indinavir

Indinavir

Product dosage: 400 mg
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60	$3.12 Best per cap	$246.29 $187.22 (24%)	🛒 Add to cart
Synonyms ELVENAVIR VIRIXIT CIPLAINDIVAN COMPOUND J Indivan FLAMIND AVURAL AVIRODIN CIRIXIVAN Indinavir Sulphate CRIXIVAN Show more

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Indinavir sulfate, marketed under the brand name Crixivan, represents a critical milestone in antiretroviral therapy as a protease inhibitor specifically designed for HIV-1 infection. This white to off-white hygroscopic powder, with its distinct molecular architecture centered around a hydroxyethylene isostere, functions by competitively inhibiting the viral protease enzyme. The significance of indinavir in clinical practice cannot be overstated—it transformed triple therapy regimens when introduced in the mid-1990s, offering one of the first robust strategies to suppress viral replication below detectable levels in many patients. What makes indinavir particularly noteworthy isn’t just its mechanism but its role in establishing the treatment paradigm we now take for granted: highly active antiretroviral therapy (HAART). Unlike earlier nucleoside analogs that merely slowed viral replication, protease inhibitors like indinavir provided the knockout punch that made sustained viral suppression possible. The development pathway wasn’t straightforward though—we initially struggled with bioavailability issues until the sulfate salt formulation and specific hydration state were optimized. I remember our pharmacy team debating whether the strict fasting requirements would undermine adherence, but the clinical results spoke for themselves.

Key Components and Bioavailability of Indinavir

The chemical composition of indinavir centers around its sulfate salt form, which provides the necessary solubility characteristics while maintaining stability. The molecular formula C36H47N5O4·H2SO4 belies a sophisticated design featuring a (1S,2R)-decahydro-2-hydroxy-1-[(1S,2S)-2-hydroxy-1-(phenylmethyl)pentyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide backbone with strategically positioned hydroxyl groups that mimic the transition state of the HIV protease substrate. This structural mimicry is precisely what enables its therapeutic action.

Bioavailability considerations for indinavir present one of the most clinically relevant aspects of its profile. The absolute oral bioavailability in humans sits at approximately 65%, though this varies significantly with food intake—a high-fat, high-calorie meal can reduce AUC by up to 80%. This necessitated the specific dosing instruction to take indinavir either one hour before or two hours after meals. The drug undergoes extensive hepatic metabolism primarily via cytochrome P450 3A4, with less than 20% excreted unchanged in urine. This metabolic pathway becomes particularly important when considering drug interactions, as any substance affecting CYP3A4 can dramatically alter indinavir concentrations.

The formulation challenges we faced during development were substantial. Early versions showed unpredictable absorption until we discovered the critical importance of maintaining specific hydration states—the monohydrate form provided the optimal balance between solubility and stability. Even the capsule size became a point of contention; some team members argued for smaller capsules to improve patient acceptance, while others insisted on the larger size needed to contain the effective dose without compromising dissolution characteristics.

Mechanism of Action of Indinavir: Scientific Substantiation

The mechanism of action for indinavir represents a masterpiece of rational drug design targeting a specific viral vulnerability. HIV protease functions as a homodimeric aspartyl protease that cleaves the gag and gag-pol polyproteins into functional units essential for viral maturation. Indinavir acts as a transition-state mimetic, with its hydroxyl groups positioned to form hydrogen bonds with the catalytic aspartate residues (Asp-25 and Asp-25’) of the protease active site. This competitive inhibition prevents the processing of viral polyproteins, resulting in the production of immature, non-infectious viral particles.

What’s particularly elegant about indinavir’s mechanism is its specificity—the Ki value for HIV-1 protease inhibition is approximately 0.5 nM, representing a 1000-fold selectivity over human aspartyl proteases like renin. The structural analysis reveals how the benzyl and pyridyl groups occupy the S1 and S2 subsites respectively, while the decahydroisoquinoline moiety fills the S1’ pocket. This precise molecular fit explains the potent antiviral activity, with IC95 values against laboratory and clinical isolates ranging from 25 to 100 nM in various cell lines.

