The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

Abstract

In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Druginduced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (C max and C max,u ) data measured in the clinic.

Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate

“…Abemaciclib administration has been associated with mild and variable but consistent elevations in SCr . Increased SCr can arise from a reduction in glomerular filtration, indicating damage to the nephron and associated reduction in renal function, or from inhibition of the active tubular secretion of creatinine.…”

“…The in vitro assessment of OCT2 and/or MATE inhibition is important in evaluating potential for drug–drug interactions (DDIs) at these transporters and for many drugs recognized as having inhibitory potential . A number of marketed drugs cause elevations in SCr by inhibition of these renal transporters . Early assessment of the clinical inhibition of renal transporters may be prudent if transporter inhibition has been identified in vitro or if increases in SCr concentrations have been identified during preclinical development, or first‐in‐human clinical trials.…”

No Effect of Plazomicin on the Pharmacokinetics of Metformin in Healthy Subjects

“…32,33 Clinically, it is important to distinguish whether serum creatinine increases are due to impairment of glomerular filtration or inhibition of renal transporters since some drugs, such as cobicistat, cause an early, mild (ß0.3 mg/dL), and transient increase in serum creatinine due to potent inhibition of renal transporters, without altering glomerular filtration rate. 32 Serum creatinine increases of ࣙ0.5 mg/dL above baseline have been observed in plazomicin-treated patients with complicated urinary tract infections in a phase 3 clinical trial. 7 The lack of a clinically significant DDI with metformin observed in the present phase 1 study suggests that inhibition of renal transporters is not likely to be the primary mechanism for serum creatinine changes following treatment with plazomicin in patients.…”

Transporters affecting biochemical test results: Creatinine‐drug interactions

“…Notable species differences and interlaboratory discrepancies have been found regarding the plasma membrane localization of OAT2/Oat2. In humans, OAT2 has been detected either both in the brush border (apical) and basolateral plasma membrane or in the basolateral membrane only, whereas, in rodents, localization of Oat2 has been limited to the apical membrane . The overall role of OAT2/Oat2 in creatinine transport in vivo , therefore, remains to be established.…”