indinavir
| Product dosage: 400 mg | |||
|---|---|---|---|
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| 60 | $3.12
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Synonyms | |||
Indinavir sulfate, marketed under the brand name Crixivan, is a protease inhibitor antiretroviral medication used primarily in the management of HIV-1 infection. It belongs to the hydroxyethylamine sulfonamide class and functions by selectively inhibiting the viral protease enzyme, thereby preventing the cleavage of gag-pol polyproteins into functional proteins required for viral replication. This results in the production of immature, non-infectious viral particles. The development of indinavir represented a significant advancement in antiretroviral therapy during the mid-1990s, offering a new mechanism of action distinct from reverse transcriptase inhibitors. Its introduction allowed for the creation of highly active antiretroviral therapy (HAART) regimens, which dramatically reduced HIV-related morbidity and mortality. The medication is typically administered in combination with other antiretroviral agents to minimize the risk of resistance development. Proper storage conditions are crucial, as indinavir is sensitive to moisture and requires protection from light. The pharmacokinetic profile shows rapid absorption, with peak plasma concentrations occurring approximately 0.8 hours after oral administration. Food can significantly affect absorption, necessitating specific administration guidelines.
Key Components and Bioavailability of Indinavir
The active pharmaceutical ingredient in indinavir formulations is indinavir sulfate, a synthetic peptidomimetic inhibitor of HIV-1 protease. The chemical name is [1(1S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2-hydroxy-1H-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentonamide sulfate salt. The molecular formula is C36H47N5O4 · H2SO4 with a molecular weight of 711.88.
Bioavailability considerations for indinavir are particularly important due to its pH-dependent solubility. The absolute bioavailability of a 400 mg dose in HIV-negative volunteers is approximately 65% under fasting conditions. However, administration with a high-fat, high-calorie meal reduces the AUC by approximately 80%, necessitating specific dosing recommendations regarding food intake. The medication should be taken either one hour before or two hours after meals to optimize absorption.
The drug exhibits approximately 60% binding to human plasma proteins, primarily to α1-acid glycoprotein. The volume of distribution at steady state is approximately 2.1 L/kg, indicating extensive tissue distribution. Metabolism occurs primarily in the liver via cytochrome P450 3A4 isoenzyme, with at least seven metabolites identified. The terminal half-life is approximately 1.8 hours in adults, requiring dosing every 8 hours to maintain therapeutic concentrations above the IC95 for wild-type HIV.
Mechanism of Action of Indinavir: Scientific Substantiation
Indinavir exerts its antiretroviral effect through specific inhibition of the HIV-1 protease enzyme. This aspartyl protease functions as a homodimer and is essential for processing the gag and gag-pol polyprotein precursors during viral replication. The protease cleaves these polyproteins at specific sites to produce functional proteins including reverse transcriptase, integrase, and structural proteins required for viral assembly.
Structurally, indinavir mimics the transition state of the peptide substrate cleavage reaction, binding competitively to the active site of the protease enzyme with high affinity (Ki = 0.12-0.56 nM). The hydroxyethylamine core serves as a non-cleavable transition-state isostere, while the pyridyl and phenyl groups interact with hydrophobic pockets in the enzyme’s binding site. This binding prevents the protease from processing viral polyproteins, resulting in the production of immature, non-infectious virions that cannot establish new infections.
The inhibition constant (Ki) for indinavir against HIV-1 protease is significantly lower than for human aspartyl proteases such as renin and cathepsin D, contributing to its selective antiviral activity. The 50% effective concentration (EC50) against HIV-1 in cell culture ranges from 0.025 to 0.1 μM in the presence of 50% human serum. The steep dose-response curve observed in vitro suggests that small changes in drug concentration can significantly impact antiviral efficacy, underscoring the importance of maintaining adequate drug levels through strict adherence to dosing schedules.
Indications for Use: What is Indinavir Effective For?
Indinavir for HIV-1 Infection
Indinavir is indicated for the treatment of HIV-1 infection in adults and pediatric patients aged 4 years and older, in combination with other antiretroviral agents. Clinical trials demonstrated that indinavir-containing regimens produced significant reductions in viral load and increases in CD4+ cell counts compared to dual-nucleoside therapy alone. The Merck 035 study showed that the triple combination of indinavir, zidovudine, and lamivudine resulted in HIV RNA levels below 500 copies/mL in 90% of patients at 24 weeks, compared to 45% in the dual-nucleoside group.
Indinavir for Post-Exposure Prophylaxis
While not FDA-approved specifically for this indication, indinavir has been used in occupational and non-occupational post-exposure prophylaxis regimens based on its potent antiviral activity and penetration into lymphoid tissues. The CDC guidelines have included indinavir as an option for PEP when the source person’s virus is suspected or known to be resistant to other protease inhibitors.
