Bosutinib
Bosulif · BCR-ABL TKI
Reversible eGFR decline.
PSEUDOPRE
MildOpen →
HER2 TKI
Tucatinib
Tukysa · TUCA
The textbook 'pseudo-AKI' drug: a creatinine bump from blocked tubular secretion, not real kidney injury.
MildHER2 tyrosine kinase inhibitor · approved 2020
HER2-positive metastatic breast cancer (incl. brain metastases)HER2-positive colorectal cancer
Signature kidney injury
Pseudo-AKI
A mild creatinine increase is common and expected, but it reflects inhibition of tubular creatinine secretion (a 'pseudo-AKI' artifact) rather than true GFR loss. Dedicated transporter/PK studies show tucatinib inhibits renal OCT2 and MATE1/MATE2-K without changing iohexol-measured GFR.
Source: Topletz-Erickson et al., J Clin Pharmacol 2020
Mechanism of kidney injury
Tucatinib inhibits the renal organic cation transporter OCT2 (basolateral uptake) and MATE1/MATE2-K (apical efflux), which together secrete creatinine from blood into the proximal-tubule lumen. Creatinine is filtered AND secreted; blocking the secretory component raises serum creatinine while filtration (true GFR) is unchanged. This is an artifactual ('pseudo-AKI') rise — confirmed because iohexol-measured GFR is preserved.
Clinical presentation
Modest, early, stable creatinine elevation (often plateaus quickly) with completely bland urinalysis, no electrolyte derangement, no proteinuria, and preserved true GFR (cystatin C / measured GFR unchanged).
Onset
Within the first weeks of therapy; plateaus and is fully reversible within days of discontinuation.
Reversibility
Reversible
Anticancer mechanism
Oral, highly HER2-selective tyrosine kinase inhibitor (minimal EGFR activity). Approved with trastuzumab and capecitabine for advanced HER2-positive breast cancer including brain metastases, and with trastuzumab for HER2-positive RAS-wild-type colorectal cancer.
Management
Recognize as pseudo-AKI: do not discontinue tucatinib for an isolated stable creatinine rise with bland sediment. Confirm with cystatin C/measured GFR if needed. No specific renal treatment required. Note that the creatinine artifact can also confound capecitabine dose decisions that rely on Cockcroft-Gault.
Risk factors
- Baseline CKD (makes the creatinine shift more conspicuous)
- Concurrent drugs that also inhibit creatinine secretion (e.g., trimethoprim, cimetidine, dolutegravir, cobicistat)
Prevention
- Anticipate the benign creatinine rise and avoid unnecessary therapy interruption
- Use cystatin C or measured GFR to confirm preserved true function before stopping effective therapy
Note · ASON-flagged as a classic pseudo-AKI / creatinine-secretion artifact. Dedicated transporter PK data support the mechanism; this is the best-characterized example in this batch.
Clinical depth
Renal dose adjustment
No renal dose adjustment for mild-moderate impairment. Importantly, the creatinine rise is NOT a reason to reduce tucatinib; but it can falsely lower estimated CrCl and inappropriately trigger capecitabine dose reduction — use cystatin C-based GFR or measured GFR for companion-drug dosing decisions. Limited data in severe impairment.
Dialyzability & ESKD dosing
Not characterized; highly protein-bound, hepatically (CYP2C8/3A) cleared small molecule, unlikely to be appreciably dialyzed. No ESKD dosing data.
Differential diagnosis
Pseudo-AKI vs true AKI: pseudo-AKI shows an early, modest, stable creatinine rise with bland sediment, no electrolyte/proteinuria changes, and a NORMAL cystatin C-based or measured GFR. A discordant creatinine-up / cystatin C-stable pattern is the signature.
Monitoring
- Serum creatinine with a low threshold to add cystatin C if a rise prompts concern
- Urinalysis (expected bland) to confirm absence of true injury
- LFTs per label (hepatotoxicity is the more clinically relevant toxicity)
Key trials & series
- Topletz-Erickson, J Clin Pharmacol 2020 — dedicated renal-transporter/GFR study establishing pseudo-AKI
- HER2CLIMB — registrational efficacy trial (clinical context)
Clinical pearls
- Cystatin C is the tie-breaker: creatinine up but cystatin C/measured GFR normal = pseudo-AKI, keep treating.
- The artifact can sabotage Cockcroft-Gault-based capecitabine dosing — don't dose-reduce the partner drug off a falsely low CrCl.
- This is the best-characterized OCT2/MATE creatinine-secretion artifact in oncology — the canonical teaching example.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Pseudo-AKIPrerenal / Hemodynamic AKI
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkTucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects.Topletz-Erickson AS et al. · J Clin Pharmacol 2020 · PMID 32989831Directly demonstrates the OCT2/MATE-mediated creatinine-secretion artifact with preserved measured GFR — the mechanistic basis for pseudo-AKI.LandmarkQuantitative Consideration of Clinical Increases in Serum Creatinine Caused by Renal Transporter Inhibition.Nakada T et al. · Drug Metab Dispos 2023 · PMID 36859345Quantitative review showing how OCT2/MATE inhibition (including by TKIs) raises serum creatinine without true GFR change and can falsely meet AKI criteria.PMIDInhibitory effect of flavonoids on multidrug and toxin extrusion protein 1 function: Implications for food/herb-drug interaction and drug-induced kidney injury.Duan X et al. · J Appl Toxicol 2024 · PMID 38760888Mechanistic support that MATE1 is the apical creatinine/cation efflux transporter whose inhibition raises serum creatinine and modulates nephrotoxin handling.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int 2015 · PMID 25671763Onconephrology review noting transporter-mediated creatinine elevations among targeted-agent renal phenomena to distinguish from true AKI.