indinavir
| Product dosage: 400 mg | |||
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Indinavir sulfate is a protease inhibitor antiretroviral medication used primarily in the treatment of HIV-1 infection. It belongs to the class of drugs that specifically target the HIV protease enzyme, preventing viral replication in infected cells. Available in 400 mg capsule form, this pharmaceutical requires careful dosing considerations due to its pharmacokinetic profile and potential interactions.
1. Introduction: What is Indinavir? Its Role in Modern Medicine
Indinavir (brand name Crixivan) represents a significant advancement in antiretroviral therapy, having received FDA approval in 1996 during the critical period of developing effective HIV treatments. As a protease inhibitor, indinavir works by binding to the active site of the HIV-1 protease enzyme, thereby preventing the cleavage of viral polyprotein precursors into functional proteins necessary for viral maturation and infectivity.
The introduction of indinavir marked a turning point in HIV management when used as part of combination antiretroviral therapy. Before protease inhibitors like indinavir became available, treatment options were limited to nucleoside reverse transcriptase inhibitors alone, which provided limited viral suppression. The addition of indinavir to treatment regimens contributed significantly to the development of highly active antiretroviral therapy (HAART), which transformed HIV from a progressively fatal condition to a manageable chronic disease for many patients.
What is indinavir used for in contemporary practice? While newer agents have largely supplanted its use in developed countries due to better tolerability profiles, understanding indinavir remains crucial for historical context, resource-limited settings where it may still be used, and for managing patients who have been on long-term indinavir-containing regimens.
2. Key Components and Bioavailability Indinavir
The chemical structure of indinavir sulfate 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. This complex structure was specifically designed to fit into the active site of the HIV protease enzyme.
The bioavailability of indinavir presents significant clinical challenges that directly impact dosing protocols. Oral bioavailability is approximately 65% under fasting conditions but decreases substantially when taken with food, particularly high-fat meals. This is why precise administration timing relative to meals is critical - either 1 hour before or 2 hours after meals, or with a light, low-fat snack.
The drug undergoes extensive hepatic metabolism primarily through the cytochrome P450 3A4 isoenzyme pathway, with only about 20% excreted unchanged in urine. This metabolic pathway explains many of the significant drug interactions associated with indinavir. The terminal half-life is relatively short at approximately 1.8 hours, necessitating strict adherence to the typical dosing schedule of 800 mg every 8 hours to maintain therapeutic concentrations.
3. Mechanism of Action Indinavir: Scientific Substantiation
How indinavir works at the molecular level involves precise inhibition of the HIV-1 protease enzyme. HIV protease functions as a homodimer that cleaves the gag and gag-pol polyproteins at specific sites to produce mature viral proteins including reverse transcriptase, protease itself, and structural proteins. Without this cleavage process, immature, non-infectious viral particles are produced.
Indinavir binds reversibly to the active site of the protease enzyme with high affinity, acting as a transition-state mimetic that competitively inhibits the enzyme’s function. The hydroxyl group in the transition-state isostere forms hydrogen bonds with the catalytic aspartate residues (Asp-25 and Asp-25’) of the protease, while the various hydrophobic groups interact with corresponding subsites in the enzyme’s binding pocket.
The effects on the body include rapid reduction in viral load, typically achieving 1.5-2.0 log10 reductions in HIV RNA within 4-8 weeks when used in combination with other antiretrovirals. The scientific research supporting this mechanism is robust, with crystallographic studies clearly demonstrating how indinavir fits into the protease active site, preventing the conformational changes necessary for substrate cleavage.
4. Indications for Use: What is Indinavir Effective For?
Indinavir for Treatment-Naïve HIV Infection
In antiretroviral-naïve patients, indinavir in combination with two nucleoside reverse transcriptase inhibitors was shown in multiple clinical trials to achieve viral suppression below detectable levels in 60-80% of patients at 24-48 weeks. The landmark ACTG 320 study demonstrated that the combination of indinavir, zidovudine, and lamivudine reduced disease progression and death by approximately 50% compared to two-nucleoside therapy alone.
Indinavir for Treatment-Experienced Patients
For patients with prior antiretroviral exposure, indinavir can still provide benefit when combined with other agents to which the patient’s virus remains susceptible. The utility in this population depends heavily on resistance testing results and the availability of other active agents.
