indinavir
| Product dosage: 400 mg | |||
|---|---|---|---|
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| 60 | $3.14
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Synonyms | |||
Indinavir sulfate is a protease inhibitor antiretroviral medication formulated as 400 mg capsules, primarily indicated for the management of HIV-1 infection in combination with other antiretroviral agents. As one of the early breakthrough drugs in the HAART era, it represented a significant advancement in AIDS therapeutics when introduced in the 1990s, though its clinical use has diminished with the development of better-tolerated alternatives. The drug works through selective inhibition of the HIV-1 protease enzyme, preventing cleavage of viral polyprotein precursors into functional proteins required for viral replication.
Indinavir: Effective HIV-1 Management Through Protease Inhibition - Evidence-Based Review
1. Introduction: What is Indinavir? Its Role in Modern Medicine
What is indinavir exactly? It’s a synthetic peptidomimetic inhibitor specifically designed to target the HIV-1 protease enzyme, belonging to the class of antiretroviral drugs known as protease inhibitors. Developed during the urgent search for effective AIDS treatments in the early 1990s, indinavir was among the first drugs to demonstrate that viral load suppression was achievable in HIV-infected individuals.
The significance of indinavir in HIV treatment history cannot be overstated - it was part of the original triple-drug cocktails that transformed HIV from a uniformly fatal diagnosis to a manageable chronic condition. While current guidelines favor newer agents with better tolerability and convenience profiles, understanding what indinavir is used for remains relevant for historical context, resource-limited settings, and salvage therapy scenarios.
The benefits of indinavir include its well-characterized resistance profile, established efficacy data, and the extensive clinical experience accumulated since its approval in 1996. However, its use requires careful consideration of administration requirements and potential adverse effects.
2. Key Components and Bioavailability Indinavir
The active pharmaceutical ingredient is indinavir sulfate, chemically designated as [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.
Composition indinavir in the commercial formulation includes the active compound along with excipients: magnesium stearate, anhydrous lactose, and hypromellose in the capsule shell. The standard formulation is available as 200 mg, 333 mg, and 400 mg capsules.
Bioavailability indinavir presents one of the key clinical challenges. The absolute bioavailability is approximately 65% under fasting conditions, but food significantly impacts absorption. A high-fat, high-calorie meal reduces AUC by approximately 80%, necessitating administration on an empty stomach or with a light, low-fat snack. The timing of administration relative to meals is crucial - ideally 1 hour before or 2 hours after meals.
The drug exhibits pH-dependent solubility, with significantly higher solubility at acidic pH. This characteristic explains why coadministration with acidic beverages like grapefruit juice should be avoided, as it may alter absorption. The complex indinavir pharmacokinetics require careful patient education about administration requirements.
3. Mechanism of Action Indinavir: Scientific Substantiation
Understanding how indinavir works requires examining the HIV replication cycle. The HIV-1 protease enzyme functions as a molecular scissors, cleaving the Gag and Gag-Pol polyprotein precursors into individual functional proteins including reverse transcriptase, protease, integrase, and structural proteins. Without this cleavage step, the virus cannot assemble infectious viral particles.
The mechanism of action involves competitive inhibition of the protease active site. Indinavir mimics the natural peptide substrate’s transition state but cannot be cleaved, effectively blocking the enzyme. The drug’s hydroxyethylene isostere replacement for the normal peptide bond creates a non-cleavable transition-state analog that binds with high affinity to the protease active site.
The effects on the body at the cellular level include accumulation of immature, non-infectious viral particles within infected cells. This interruption of the viral life cycle prevents infection of new cells and reduces viral replication in already infected cells. The net result is decreased viral load and potentially increased CD4+ cell counts when used in combination with other antiretroviral agents.
Scientific research has elucidated the precise binding interactions through X-ray crystallography studies, showing how indinavir forms hydrogen bonds with the catalytic aspartate residues (Asp-25 and Asp-125) of the protease enzyme. This structural understanding has informed the development of subsequent protease inhibitors with improved pharmacological properties.
4. Indications for Use: What is Indinavir Effective For?
Indinavir for HIV-1 Infection
The primary indication remains treatment of HIV-1 infection in combination with other antiretroviral agents. Current guidelines position it as an alternative option rather than first-line therapy, but it remains viable when newer options are contraindicated or unavailable.
Indinavir for Treatment-Experienced Patients
In patients with extensive treatment history and resistance patterns, indinavir may still have utility when combined with other active agents, particularly if resistance testing indicates preserved susceptibility.
