What are drug interactions with protease inhibitors (PIs) in antiretroviral therapy?

Answer

Protease inhibitors (PIs) are metabolized in the liver by CYP3A isoenzymes; therefore, their metabolism may be altered by CYP inducers or inhibitors. Coadministration of PIs with ritonavir (RTV), a potent CYP3A inhibitor, is used to intentionally increase PI systemic exposure (ie, pharmacokinetic enhancing, or ”boosting”).^[6]

Coadministration of PIs with potent CYP3A inducers may result in suboptimal drug concentrations and reduced therapeutic effects of the PI. These drug combinations should be avoided if alternative agents can be used. If this is not possible, close monitoring of plasma HIV RNA, with or without ARV dosage adjustment, and therapeutic drug monitoring, may be warranted.

Some PIs may also induce or inhibit other CYP isoenzymes, P-gp, or other transporters in the gut and elsewhere. Tipranavir (TPV) is a potent inducer of CYP3A4 and P-gp. However, the net effect of ritonavir-boosted TPV (TPV/r) on CYP3A in vivo appears to be enzyme inhibition. Thus, concentrations of drugs that are substrates for only CYP3A are most likely to be increased if the drugs are given with TPV/r. The net effect of TPV/r on a drug that is a substrate of both CYP3A and P-gp cannot be confidently predicted. Significant decreases in saquinavir (SQV), amprenavir (APV), and lopinavir (LPV) concentrations have been observed in vivo when the PIs were given with TPV/r.

The use of a CYP3A substrate that has a narrow margin of safety in the presence of a potent CYP3A inhibitor may result in a prolonged elimination half-life and toxic drug accumulation. Avoid coadministration or reduce the dose of the affected drug, along with close monitoring for dose-related toxicities or measuring serum drug levels, if appropriate.

The list of drugs that may have significant interactions with PIs is extensive and continues to grow. Some examples of these drugs include lipid-lowering agents (eg, statins), benzodiazepines, calcium channel blockers, immunosuppressants (eg, cyclosporine, tacrolimus), anticonvulsants, rifamycins, erectile dysfunction agents (eg, sildenafil), ergot derivatives, azole antifungals, macrolide antibiotics, oral contraceptives, methadone, and HCV protease inhibitors. Herbal products (eg, St. John’s wort) can also cause interactions that increase the risk of adverse clinical effects.

For more information, see NIH Guidelines for Drug Interactions between PIs and Other Drugs

Table 2. PIs and Their Metabolic Pathways^[6] (Open Table in a new window)

Generic (Brand)	Metabolized by (ie, substrate of)	Induces	Inhibits
Atazanavir (Reyataz) ATV	CYP3A4 P-gp	P-gp	CYP3A4 CYP2C8 (weak) P-gp UGT1A1
Darunavir (Prezista) DRV	CYP3A4 P-gp	P-gp	CYP3A4
Fosamprenavir (Lexiva) FPV	CYP3A4 P-gp	CYP3A4 (weak)	CYP3A4 P-gp
Indinavir (Crixivan) IDV	CYP3A4	-	CYP3A4 CYP2D6 (weak)
Lopinavir/ritonavir (Kaletra) LPV/r	CYP3A4 P-gp	-	CYP3A4
Nelfinavir (Viracept) NFV	CYP3A4 CYP2C19	-	CYP3A4
Ritonavir (Norvir) RTV*	CYP3A4 CYP2D6 P-gp	CYP1A2 CYP2C8 CYP2C9 CYP2C19 UGT1A1	CYP3A4 (primarily) CYP2D6 (to a lesser extent) P-gp
Saquinavir (Invirase) SQV	CYP3A4 P-gp	-	CYP3A4 P-gp
Tipranavir (Aptivus) TPV	CYP3A4 P-gp	CYP3A4 CYP1A2 CYP2C19 P-gp	CYP2D6
*Also see section on pharmacokinetic enhancers.

Generic (Brand)

Metabolized by (ie, substrate of)

Induces

Inhibits

Atazanavir (Reyataz)

ATV

CYP3A4

P-gp

CYP3A4

CYP2C8 (weak)

P-gp

UGT1A1

Darunavir (Prezista)

DRV

CYP3A4

P-gp

CYP3A4

Fosamprenavir (Lexiva)

FPV

CYP3A4

P-gp

CYP3A4 (weak)

CYP3A4

P-gp

Indinavir (Crixivan)

IDV

CYP3A4

CYP2D6 (weak)

Lopinavir/ritonavir (Kaletra)

LPV/r

CYP3A4

P-gp

CYP3A4

Nelfinavir (Viracept)

NFV

CYP3A4

CYP2C19

CYP3A4

Ritonavir (Norvir)

RTV*

CYP3A4

CYP2D6

P-gp

CYP1A2

CYP2C8

CYP2C9

CYP2C19

UGT1A1

CYP3A4 (primarily)

CYP2D6 (to a lesser extent)

P-gp

Saquinavir (Invirase)

SQV

CYP3A4

P-gp

CYP3A4

P-gp

Tipranavir (Aptivus)

TPV

CYP3A4

P-gp

CYP3A4

CYP1A2

CYP2C19

P-gp

CYP2D6

*Also see section on pharmacokinetic enhancers.

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