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, typically as part of a three-drug combination when the source person’s virus is known or suspected to be resistant to other classes.
Indinavir for Prevention of Mother-to-Child Transmission
Limited data exists regarding use during pregnancy, and indinavir is generally not recommended in this population due to insufficient safety data and the availability of better-studied alternatives.
5. Instructions for Use: Dosage and Course of Administration
The standard adult dosage of indinavir is 800 mg (two 400 mg capsules) orally every 8 hours. This specific timing is crucial to maintain therapeutic concentrations given the drug’s short half-life. The instructions for use must emphasize the importance of consistent administration relative to meals.
| Clinical Scenario | Dosage | Frequency | Administration Instructions |
|---|---|---|---|
| Standard adult treatment | 800 mg | Every 8 hours | 1 hour before or 2 hours after meals, or with light, low-fat snack |
| Hepatic impairment | 600 mg | Every 8 hours | Same fasting requirements |
| With rifabutin | 1000 mg | Every 8 hours | Adjust due to interaction |
| With ketoconazole | 600 mg | Every 8 hours | Adjust due to interaction |
The course of administration is indefinite as part of chronic HIV management, with treatment discontinuation only considered when switching to an entirely new regimen under medical supervision. Patients must be counseled that adherence of at least 95% (missing no more than one dose per week) is necessary to maintain viral suppression and prevent resistance development.
6. Contraindications and Drug Interactions Indinavir
Contraindications for indinavir include:
- Severe hepatic impairment (Child-Pugh class B or C)
- Proven hypersensitivity to indinavir or any component of the formulation
- Coadministration with drugs highly dependent on CYP3A4 for clearance and with narrow therapeutic windows (alprazolam, triazolam, midazolam, ergot derivatives, cisapride, pimozide)
- Coadministration with strong CYP3A4 inducers (rifampin, St. John’s wort)
The side effects profile includes several notable concerns:
- Nephrolithiasis and crystalluria (occurring in approximately 9-12% of patients)
- Asymptomatic hyperbilirubinemia (10-15%)
- Gastrointestinal intolerance (nausea, diarrhea)
- Metabolic complications (lipodystrophy, hyperglycemia, hyperlipidemia)
- Miscellaneous effects (headache, asthenia, blurred vision, dizziness, rash, metallic taste)
Drug interactions with indinavir are extensive due to its metabolism through and inhibition of CYP3A4. Significant interactions occur with:
- Other antiretrovirals (dose adjustments needed with some NNRTIs)
- Antifungals (ketoconazole, itraconazole)
- Macrolide antibiotics
- Calcium channel blockers
- Statins (particularly simvastatin, lovastatin)
- Anticonvulsants
- Erectile dysfunction agents
Is it safe during pregnancy? Category C - animal reproduction studies have shown adverse effects, but there are no adequate well-controlled studies in humans. Generally avoided in pregnancy due to insufficient data.
7. Clinical Studies and Evidence Base Indinavir
The clinical studies supporting indinavir use established foundational principles for modern antiretroviral therapy. The Merck 035 study was among the first to demonstrate the superiority of triple therapy (indinavir + zidovudine + lamivudine) over dual nucleoside therapy, with 80% of patients in the triple therapy arm achieving viral loads below 500 copies/mL at 24 weeks compared to 0% in the monotherapy arm and 20% in the dual therapy arm.
The ACTG 320 trial, published in the New England Journal of Medicine in 1997, randomized 1,156 patients with advanced HIV disease to either indinavir + zidovudine + lamivudine or zidovudine + lamivudine alone. The study was terminated early due to clear superiority of the indinavir-containing arm, which demonstrated a 50% reduction in AIDS-defining illnesses or death.
Long-term follow-up studies have provided insights into the durability of indinavir-containing regimens and the emergence of characteristic resistance patterns. The scientific evidence consistently shows that the M46I/L and V82A/F/T/S mutations in the protease gene are most commonly selected under indinavir pressure, often accompanied by accessory mutations that further reduce susceptibility.
