Masoud Jamei1, Dr Mailys De Sousa Mendes1, Dr Ian Sorell1
1Certara UK Limited
Introduction: The volume of distribution (Vd) is a theoretical value defining the relationship between the measured systemic concentration and amount of drug around the body which does not represent any physiological volume. The volume of distribution depends on several factors including the drug lipophilicity, plasma protein binding, and tissues composition. In addition, active transport of drugs into or outside tissues may affect the volume of distribution. Volume of distribution changes over time (Vd(t)), however in conventional compartmental and typical PopPK analysis or even minimal physiologically based pharmacokinetic (mPBPK) models the volume of distribution at steady-state (Vss) is used. Whole body PBPK models, by their very nature, do not use Vss and simulate Vd(t) which can be important when drug transporters are driving the drug disposition. Objectives: we sought to understand and demonstrate how covariates such as drug transporter activity/phenotypes, and transporters-mediated drug-drug interactions may affect volume of distribution and should be considered when identifying volumes of distribution covariates. Methods: Given, in general, interactions at uptake transporters at the liver may lead to a significant change in volume of distribution in comparison with those at the renal tubules [2] we focused on drugs where the liver update transporters are involved. Repaglinide is an OATP1B1 substrate. Within the Simcyp Simulator (V24) Repaglinide is modelled using a first order absorption model and a full PBPK model. The liver is represented by a permeability limited tissue incorporating both the metabolising enzymes and OATP1B1 liver update transporters. Simulations were conducted for a representative healthy male receiving 0.25 mg oral dose. Simulation duration was 12 hours using 4 different OATP1B1 phenotypes, namely poor transporter (PE), intermediate transporter (IT), extensive transporter (ET) and ultra-rapid transporter. The frequency of transporter phenotype differs between populations determining the abundance and therefore function of transporters in individuals. In addition, a drug-drug interaction using gemfibrozil (600 mg oral dose) and its metabolite were given along with repaglinide for an ET subject. Results: After running all simulations the clearance and time-varying volume of distribution (at the end of the simulation) for all 5 simulated scenarios were collected which are as follows. Volume of distribution for PT, IT, ET and UT and for the DDI scenario are 0.26, 0.30, 0.33, 0.35, 0.28 (L/kg) respectively. These shows 20%, 8%, 7% and 14% changes in Vd for each case when compared against that of ET subject. Clearance for PT, IT, ET and UT and for the DDI scenario are 35.7, 58.95, 82.96, 112.2, and 20.40 (L/h) respectively. These shows 57%, 29%, 35% and 75% changes in clearance for each case when compared against that of ET subject. The results show the transporter phenotype and DDI affected both clearance and volume of distribution. For the PT subject, due to reduced transporter function the volume of distribution has reduced because the drug stays in circulation and since the main site of Repaglinide elimination is liver the clearance is reduced too. Gemfibrozil and its metabolite inhibit both the CYP2C8 enzyme and OATP1B1 therefore apart from reducing Repaglinide clearance, the volume of distribution is reduced too. Conclusions: This work demonstrates that apart from body weight there are other potentially important covariates for volume of distribution that should be considered specifically when drug transporters are involved. Drug transporters expression, phenotype, disease state (e.g. hepatic impairment), ethnic differences as well as transporters saturation kinetics and drug-drug interaction can affect both clearance and volume of distribution and ignoring these changes may cause inaccurate dose recommendation.
Reference: PAGE 33 (2025) Abstr 11480 [www.page-meeting.org/?abstract=11480]
Poster: Drug/Disease Modelling - Absorption & PBPK