Bridging the gap between in silico and in vivo by modeling opioid disposition in a kidney proximal tubule microphysiological system

Tomoki Imaoka,Dale W Hailey,Nina Isoherranen,Shih-Yu Chang,Sara Shum,Catherine K Yeung,Alenka Chapron,Edward J Kelly,Weize Huang,Jonathan Himmelfarb

doi:10.1038/s41598-021-00338-y

Tomoki Imaoka, Dale W Hailey + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-00338-y

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Abstract

Opioid overdose, dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, therefore novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The present study aimed to predict renal clearance and systemic disposition of morphine and its active metabolite morphine-6-glucuronide (M6G) in CKD patients using a vascularized human proximal tubule microphysiological system (VPT-MPS) coupled with a parent-metabolite full body physiologically-based pharmacokinetic (PBPK) model. The VPT-MPS, populated with a human umbilical vein endothelial cell (HUVEC) channel and an adjacent human primary proximal tubular epithelial cells (PTEC) channel, successfully demonstrated secretory transport of morphine and M6G from the HUVEC channel into the PTEC channel. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G, resulting in successful prediction of CLr and the plasma concentration–time profiles in both healthy subjects and CKD patients. A microphysiological system together with mathematical modeling successfully predicted renal clearance and systemic disposition of opioids in CKD patients and healthy subjects.

Highlights

Opioid overdose, dependence, and addiction are a major public health crisis
To evaluate secretory transport in the vascularized human proximal tubule microphysiological system (VPT-microphysiological systems (MPS)), morphine and M6G were infused into the vascular channel in the presence and absence of an organic anion transporter (OAT) and organic cation transporter (OCT) inhibitor cocktail (1 mM probenecid and 1 mM tetraethylammonium)
Efflux of morphine and M6G were markedly attenuated by transporter inhibitors with a 74.3% decrease in morphine intrinsic clearance and of M6G by 63.6%, respectively. This suggests that active secretion, likely via OATs and OCT2, contributes to morphine and M6G renal clearance

Summary

Introduction

Dependence, and addiction are a major public health crisis. Patients with chronic kidney disease (CKD) are at high risk of opioid overdose, novel methods that provide accurate prediction of renal clearance (CLr) and systemic disposition of opioids in CKD patients can facilitate the optimization of therapeutic regimens. The in vitro data generated by VPT-MPS were incorporated into a mechanistic kidney model and parent-metabolite full body PBPK model to predict CLr and systemic disposition of morphine and M6G, resulting in successful prediction of CLr and the plasma concentration–time profiles in both healthy subjects and CKD patients. Due to the increased risk of opioid overdose in people with CKD12–14, the developed model can be extrapolated[15] to simulate systemic disposition of morphine and M6G in varying stages of CKD

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