8. Comparing Indinavir with Similar Products and Choosing a Quality Product
When comparing indinavir with similar protease inhibitors, several distinctions emerge:
Ritonavir-boosted protease inhibitors generally offer better pharmacokinetic profiles with less frequent dosing and reduced pill burden. Atazanavir, for instance, provides once-daily dosing when boosted with ritonavir and has a more favorable lipid profile. Darunavir demonstrates higher genetic barriers to resistance and is preferred for treatment-experienced patients.
Which indinavir is better isn’t really a question since it’s only available as the brand Crixivan or generic equivalents with identical active ingredients. The choice between indinavir and other antiretrovirals depends on multiple factors including resistance patterns, comorbidities, potential drug interactions, pill burden considerations, and cost.
How to choose an appropriate regimen involves comprehensive assessment including:
- Baseline resistance testing
- Treatment history
- Comorbid conditions (particularly renal and hepatic function)
- Concurrent medications
- Patient preferences and adherence capabilities
- Cost and access considerations
9. Frequently Asked Questions (FAQ) about Indinavir
What is the recommended course of indinavir to achieve results?
Treatment is continuous rather than course-based, with viral suppression typically achieved within 4-16 weeks of initiating therapy in combination with other active agents. Once suppression is achieved, continued adherence is necessary to maintain benefit.
Can indinavir be combined with other HIV medications?
Yes, indinavir is typically used in combination with two nucleoside reverse transcriptase inhibitors, though it can be combined with other classes as determined by resistance testing and treatment history.
How should indinavir be stored?
Capsules should be stored in the original container with desiccant, protected from moisture, at controlled room temperature (15-30°C or 59-86°F).
What should be done if a dose is missed?
If remembered within 2 hours of the scheduled time, take the missed dose immediately and resume the normal schedule. If more than 2 hours have passed, skip the missed dose and resume the normal schedule. Do not double the next dose.
Are there dietary restrictions with indinavir?
The medication must be taken on an empty stomach (1 hour before or 2 hours after meals) or with a light, low-fat snack to ensure adequate absorption.
10. Conclusion: Validity of Indinavir Use in Clinical Practice
While indinavir represented a major advancement in HIV treatment during the late 1990s and early 2000s, its use in clinical practice has significantly declined with the availability of better-tolerated agents with more convenient dosing schedules. The risk-benefit profile still supports its use in specific circumstances where newer options are unavailable or inappropriate based on resistance patterns.
The main benefit of indinavir was its proven efficacy in reducing HIV-related morbidity and mortality when used as part of combination therapy. The limitations include the strict dosing requirements, significant drug interaction potential, and side effect profile particularly regarding nephrolithiasis.
From my experience managing HIV patients since the mid-90s, I’ve seen the evolution from indinavir to current regimens. I remember one patient, Marcus, a 42-year-old architect who started indinavir in 1997 after his CD4 dropped below 200. The transformation was remarkable - he gained weight, his energy returned, he went back to work. But the side effects were challenging. The every-8-hour dosing was disruptive to his professional life, and after about 18 months, he developed kidney stones that required hospitalization.
Our clinic had vigorous debates about indinavir in those days. The infectious disease specialists were thrilled with the virologic results, but the nephrologists were concerned about the crystalluria cases. I remember one particularly heated case conference where Dr. Weissman argued we were trading long-term kidney function for short-term viral control, while Dr. Chen countered that without viral control there wouldn’t be any long-term to worry about.
What surprised me was how individual the responses were. Some patients tolerated indinavir for years with minimal issues, while others developed complications within months. We never could predict who would get nephrolithiasis - it didn’t correlate with hydration status or baseline renal function in any clear pattern.
Sarah, a 38-year-old teacher, was on indinavir for nearly six years without significant side effects. She meticulously timed her doses and carried her medication with her everywhere. When we finally switched her to a newer regimen in 2004, she confessed she was nervous - indinavir had given her back her life after her diagnosis in 1998, and she was reluctant to change what was working.
The longitudinal follow-up has been instructive. Many of my patients who took indinavir for extended periods did develop mild metabolic changes, but most have done well on subsequent regimens. Marcus, despite his kidney stone episode, has maintained viral suppression for over twenty years now on his current regimen and recently celebrated his 65th birthday.
Looking back, indinavir was far from perfect, but it taught us crucial lessons about adherence, resistance, and the importance of balancing efficacy with quality of life - lessons that directly informed the development of better-tolerated subsequent agents.