Simvastatin and Lorlatinib: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 4, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Lorlatinib
Simvastatin
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Let's talk about taking lorlatinib (Lorbrena) with simvastatin (Zocor). Lorlatinib can speed up how your body breaks down simvastatin. That means there may be less simvastatin working in your body, so it might not lower your cholesterol as well as it should.
The good news is this is very manageable. Your care team can check your cholesterol numbers and, if needed, adjust your dose or choose a different medicine. Please don't change anything on your own. Just keep taking both as prescribed and let your pharmacist or doctor know you are on both so they can keep an eye on things.
Effect: Lorlatinib is a moderate CYP3A inducer and is expected to decrease exposure of CYP3A substrates. Simvastatin is a sensitive CYP3A4 substrate, so its AUC/Cmax may fall, potentially reducing lipid-lowering efficacy.
- Mechanism: Induction of CYP3A-mediated metabolism by lorlatinib.
- Magnitude: For midazolam (index substrate), AUC decreased ~64%; simvastatin effect extrapolated.
- Evidence: Theoretical for this pair. Onset: unspecified.
- Management: Avoid combination where possible. Monitor lipid panel; dose may need to be increased and individualized, or consider an alternative statin.
What happens
Decreased exposure of the CYP3A substrate
Interaction Deep Dive
Because lorlatinib acts as a CYP3A inducer, taking it together with CYP3A substrates lowers the levels of those substrates, potentially diminishing their effectiveness. For CYP3A substrates in which even small drops in concentration can result in serious therapeutic failure, coadministration with lorlatinib should be avoided. In a coadministration study, pairing lorlatinib with midazolam (a sensitive CYP3A substrate) produced a 64% reduction in midazolam AUC(infinity). Should combined use be unavoidable, it may be necessary to raise the dose of the CYP3A substrate1.
Why it happens (mechanism)
Induction of CYP3A substrate metabolism by lorlatinib
How to manage this interaction
Here is how a care team usually handles this pairing:
- Keep taking both exactly as prescribed unless your prescriber tells you otherwise.
- Your team may monitor your cholesterol more closely to make sure the simvastatin is still working.
- If needed, your simvastatin dose may be adjusted and individualized, or your team may pick a different cholesterol medicine that isn't affected in the same way.
Ask your pharmacist or doctor whether your combination is right for you, and mention any changes in your recent cholesterol results.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) When lorlatinib 150 mg was given orally once daily for 15 days together with a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate), the midazolam AUC(infinity) fell by 64% and the Cmax fell by 50% 1.
Common questions
Can I take Simvastatin and Lorlatinib together?
Lorlatinib can lower simvastatin levels and make it less effective at controlling cholesterol, so your care team may monitor your lipids and adjust your dose or choose another statin. Keep taking both as prescribed and confirm the plan with your pharmacist or doctor. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Simvastatin and Lorlatinib interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Simvastatin and Lorlatinib interaction managed?
Here is how a care team usually handles this pairing: Keep taking both exactly as prescribed unless your prescriber tells you otherwise. Your team may monitor your cholesterol more closely to make sure the simvastatin is still working. If needed, your simvastatin dose may be adjusted and individualized, or your team may pick a different cholesterol medicine that isn't affected in the same way. Ask… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Simvastatin or Lorlatinib need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (1)
- Product Information: LORBRENA(R) oral tablets, lorlatinib oral tablets. Pfizer Labs (per FDA), New York, NY, 2018. DailyMed
Keep reading about Lorlatinib
Keep reading about Simvastatin
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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