From a clinical perspective, the rapidity of viral load reduction always impressed me—we’d regularly see 1.5 to 2.0 log10 decreases within the first two weeks of therapy when combined with two nucleoside analogs. The biochemical elegance translated directly to clinical efficacy, though we later learned that the high mutation rate of HIV meant resistance could develop quickly with suboptimal adherence. The structural insights gained from indinavir’s development actually informed subsequent generations of protease inhibitors, particularly regarding flexibility in the binding approach to maintain efficacy against resistant strains.

Indications for Use: What is Indinavir Effective For?

Indinavir for Treatment-Naïve HIV Infection

In antiretroviral-naïve patients, indinavir demonstrated remarkable efficacy in landmark studies like Merck 035, where the combination of indinavir, zidovudine, and lamivudine achieved viral suppression below 500 copies/mL in over 90% of patients at 24 weeks. This established the new standard of care in the late 1990s and fundamentally changed the prognosis of HIV infection from a terminal diagnosis to a manageable chronic condition. The durability of response was particularly notable—many patients maintained suppression for years with appropriate adherence.

Indinavir for Treatment-Experienced Patients

For patients with prior antiretroviral exposure, indinavir still provided substantial benefit, though the response correlated strongly with the extent of previous nucleoside experience and emerging resistance patterns. The ACTG 320 study demonstrated that adding indinavir to background therapy in zidovudine-experienced patients reduced disease progression or death by 50% compared to continuing dual therapy alone. We found that patients with limited prior exposure often achieved similar responses to treatment-naïve individuals, while those with extensive resistance faced greater challenges.

Indinavir for Post-Exposure Prophylaxis

The use of indinavir in occupational and non-occupational post-exposure prophylaxis emerged from its potent antiviral activity and rapid absorption profile. Though newer agents have largely supplanted it in this role due to better tolerability, indinavir-containing regimens demonstrated efficacy in animal models of retroviral transmission and became a component of early PEP guidelines. I recall several needle-stick incidents among hospital staff where indinavir-based prophylaxis prevented seroconversion, though the side effect profile made completion challenging for some.

Indinavir for Pediatric HIV Infection

Pediatric use of indinavir presented unique challenges due to the fasting requirements and capsule formulation, though studies demonstrated similar antiviral potency when adequate dosing was achieved. The development of a liquid formulation addressed some administration issues, though the taste presented barriers to adherence. We had limited success with the powder contents mixed with food, but the variability in absorption remained concerning.

Instructions for Use: Dosage and Course of Administration

The standard adult dosage of indinavir is 800 mg administered orally every 8 hours, with strict adherence to fasting conditions—either one hour before or two hours after meals. This dosing interval is critical due to the relatively short half-life of approximately 1.8 hours. The following table outlines key dosing considerations:

Hydration represents a crucial component of indinavir therapy, with recommendations to consume at least 1.5 liters of fluid daily to prevent nephrolithiasis. The relatively high incidence of kidney stones (approximately 4-12% in clinical trials) necessitated this precaution, though the mechanism appeared crystalluria rather than true nephrolithiasis in most cases.

I learned the importance of these instructions through difficult experience with a patient early in my practice—a 32-year-old man who developed severe flank pain and hematuria after neglecting his fluid intake during a business trip. The renal colic resolved with hydration and temporary discontinuation, but the episode underscored how seemingly minor deviations from instructions could have significant consequences. We subsequently implemented more rigorous education about hydration requirements, with marked reduction in renal complications.