Indinavir for Post-Exposure Prophylaxis
While not a labeled indication in many regions, indinavir has been used in occupational and non-occupational post-exposure prophylaxis regimens, though newer agents are generally preferred due to better tolerability.
Indinavir for Prevention of Mother-to-Child Transmission
Historical use included prevention of perinatal transmission, though current guidelines recommend alternative regimens with more favorable safety profiles during pregnancy.
5. Instructions for Use: Dosage and Course of Administration
The recommended adult dosage is 800 mg (two 400 mg capsules) every 8 hours. The strict 8-hour dosing interval is necessary due to the drug’s relatively short half-life of approximately 1.8 hours. Maintaining consistent drug levels above the inhibitory concentration is crucial for preventing viral breakthrough and resistance development.
| Indication | Dosage | Frequency | Administration |
|---|---|---|---|
| HIV-1 Treatment | 800 mg | Every 8 hours | On empty stomach or with light, low-fat meal |
| Dose Adjustment with Hepatic Impairment | 600 mg | Every 8 hours | Reduced dose with moderate hepatic insufficiency |
| Concomitant with Rifabutin | 1000 mg | Every 8 hours | Increased indinavir dose when coadministered |
The course of administration typically continues indefinitely as part of a suppressive antiretroviral regimen. Treatment interruptions are generally avoided due to risk of viral rebound and potential selection of resistance mutations.
Important administration instructions: Patients must maintain adequate hydration (at least 1.5 liters daily) to reduce risk of nephrolithiasis. The capsules should be swallowed whole with water. If a dose is missed by more than 2 hours, the missed dose should be skipped and the regular schedule resumed to avoid double dosing.
6. Contraindications and Drug Interactions Indinavir
Contraindications include hypersensitivity to indinavir or any component of the formulation. Concurrent administration with drugs highly dependent on CYP3A4 for metabolism and with narrow therapeutic windows is contraindicated due to risk of serious adverse events.
Significant drug interactions occur due to indinavir’s metabolism primarily by CYP3A4 and its role as a CYP3A4 inhibitor. Notable interactions include:
- Contraindicated combinations: Astemizole, terfenadine, cisapride, triazolam, midazolam, ergot derivatives, simvastatin, lovastatin, pimozide, rifampin, St. John’s wort
- Requiring dose adjustment: Rifabutin (requires 50% dose reduction), ketoconazole (consider indinavir dose reduction to 600 mg every 8 hours)
- Requiring monitoring: Sildenafil (starting dose should not exceed 25 mg in 48 hours), calcium channel blockers, immunosuppressants, anticonvulsants
The side effects profile includes nephrolithiasis (occurring in approximately 9% of patients), asymptomatic hyperbilirubinemia (14%), nausea (12%), abdominal pain (9%), headache (6%), and taste perversion (3%). Less common but serious adverse effects include acute hemolytic anemia, diabetes mellitus exacerbation, and fat redistribution.
Regarding safety during pregnancy, indinavir is classified as Pregnancy Category C. Animal studies have shown embryolethality and teratogenic effects, though adequate human studies are lacking. Use during pregnancy requires careful risk-benefit assessment.
7. Clinical Studies and Evidence Base Indinavir
The clinical studies supporting indinavir approval demonstrated significant antiviral activity. The landmark Merck 028 study showed that triple therapy with indinavir, zidovudine, and lamivudine resulted in HIV RNA below detection (<500 copies/mL) in 90% of patients at 24 weeks compared to 0% with zidovudine alone.
Long-term follow-up data from the ACTG 320 trial confirmed durable viral suppression with indinavir-containing regimens, though with notable discontinuations due to adverse effects and regimen complexity. The scientific evidence base includes over 200 clinical trials and numerous observational studies establishing efficacy across various patient populations.
More recent effectiveness data from cohort studies have documented outcomes in routine clinical practice, generally confirming maintained virologic suppression but highlighting challenges with adherence due to dosing frequency and food restrictions.
Physician reviews of the accumulated evidence acknowledge indinavir’s historical importance while noting that contemporary treatment goals favor regimens with lower pill burden, fewer food restrictions, and reduced toxicity profiles.
8. Comparing Indinavir with Similar Products and Choosing a Quality Product
When comparing indinavir similar agents, several dimensions require consideration. Among protease inhibitors, indinavir offers the advantage of not requiring pharmacokinetic boosting, unlike many contemporary agents that require ritonavir or cobicistat. However, the three-times-daily dosing presents adherence challenges compared to once-daily alternatives.