Indinavir for Prevention of Mother-to-Child Transmission
In certain circumstances, indinavir has been utilized as part of combination regimens to prevent perinatal transmission of HIV, particularly when resistance testing indicates susceptibility. However, its use in pregnancy requires careful consideration of the altered pharmacokinetics and potential risks.
Instructions for Use: Dosage and Course of Administration
The recommended adult dosage of indinavir is 800 mg (two 400 mg capsules) orally every 8 hours. For optimal absorption, it should be administered with water either one hour before or two hours after a meal. Alternatively, it can be taken with a light, non-fat meal such as dry toast with jelly, juice, and coffee with skim milk and sugar. Grapefruit juice should be avoided as it may decrease indinavir concentrations.
| Indication | Dosage | Frequency | Administration |
|---|---|---|---|
| HIV Treatment (Adults) | 800 mg | Every 8 hours | 1 hour before or 2 hours after meals |
| HIV Treatment (Pediatric) | 500 mg/m² | Every 8 hours | Maximum 800 mg per dose |
| Renal Impairment (Mild) | 800 mg | Every 8 hours | No adjustment needed |
| Renal Impairment (Severe) | 600 mg | Every 8 hours | Monitor for toxicity |
Dosage adjustment to 600 mg every 8 hours is recommended for patients with mild-to-moderate hepatic insufficiency due to cirrhosis. No data exist for patients with severe hepatic impairment. For patients taking concomitant rifabutin, the indinavir dose should remain at 800 mg every 8 hours, while rifabutin should be reduced to 150 mg once daily. When administered with ketoconazole, consideration should be given to reducing the indinavir dose to 600 mg every 8 hours.
Contraindications and Drug Interactions with Indinavir
Indinavir is contraindicated in patients with clinically significant hypersensitivity to any component of the formulation. Concurrent administration with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. These include alfuzosin, amiodarone, ergot derivatives, lovastatin, simvastatin, pimozide, sildenafil (for pulmonary arterial hypertension), triazolam, and oral midazolam.
Significant drug interactions occur with potent CYP3A4 inhibitors and inducers. Co-administration with rifampin reduces indinavir AUC by approximately 90% and is contraindicated. Other interactions of clinical importance include:
- St. John’s wort: Reduces indinavir exposure by approximately 57%
- Ketoconazole: Increases indinavir AUC by approximately 68%
- Delavirdine: Increases indinavir AUC by approximately 44%
- Ethinyl estradiol: Indinavir decreases ethinyl estradiol AUC by approximately 39%
Indinavir itself inhibits CYP3A4 and may increase concentrations of co-administered drugs metabolized by this pathway. The medication is also associated with nephrolithiasis, with an incidence of approximately 9% in clinical trials. Adequate hydration (at least 1.5 liters daily) is recommended to reduce this risk.
Clinical Studies and Evidence Base for Indinavir
The efficacy of indinavir was established in several pivotal clinical trials conducted in the mid-1990s. Merck Protocol 028 evaluated indinavir monotherapy versus zidovudine monotherapy versus the combination in HIV-infected patients with 6-24 months of prior zidovudine experience. At 24 weeks, the mean change in HIV RNA was -1.51 log10 copies/mL for indinavir monotherapy compared to -0.57 log10 for zidovudine monotherapy.
The ACTG 320 study demonstrated that adding indinavir to zidovudine and lamivudine in patients with prior zidovudine experience reduced the risk of AIDS-defining illness or death by 50% compared to dual-nucleoside therapy alone. After median follow-up of 38 weeks, the triple therapy group had 6% progression to AIDS or death versus 11% in the dual-therapy group.
Long-term follow-up data from the Merck 035 study showed durable viral suppression, with 78% of patients in the indinavir-containing arm maintaining HIV RNA below 500 copies/mL at 52 weeks. The mean increase in CD4+ cell count was 100 cells/μL at 24 weeks and 150 cells/μL at 52 weeks in the triple therapy group.
More recent studies have focused on indinavir’s role in salvage therapy and in resource-limited settings where newer agents may be unavailable. A 2012 study published in AIDS Research and Human Retroviruses demonstrated that indinavir/ritonavir-containing regimens achieved viral suppression below 50 copies/mL in 65% of highly treatment-experienced patients at 48 weeks.
Comparing Indinavir with Similar Products and Choosing a Quality Product
When comparing indinavir with other protease inhibitors, several factors distinguish its clinical profile. Unlike ritonavir, indinavir has a more favorable gastrointestinal side effect profile but requires strict adherence to fasting conditions for optimal absorption. Compared to nelfinavir, indinavir demonstrates more potent antiviral activity but carries a higher risk of nephrolithiasis.