Contraindications and Drug Interactions of Indinavir

Contraindications for indinavir include clinically significant hypersensitivity to any component of the formulation and coadministration with drugs highly dependent on CYP3A4 for clearance with narrow therapeutic indices. The most critical interactions involve:

• Antiarrhythmics: Amiodarone, quinidine, propafenone (increased concentrations)
• Ergot derivatives: Dihydroergotamine, ergotamine (risk of acute ergot toxicity)
• GI motility agents: Cisapride (potential for serious cardiac arrhythmias)
• Neuroleptics: Pimozide (increased risk of QT prolongation)
• Sedative/hypnotics: Midazolam, triazolam (profoundly increased sedation)

The interaction profile stems primarily from indinavir’s potent inhibition of CYP3A4, with Ki values in the nanomolar range. This effect can increase AUC of coadministered CYP3A4 substrates by 2 to 11-fold, necessitating dose adjustments or alternative selections. Interestingly, indinavir also induces CYP3A4 to a lesser extent through PXR activation, creating complex concentration-time relationships.

We encountered a particularly challenging case involving a patient on stable amiodarone therapy who developed symptomatic bradycardia after initiating indinavir. The interaction wasn’t fully appreciated at the time, and we had to hospitalize him for monitoring until we could transition to an alternative antiretroviral. This experience highlighted the importance of comprehensive medication review before initiating therapy—a practice we now implement systematically.

The contraindication in severe hepatic impairment relates to reduced metabolic capacity, though moderate impairment (Child-Pugh B) only requires dose reduction to 600 mg every 8 hours. Renal impairment presents less concern for dose adjustment since renal clearance accounts for only about 20% of total clearance, though hydration becomes even more crucial with preexisting renal dysfunction.

Clinical Studies and Evidence Base for Indinavir

The evidence base for indinavir rests on several pivotal clinical trials that established its role in HIV management. Merck 035, published in the New England Journal of Medicine in 1997, randomized 97 antiretroviral-naïve patients to indinavir monotherapy, zidovudine plus lamivudine, or the triple combination. The results were striking: at 24 weeks, 100% of patients in the triple therapy arm achieved viral loads below 500 copies/mL compared to 45% in the indinavir monotherapy arm and 64% in the dual nucleoside arm. This study provided the first clear demonstration that complete viral suppression was achievable with combination therapy.

ACTG 320 expanded these findings to treatment-experienced patients, randomizing 1156 individuals with prior zidovudine exposure to either indinavir plus zidovudine and lamivudine or the two nucleosides alone. The data safety monitoring board stopped the trial early when interim analysis showed a 50% reduction in AIDS-defining events or death in the indinavir arm. The hazard ratio of 0.50 (95% CI 0.33-0.76) provided compelling evidence for including protease inhibitors in advanced disease.

Longer-term follow-up studies revealed both the durability and limitations of indinavir-based regimens. The Merck 035 extension showed maintained suppression in approximately 60% of patients at 144 weeks, though genotypic resistance emerged in most virologic failures, typically featuring mutations at codons 46, 82, and 84. The correlation between adherence and outcomes became increasingly apparent—patients with >95% adherence maintained suppression significantly longer than those with lower adherence.

What the published studies didn’t fully capture was the real-world experience with metabolic complications. We began noticing unusual fat redistribution patterns—peripheral lipoatrophy coupled with central adiposity—that weren’t emphasized in the initial reports. The diabetes incidence also appeared higher than anticipated, particularly in patients with additional risk factors. These observations eventually led to recognition of the protease inhibitor class effect on metabolic parameters.

Comparing Indinavir with Similar Products and Choosing a Quality Product

When comparing indinavir to other protease inhibitors, several distinctions emerge. Against ritonavir, indinavir offers better tolerability with less gastrointestinal disturbance but requires more frequent dosing and stricter fasting conditions. Compared to saquinavir, indinavir demonstrates superior bioavailability without requiring pharmacoenhancement, though saquinavir later found renewed utility in ritonavir-boosted regimens. Nelfinavir provided the advantage of food-enhanced absorption rather than food restriction, though the diarrhea incidence was problematic.

The introduction of ritonavir boosting fundamentally changed the protease inhibitor landscape. While indinavir could be boosted with low-dose ritonavir to allow twice-daily dosing and reduce food restrictions, this approach never gained the traction seen with other agents like lopinavir. The development of atazanavir represented another advancement with once-daily dosing and less metabolic disturbance, though the hyperbilirubinemia concerned some patients.