The comparison with other protease inhibitors reveals trade-offs: indinavir has less impact on lipid metabolism than some alternatives but carries higher risks of nephrolithiasis and gastrointestinal intolerance. The which indinavir is better question depends on individual patient factors including comorbidities, concomitant medications, and lifestyle considerations.
Regarding how to choose between antiretroviral classes, current guidelines generally reserve protease inhibitors for specific scenarios such as treatment-experienced patients with resistance or those with contraindications to first-line agents. Within the protease inhibitor class, boosted agents typically offer preferable dosing and efficacy profiles.
Quality considerations for indinavir products focus on bioequivalence to the reference product, manufacturing standards, and supply chain reliability, particularly important given the declining use and potential for discontinuation by manufacturers.
9. Frequently Asked Questions (FAQ) about Indinavir
What is the recommended course of indinavir to achieve results?
Treatment continues indefinitely as part of combination antiretroviral therapy. Viral load reduction typically occurs within 2-4 weeks, with maximal suppression by 12-24 weeks in treatment-naïve patients.
Can indinavir be combined with other HIV medications?
Yes, indinavir must be used in combination with other antiretroviral agents, typically two nucleoside reverse transcriptase inhibitors. Monotherapy is not recommended due to rapid resistance development.
What should I do if I miss a dose of indinavir?
If remembered within 2 hours of the scheduled time, take the missed dose immediately. If more than 2 hours have passed, skip the missed dose and resume the regular schedule. Do not double dose.
How does indinavir affect kidney function?
Nephrolithiasis occurs in approximately 9% of patients, typically within the first several months of therapy. Maintaining adequate hydration (1.5-2 liters daily) significantly reduces this risk. Periodic monitoring of renal function is recommended.
Are there dietary restrictions with indinavir?
Administration should occur on an empty stomach (1 hour before or 2 hours after meals) or with a light, low-fat meal. High-fat meals significantly reduce absorption. Grapefruit juice should be avoided.
10. Conclusion: Validity of Indinavir Use in Clinical Practice
The risk-benefit profile of indinavir reflects its position as a historically important agent with limitations in contemporary practice. While effective for viral suppression when adherence is maintained, the dosing frequency, food restrictions, and toxicity concerns have diminished its role in initial treatment strategies. However, it remains a viable option in specific clinical scenarios and retains importance in the historical context of HIV treatment development.
I remember when we first started using indinavir back in ‘97 - the excitement in the HIV clinic was palpable. We had this 38-year-old guy, Marcus, who’d been through every available treatment with his CD4 count stubbornly hovering around 80. Started him on the new triple therapy with indinavir, AZT, and 3TC. Within three months, his viral load went from over 300,000 to undetectable. Never seen anything like it at the time - felt like we’d witnessed a medical miracle.
But the reality set in quickly. Marcus developed kidney stones twice in the first year, ended up in the ED both times. The dosing schedule was brutal - he worked construction and trying to coordinate empty stomach dosing with his breaks was nearly impossible. Our team had heated debates about whether the side effects and adherence challenges outweighed the benefits. The pharmacokinetics specialist kept emphasizing the narrow therapeutic window, while the infectious disease attending argued we had to accept some toxicity for survival benefit.
What surprised me was the variability in side effects. Another patient, Lena, a 52-year-old woman, tolerated indinavir beautifully for years with only mild hyperbilirubinemia. Meanwhile, a 29-year-old developed such severe lipodystrophy that he stopped treatment against medical advice. We learned that genetic factors we didn’t fully understand at the time played a huge role in tolerability.
The most valuable insight came from following these patients long-term. Marcus eventually switched to a simpler regimen in 2004, but he always credited indinavir with saving his life during those critical years. At his last follow-up, his viral load remained suppressed on a once-daily single tablet regimen. Lena stayed on indinavir until 2010 when she developed diabetes - we’ll never know for certain if the indinavir contributed, but the timing was suspicious.
Looking back, the development struggles we witnessed - the balancing act between efficacy and quality of life - fundamentally shaped how we approach HIV treatment today. Those early indinavir patients taught us that survival alone wasn’t enough; people needed regimens that allowed them to live their lives. The current generation of HIV specialists might view indinavir as a historical artifact, but for those of us who practiced through that transition, it represents both the remarkable progress and hard lessons of the antiretroviral revolution.