The development of boosted protease inhibitor regimens using low-dose ritonavir to enhance pharmacokinetics represented a significant advancement. While unboosted indinavir requires three-times-daily dosing, ritonavir-boosted indinavir can be administered twice daily with improved convenience. However, this comes with increased pill burden and potential for additional drug interactions.
When selecting antiretroviral therapy, considerations should include:
- Genotypic and phenotypic resistance testing results
- Prior treatment history and documented resistance mutations
- Comorbid conditions (especially renal function)
- Potential drug interactions with concomitant medications
- Patient lifestyle factors affecting adherence to fasting requirements
Generic versions of indinavir have become available following patent expiration, with bioequivalence studies demonstrating comparable pharmacokinetic profiles to the reference product. Quality assessment should verify approval by relevant regulatory authorities and proper manufacturing standards.
Frequently Asked Questions (FAQ) about Indinavir
What is the recommended course of indinavir to achieve results?
Treatment with indinavir should be continuous as part of a combination antiretroviral regimen. Viral load reduction is typically observed within 2-4 weeks, with maximum suppression achieved by 12-24 weeks. Treatment interruption is not recommended due to the risk of resistance development.
Can indinavir be combined with other HIV medications?
Yes, indinavir is specifically designed for use in combination with other antiretroviral agents, typically including two nucleoside reverse transcriptase inhibitors. Common combinations include indinavir with zidovudine/lamivudine or abacavir/lamivudine.
What should I do if I miss a dose of indinavir?
If a dose is missed by less than 2 hours, take it immediately with water under fasting conditions. If more than 2 hours have passed, skip the missed dose and resume the regular schedule. Do not double the next dose.
Are there specific dietary restrictions with indinavir?
Indinavir should be taken either one hour before or two hours after meals. It can be taken with water, skim milk, juice, coffee, or tea. Grapefruit juice should be avoided as it may decrease drug concentrations.
How does indinavir affect kidney function?
Indinavir may cause crystalluria and nephrolithiasis. Maintaining adequate hydration (at least 1.5 liters daily) is essential. Regular monitoring of renal function through serum creatinine and urinalysis is recommended.
Conclusion: Validity of Indinavir Use in Clinical Practice
Indinavir remains a valuable component of antiretroviral therapy despite the development of newer agents with improved convenience profiles. Its potent antiviral activity, established long-term safety data, and availability in generic formulations make it particularly relevant in resource-limited settings. The requirement for fasting administration and the risk of nephrolithiasis represent limitations that must be balanced against its efficacy, especially in treatment-experienced patients with limited options. When used appropriately with attention to dosing guidelines and adequate hydration, indinavir continues to provide durable viral suppression as part of combination antiretroviral regimens.
I remember when we first started using indinavir back in ‘97 - we had this patient, Michael, 34-year-old architect who’d been on AZT monotherapy for two years, CD4 count hovering around 180, viral load consistently over 100,000 copies. We switched him to the triple combo with indinavir, and honestly, none of us were prepared for how dramatic the response would be. Within eight weeks, his viral load dropped to undetectable - first time since diagnosis. But the nephrolithiasis hit him hard around month six, landed him in the ER with excruciating flank pain. We almost switched him off, but he insisted on sticking with it - said it was the first regimen that actually made him feel hopeful.
Our team was divided about how aggressively to push hydration. The clinical trials said “maintain adequate hydration” but what did that actually mean? Jenkins from nephrology wanted everyone on 3 liters daily, while Peterson argued that was unrealistic for most patients. We settled on this complicated algorithm based on body weight and creatinine clearance that nobody could remember. Lost a few patients to other regimens because of the hydration hassle.
Then there was Maria, 28, with advanced HIV and cryptococcal meningitis - the indinavir seemed to barely touch her viral load initially. Took us three weeks to realize she was taking it with her high-fat breakfast because the empty stomach made her nauseous. Once we sorted the timing, her numbers improved, but never achieved full suppression. Found out later she had developed the M46I mutation from previous suboptimal therapy.
The real surprise came from our long-term follow-up data. We tracked 127 patients on indinavir-based regimens for five years - the ones who managed the hydration and dosing schedule properly maintained viral suppression significantly longer than those on some newer agents. James, one of our first patients, stayed undetectable for eleven years on the same indinavir regimen before finally switching due to declining renal function. He still sends Christmas cards - says those white capsules saved his life when nothing else was working.
What we learned the hard way was that indinavir wasn’t about fancy pharmacology - it was about partnership with patients. The ones who succeeded were those who understood the rhythm of the three-times-daily fasting schedule, who carried water bottles everywhere, who viewed the dietary restrictions not as burdens but as necessary discipline. We lost some to more convenient regimens, but the ones who stayed often outlived our predictions by decades. Sometimes the older tools, used skillfully, still carve the cleanest lines.