Indinavir is an alpha-amino acid amide protease inhibitor used as a treatment therapy for Human immunodeficiency virus (HIV) infections, which can lead to acquired immunodeficiency syndrome (AIDS). The FDA approved indinavir in 1996 as it was among the first HIV protease inhibitors authorized for use in the United States.[1] Indinavir has been shown to decrease the likelihood of death as a result of AIDS progression.

For patients to obtain maximal benefit from the medication, indinavir use is commonly in combination with other HIV antiretroviral medications, such as the HIV protease inhibitor ritonavir. Indinavir is also subject to a high rate of mutation of the viral protease gene. Therefore an Indinavir monotherapy regime is rarely used to prevent the likelihood of drug resistance.[2]

Indinavir metabolism occurs via hepatic cytochrome CYP450, specifically the subfamily CYP3A4, with 20% excreted through urine.[3] Due to the high percentage of urine excretion of unaltered indinavir, a high risk of lithiasis exists.

Recent studies have analyzed the effects of indinavir as an anti-cancer agent. [4] Human papillomavirus is known to be induced by increased expression of eukaryotic translation initiation factor 4E (eIF4E), potentially leading to cervical cancer. Indinavir is an inhibitor of eIF4E. Therefore, recent research has examined its role as a possible cervical cancer treatment.[5]

Indinavir acts through a competitive inhibition mechanism. The medication binds the active catalytic site of HIV protease, thereby inhibiting the enzyme's ability to cleave polypeptides into active, infectious proteins. This inhibition, in turn, decreases the number of cleaved polypeptides in the blood, which therefore aids in reducing the amount of active HIV RNA in vivo.

Metabolism:

As previously stated, indinavir metabolism occurs through cytochrome CYP3A4. Therefore, patients currently taking medications that are also metabolized by CYP3A4 may cause an increase in the metabolism of Indinavir. Thus, since indinavir's concentration in a patient's bloodstream increases, its adverse effects will become exacerbated by increased drug clearance. This effect commonly occurs with herbal supplements such as St. John’s wort (Hypericum perforatum) and primarily occurs as a result of the activation of pregnane-X-receptor (PXR).[6][7] On the contrary, if patients take indinavir with a medication that inhibits CYP3A4 activity, indinavir's clearance will decrease, which will cause elevated levels of indinavir in the bloodstream. Therefore, indinavir will be metabolized slower, potentially leading to reduced efficacy.

Patients on antiretroviral therapy (ART) have an increased risk for renal insufficiency.[8] Indinavir is commonly known for causing lithiasis, specifically nephrolithiasis and/or ureterolithiasis.[1][3][9] This effect is because Indinavir is only soluble in acidic conditions.[10] Additionally, asymptomatic crystalluria has a 66% incidence.[3] The following also increases the risk of lithiasis: Hepatitis B and hepatitis C comorbidities, inadequate hydration, predisposing kidney conditions, and immune deficiencies.[1][3]

Indinavir is ingested orally, as 100 mg, 200 mg, 333 mg, and 400 mg capsules. The most common dosage of indinavir is 800 mg, which is taken as two 400 mg capsules every 8 hours. Recommendations are that patients do not take the medication with food, only water or other liquids (i.e., tea, juice, or coffee). Patients may choose to take indinavir either 1 hour before a meal or two hours after consuming a meal to maximize absorption. If taken with a large meal that is rich in protein and/or fat, it will diminish the drug's efficacy because of reduced absorption. [1] However, foods such as bread and milk may be consumed with Indinavir as long as the portions remain small. If a patient misses a dose, the recommendation is that patients take the next dose at the appropriate time interval. Therefore, one should not take multiple doses at the same time.

1. Dual Combination Therapy with Protease Inhibitors (PI)

The following are protease inhibitors used in combination with indinavir. Only one PI would typically be administered concurrently with indinavir. The most common regiment for dual therapy is as follows:

Indinavir (800 mg, orally, every 8 hours) + ritonavir (100 mg to 200 mg, orally, twice a day) Note: take ritonavir with 48 oz of water.[11]

2.  Combination Therapy with two Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Indinavir (800 mg, orally, every 8 hours) + zidovudine (200 mg, orally, every 8 hours) + lamivudine (150 mg, orally, twice a day) reduces HIV RNA levels below 500 copies per milliliter.[12]

Studies suggest that both treatment plans result in similar plasma HIV RNA and CD4+ levels.[13]

If a patient has a diagnosis of hepatic insufficiency before starting treatment, the prescriber should lower the dosage of indinavir to 600 mg.[14] Additionally, if nephrolithiasis or urolithiasis occurs, the medication should either be ceased for 24 to 72 hours or discontinued altogether.[14] Furthermore, patients should consume an average of 1.5 liters or approximately six glasses of 8 fluid ounces of liquid each day to ensure adequate hydration. Remaining hydrated will help with the prevention and severity of both nephrolithiasis and/or urolithiasis.[14] 

Optimal dosing remains undetermined for pediatric and pregnant patients. However, indinavir was considered a category C medication under the prior FDA categorization for drugs in pregnancy.

The most common adverse reactions include:

• Nephrolithiasis/urolithiasis: This may occur with symptoms such as flank pain and hematuria, or it may be asymptomatic.
  • Renal insufficiency
  • Hepatic insufficiency
• Kidney stones, leading to kidney failure
  • Flank pain
  • Hematuria
• Kidney inflammation
• Symptomatic hyperbilirubinemia
• Asymptomatic hyperbilirubinemia
• Hyperglycemia, leading to insulin resistance
• Heart attack
• Diabetes, leading to ketoacidosis
• Hemolytic anemia
• Loss or gain of body fat

The most common less serve side effects include:

• Diarrhea
• Nausea
• Vomiting
• Fatigue

Some rare side effects include:

• Hydronephrosis
• Jaundice (skin or eyes)

Indinavir inhibits CYP3A4, and therefore, medications that also act through this mechanism of action are contraindicated.

• Alpha 1-adrenoreceptor antagonists
• Antiarrhythmics
• Ergot derivatives
• Sedatives and hypnotics
• Gastrointestinal motility agents
• Neuroleptics
• HMG-CoA reductase inhibitors
• PDE5 inhibitors

Additionally, patients taking phosphodiesterase inhibitors type 5 (PDE5) to treat erectile dysfunction such as sildenafil and tadalafil can cause unwanted side effects such as hypotension and prolonged erections. These side effects may become exacerbated when taken with indinavir.