Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

Abstract

PF‐04991532 ((S)‐6‐(3‐Cyclopentyl‐2‐(4‐(trifluoromethyl)‐1H‐imidazol‐1‐yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato‐selectivity via organic anion‐transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF‐04991532 oral pharmacokinetics. Cyclosporine (600 mg single dose) increased mean area under the plasma curve (AUC) of PF‐04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF‐04991532 AUC values were ~ 2.3‐fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically‐based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter‐mediated disposition based on in vitro inputs, and verified using first‐in‐human data, indicated the key role of OATP‐mediated hepatic uptake in the systematic and target‐tissue exposure of PF‐04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~ 35%) and renal organic anion transporter (OAT)3 (80–90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter‐mediated disposition.

A Microdose Cocktail to Evaluate Drug Interactions in Patients with Renal Impairment

“…Because hepatic OATP1B-mediated uptake has been shown to be the rate-determining step in PTV elimination, 29,30 it has been hypothesized that RI causes a reduction in OATP1B activity, either through inhibition or downregulation by uremic toxins. [31][32][33] This is consistent with the increase in PTV exposure and unchanged lactone exposure: the latter not being an OATP1B substrate. 34 Indeed, these observed changes are within the range of the reported ~60% reduction in hepatic OATP1B function found to match the observed increase in PTV Figure 2 Impact of RI on unbound AUC and C max for microdose cocktail components.…”

“…In contrast, the PK of the lactone metabolite were not altered. Because hepatic OATP1B‐mediated uptake has been shown to be the rate‐determining step in PTV elimination, 29,30 it has been hypothesized that RI causes a reduction in OATP1B activity, either through inhibition or downregulation by uremic toxins 31–33 . This is consistent with the increase in PTV exposure and unchanged lactone exposure: the latter not being an OATP1B substrate 34 .…”

Quantitative prediction of breast cancer resistant protein mediated drug‐drug interactions using physiologically‐based pharmacokinetic modeling

“…Cyclosporine PBPK model, previously developed and verified with several known OATP probe drugs, was applied without any modification. 13,37 Rifampicin, gemfibrozil/glucuronide parent-metabolite pair, and itraconazole simulator default…”

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

“…passive reabsorption. [19][20][21]40,41 Although these models recovered the drug disposition in CKD, inconsistent scaling factors, such as relative activity factor (scalars ranging from 0.28 41 to 3 40 ) and proximal tubular cells per gram of kidney (scalars up to 15) 19 have been applied, to allow the model to recover the observed data in healthy subjects and patients . The performance of adaptive and proportional model was evaluated at CKD stages 4 and 5 (GFR ≤ 30 mL/min) using calculated absolute fold-error (AFE) A (shown in red) and AFE P (shown in blue), respectively (d-f, j-l).…”

“…Over the recent decade, PBPK modeling has been used to model CKD effects on renal elimination, primarily for highly secreted drugs that do not have significant permeability or passive reabsorption 19–21,40,41 . Although these models recovered the drug disposition in CKD, inconsistent scaling factors, such as relative activity factor (scalars ranging from 0.28 41 to 3 40 ) and proximal tubular cells per gram of kidney (scalars up to 15) 19 have been applied, to allow the model to recover the observed data in healthy subjects and patients with CKD. This suggests low confidence on both in vitro ‐to‐ in vivo extrapolation of renal transport and understanding of CKD effect on renal drug handling.…”