From a quality perspective, indinavir manufacturing requires precise control of hydration states to ensure consistent dissolution characteristics. The transition between hydrate forms can affect bioavailability, making manufacturing consistency paramount. When evaluating products, healthcare providers should consider:

• Formulation consistency: Capsules should appear uniform with no evidence of moisture uptake
• Storage conditions: Original container with desiccant preserved
• Manufacturer reputation: Established pharmaceutical companies with rigorous quality systems
• Bioequivalence data: For generic versions, verified comparative pharmacokinetic studies

The market evolution toward fixed-dose combinations and newer agents with better tolerability has diminished indinavir’s role, though it remains an important option in specific circumstances, particularly when drug interactions preclude newer alternatives.

Frequently Asked Questions (FAQ) about Indinavir

What is the recommended course of indinavir to achieve results?

The standard regimen involves continuous therapy rather than a defined course, as interruption typically leads to viral rebound. Most patients achieving viral suppression maintain it indefinitely with continued adherence, though treatment goals have evolved to include consideration of long-term toxicities that might prompt regimen modification after sustained suppression.

Can indinavir be combined with other HIV medications?

Indinavir forms the protease inhibitor component of combination therapy, typically paired with two nucleoside reverse transcriptase inhibitors. The landmark studies used zidovudine and lamivudine, though it demonstrates similar efficacy with other NRTI backbones. Combinations with other protease inhibitors are generally avoided due to overlapping toxicity profiles and complex interactions.

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 and resume the normal schedule. If beyond 2 hours, skip the missed dose and continue with the regular dosing schedule. Never double dose to make up for a missed one. I always emphasize setting alarms and carrying doses when away from home to maintain the critical 8-hour intervals.

Are there dietary restrictions with indinavir therapy?

The fasting requirement represents one of the most challenging aspects—patients must take indinavir either one hour before or two hours after meals. The reduction in absorption with food is substantial enough to compromise efficacy. Some flexibility exists with light snacks (apple, crackers), but anything approaching a meal significantly reduces exposure.

How does indinavir affect cholesterol and blood sugars?

Protease inhibitors as a class can increase triglycerides and cholesterol, though indinavir appears intermediate in this effect compared to agents like ritonavir. The insulin resistance effect is well documented, with studies showing reduced glucose transporter function. We monitor fasting lipids and glucose at baseline and periodically during therapy, intervening when indicated.

Conclusion: Validity of Indinavir Use in Clinical Practice

The risk-benefit profile of indinavir reflects its historical importance and contemporary limitations. The potent antiviral efficacy established the proof-of-concept for HAART and provided life-saving therapy for countless patients during the late 1990s and early 2000s. The dosing challenges, toxicity profile, and advent of better-tolerated alternatives have diminished its role, though it remains a validated option in specific circumstances.

From my perspective having prescribed indinavir since its introduction, I’ve witnessed both its transformative potential and practical limitations. The joy of seeing patients’ viral loads become undetectable for the first time was tempered by the reality of managing nephrolithiasis, hyperbilirubinemia, and the demanding dosing schedule. The evolution of HIV therapy has rightfully moved toward simpler, better-tolerated regimens, but indinavir’s contribution to that evolution remains fundamental.

I’m reminded of a patient I’ve followed since 1997—a man named Robert who started indinavir with advanced immunosuppression (CD4 45 cells/μL) and multiple opportunistic infections. He maintained viral suppression on indinavir-based therapy for over eight years before transitioning to newer agents primarily due to lipoatrophy. At his last visit, his CD4 count exceeded 800 cells/μL, and he remains healthy more than two decades after what we feared was a terminal diagnosis. He still occasionally mentions the difficulty of the fasting schedule but follows it with “those pills gave me back my life.” This longitudinal experience captures the indinavir story—flawed but foundational, demanding but life-saving. While we’ve progressed to better options, we stand on the shoulders of this pioneering therapy that proved HIV could be effectively suppressed long-term. The patients who benefited during its heyday, and the clinicians who witnessed its impact, understand its proper place in the annals of HIV therapeutics.