Mechanistic PBPK Modeling of Urine pH Effect on Renal and Systemic Disposition of Methamphetamine and Amphetamine

Abstract

AUC, area under the plasma drug concentration versus time curve B/P, blood-to-plasma ratio CL, total plasma clearance CLf, formation clearance of the metabolite CLint, intrinsic clearance for the drug CLint,m, intrinsic clearance for the metabolite CLr, renal clearance CYP2D6, Cytochrome P450 2D6 enzyme DDI, drug-drug interaction fe, fraction elimination of kidney fu,p, unbound fraction in plasma ka, absorption constant Kp, tissue-to-plasma partition coefficient for the drug Kp,m, tissue-to-plasma partition coefficient for the metabolite Meth, S(+)-methamphetamine MDCK, Madin-Darby canine kidney PBPK, physiologically-based pharmacokinetics PET, positron emission tomography PK, pharmacokinetics Vss, volume of distribution at steady state This article has not been copyedited and formatted. The final version may differ from this version.

Novel Mechanistic PBPK Model to Predict Renal Clearance in Varying Stages of CKD by Incorporating Tubular Adaptation and Dynamic Passive Reabsorption

“…This is concerning as many renally secreted drugs, such as amphetamines, also have considerable permeability and reabsorption. 42 For such drugs, the practice of empirically optimizing active secretion using data from healthy subjects and extrapolating to patients with CKD may result in erroneous parameter optimization and misleading prediction of unstudied scenarios, as recently demonstrated in the context of full-body PBPK modeling. 43 As such, the adaptive system model shown here was entirely developed based on physiologic knowledge independent of drug molecules, and was collectively verified against 20 test compounds with different permeabilities throughout CKD stages without any optimization or empirical scaling for any of the test compounds.…”

“…This suggests low confidence on both in vitro ‐to‐ in vivo extrapolation of renal transport and understanding of CKD effect on renal drug handling. This is concerning as many renally secreted drugs, such as amphetamines, also have considerable permeability and reabsorption 42 . For such drugs, the practice of empirically optimizing active secretion using data from healthy subjects and extrapolating to patients with CKD may result in erroneous parameter optimization and misleading prediction of unstudied scenarios, as recently demonstrated in the context of full‐body PBPK modeling 43 .…”

Bridging the gap betweenin silicoandin vivo:modeling opioid disposition in a kidney proximal tubule microphysiological system

“…In contrast, our current approach utilizes data generated from MPS, which enables estimation of active kidney secretion regardless of the mechanism of transport of compounds of interest. Also, applicability of our model to simulate human PK has also been validated for compounds for which active kidney secretion is limited and kidney elimination is sensitive to urine pH and flow (10,11) in addition to compounds with significant active transport. In this study, we assumed that the transporter-mediated active secretion of morphine and M6G decreases proportionally with GFR in accordance with the intact nephron hypothesis (45).…”

“…Our hypothesis is that incorporating the in vitro data generated from the VPT-MPS into the physiologically-based mechanistic kidney model will allow prediction of CL r of morphine and M6G in humans. Further, using the mechanistic kidney model-integrated full body parentmetabolite PBPK model (11), plasma concentration-time profile of morphine and M6G can be predicted in healthy subjects. Finally, due to the increased risk of opioid overdose in people with CKD (12)(13)(14), the developed model can be extrapolated (15) to simulate systemic disposition of morphine and M6G in varying stages of CKD.…”

“…The drug models of morphine and M6G were developed independently and then linked together using a similar workflow and strategy as previously described by us for methamphetamine and amphetamine(11). The physicochemical properties of morphine and M6G were collected from literature(16)(17)(18)21) and the permeabilities were determined using the VPT-MPS system.…”