What is the strength of Indinavir as a CYP (Cytochrome P450) 3A4 inhibitor?

Indinavir as a CYP3A4 Inhibitor

Indinavir is classified as a strong CYP3A4 inhibitor and should be avoided in combination with medications primarily metabolized by CYP3A4 due to significant risk of drug interactions that could increase morbidity and mortality. 1

Strength of Inhibition

Indinavir is a potent inhibitor of the cytochrome P450 isoform CYP3A4, though not as potent as ritonavir. Based on the available evidence:

• Indinavir has a Ki value of approximately 0.2 μM for CYP3A4 inhibition 2
• In comparative studies, the inhibitory potency ranks as: ritonavir > indinavir > saquinavir 3, 4
• Indinavir preferentially inhibits CYP3A4 (Ki = 0.2 μM) with weaker effects on CYP3A5 (Ki = 2.2 μM) and CYP3A7 (Ki = 10.6 μM) 2

Clinical Implications

The strong CYP3A4 inhibition by indinavir has several important clinical consequences:

1. Increased drug exposure: Concomitant administration of indinavir with drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of those drugs 5

2. Risk of adverse effects: These increased concentrations could enhance or prolong therapeutic and adverse effects of CYP3A4 substrates 5

3. Specific drug interactions:

   • Nilotinib: Treatment with nilotinib should be interrupted if systemic administration of indinavir is required 1
   • Ivabradine: Concomitant use with indinavir is contraindicated due to risk of significant bradycardia 1

Management Recommendations

When prescribing medications to patients on indinavir:

• Avoid combinations with drugs that are primarily metabolized by CYP3A4, especially those with narrow therapeutic indices 5

• Consider alternatives to CYP3A4 substrates when possible

• If co-administration cannot be avoided:

  • Reduce the dose of the CYP3A4 substrate
  • Monitor closely for adverse effects
  • Consider therapeutic drug monitoring when available

• Pay special attention to drugs with serious concentration-dependent toxicities (e.g., QT prolongation, rhabdomyolysis)

Comparison with Other Protease Inhibitors

In the context of other HIV protease inhibitors:

• Ritonavir is the most potent CYP3A4 inhibitor (Ki = 0.019 μM) 4
• Indinavir is an order of magnitude less potent than ritonavir but still a strong inhibitor 4
• Saquinavir is the least potent CYP3A4 inhibitor among these three (Ki = 2.99 μM) 4

This differential inhibitory potential explains why ritonavir is commonly used as a pharmacokinetic booster for other protease inhibitors, while indinavir's interactions, though significant, are less pronounced than ritonavir's.

Important Considerations

• Indinavir is metabolized by CYP3A4, so its own levels can be affected by other CYP3A4 inhibitors or inducers 5

• Unlike some other protease inhibitors, indinavir does not produce appreciable inhibition of CYP1A2, CYP2C9, or CYP2E1 catalyzed reactions 4

• The liver plays a much greater role than the intestine in first-pass metabolism of indinavir 6

• When assessing potential drug interactions, consider that indinavir may also be a weak inhibitor of CYP2D6 5