without hyperhydration in plasma.
Methods: The data used were derived from previous study which examined if hyperhydration could be used for masking misuse of the drug in urine samples [1]. Seven healthy and physically active males received a 9mg oral dose of budesonide in 3 different occasions: 1) without hyperhydration, 2) after hyperhydration with water, 3) after hyperhydration with a sports drink [1]. Concentrations of the parent drug and its two metabolites in plasma were obtained several times in the interval time of 48 hours. A combined parent-metabolite pharmacokinetic model was developed with Monolix 2021R1 that uses the SAEM (Stochastic Approximation Expectation Maximization) algorithm. Various models were considered and were assessed by Goodness of Fit, Visual Predictive check, and parameter value plausibility. Inter-individual variability (IIV) and inter-occasion variability (IOV) was estimated and various residual error models were considered.
Results: The PK data were best described by a parent-metabolite model with one compartment for each substance, a first order absorption process and linear elimination. After several models tested it has been determined that metabolism is very extensive and fast and takes place pre-systemically, during first pass effect and potentially by metabolism in the gut. This was modelled with separate absorption processes while systemic biotransformation rate constants were found to take very small values and were removed from the final model. The parent drug and the 6OH-BDS absorption processes have a time delay (Tlag) whereas the 16OH-PREDN delay of the absorption is described with transit compartments (Ktr, Mtt). The population parameter estimates are (with inter-individual variability and inter-occasion variability in brackets) Tlag=1.42 h (IOV=0.58), ka (absorption rate of BDS)=0.0079h-1 (IIV=0.22), kam (absorption rate of 60H-BDS)=0.01 h-1 (IIV=0.16), kan (absorption rate of 6OH-PREDN)=0.46 h-1 (IIV=0.23), V (volume of distribution of BDS)=46.56 L (IOV=0.46), Cl (clearance of BDS)=14.53 L/h (IOV=0.29), Clm (clearance of 60H-BDS)=9.01 L/h (IOV=0.35), Cln (clearance of 16OH-PREDN)=72.46 L/h (IOV=0.28), Ktr (transit compartment rate)=1.2 h-1 (IOV=1.76), Mtt (mean transit time)=3.12 h (IIV=0.27). There was a good estimation of the standard errors of the parameters (not over 50%). A proportional error model was used for parent drug and metabolites.
Conclusions: The developed population PK model described well the PK data. The next step of the analysis is to include the urine data which are available and then study by simulations whether there is any anti-doping benefit to collect both blood and urine from athletes in some circumstances.
References:
- [1] Athanasiadou I, Vonaparti A, Dokoumetzidis A, et al. Effect of hyperhydration on the pharmacokinetics and detection of orally administered budesonide in doping control analysis. Scand J Med Sci Sports. 2019;00:1–12.
- [2] Edsbacker S , Andersson T , et al. Pharmacokinetics of Budesonide (Entocort™ EC) Capsules for Crohn’s Disease. J Clin Pharmacokinet 2004; 43 (12): 803-821