Saquinavir Mesylate: Uses, Dosage, Precautions, Side Effects, and Pharmacological Aspects

Overview:

Saquinavir, a vital component in the treatment of HIV, is strategically combined with Ritonavir and other HIV medications to manage the infection effectively. As a protease inhibitor, Saquinavir is pivotal in reducing the viral load, contributing to enhanced immune function, and diminishing the risks of complications such as infections and cancer.

The synergy achieved by co-administering Saquinavir with Ritonavir is crucial for optimizing its efficacy. It is important to understand that while this combination significantly improves the quality of life for individuals with HIV, it does not provide a cure. Adherence to the prescribed medication regimen ensures the treatment's sustained effectiveness.

This comprehensive approach not only aids in controlling the progression of HIV but also underscores the importance of patient commitment to maintaining overall health and minimizing transmission risks. The FDA approved Saquinavir mesylate (Food and Drug Administration) in 1995. It was the first protease inhibitor, followed by Ritonavir in 1996. It continues to be used in clinical practice today due to its relatively mild adverse effect profile compared to other antiretroviral therapies.

Drug Group:

Saquinavir belongs to the protease inhibitor class of anti-retroviral drugs, a crucial component in antiretroviral therapy for managing HIV infection by inhibiting viral replication. They help in managing human immunodeficiency virus (HIV) infection. They operate by suppressing the function of the HIV protease enzyme, a crucial element for the virus to generate infectious particles. By blocking this enzyme, protease inhibitors disrupt the virus's replication, decreasing the viral load within the body. It is often used with other medications to enhance its effectiveness and control the progression of the disease.

Available Doses and Dosage Forms:

Saquinavir Mesylate Is Available in the Following Doses and Forms:

• Capsules: Light brown and green, opaque hard gelatin capsules. It is available in 200 mg (milligram) strength as a Saquinavir-free base.

• Film-coated Tablets: Light orange to greyish or brownish-orange, oval, cylindrical, biconvex film-coated tablets (500 mg strength as the Saquinavir-free base).

Indications:

Saquinavir mesylate, in conjunction with Ritonavir and other antiretroviral agents, is approved for treating HIV-1 infection in adults (16 years and older).

For Patients:

What Is HIV Infection?

HIV, or human immunodeficiency virus, is a virus that targets the immune system, diminishing the body's capacity to defend against infections. If untreated, it can progress to AIDS (acquired immunodeficiency syndrome). It transmits through specific bodily fluids, predominantly through unprotected sexual activity, needle-sharing, and from a mother to her child during birth or breastfeeding. While there is no cure, antiretroviral therapy (ART) helps control the virus and prevent its transmission. Timely identification and appropriate medical attention are essential for HIV management and sustaining a healthier lifestyle.

How Does Saquinavir Mesylate Work?

Saquinavir mesylate is a protease inhibitor used in HIV treatment. It works by blocking the protease enzyme, disrupting the virus's ability to replicate, and reducing the viral load. Typically used in combination therapy with Ritinovir, it helps control HIV infection and is part of a comprehensive antiretroviral approach.

Patient Information:

Saquinavir mesylate does not provide a remedy for HIV-1 infection, and patients may continue to encounter illnesses associated with HIV-1, including opportunistic infections. Patients must remain under the supervision of a physician while using Saquinavir mesylate.

Patients are strongly advised to take precautions to prevent the transmission of HIV-1 to others:

• Avoid sharing needles or any other injection equipment.

• Refrain from sharing personal items that may have blood or bodily fluids, such as toothbrushes and razor blades.

• Practice safe sex by consistently using latex or polyurethane condoms to reduce the risk of sexual contact with semen, vaginal secretions, or blood.

• Breastfeeding is discouraged. The safety of Saquinavir mesylate in breast milk transmission is unknown, and there is a potential risk to the baby. Mothers with HIV-1 are also cautioned against breastfeeding, as HIV-1 can be transmitted to the baby through breast milk.

What Is the Dosage of Saquinavir Mesylate?

Saquinavir mesylate is used with Ritonavir; the dosage is 1000 mg twice daily for adults (16 years and older). This can be administered through five 200 mg capsules, two 500 mg tablets, and Ritonavir 100 mg twice daily.

How Effective Is Saquinavir Mesylate?

Saquinavir mesylate is an effective protease inhibitor used in the treatment of HIV-1 infection. When utilized alongside other antiretroviral drugs, it aids in lowering the viral concentration in the bloodstream and increases clusters of differentiation 4 (CD4) (T) cell count, thereby improving the immune system. The effectiveness of Saquinavir mesylate is well-established, contributing to the management of HIV-1 and reducing the risk of opportunistic infections. However, its usage and effectiveness may vary among individuals.

What Are the Things to Inform the Doctor Before Taking Saquinavir Mesylate?

Before taking Saquinavir mesylate, discuss the following with the doctor:

• Medical History: Allergies or adverse reactions to medications, including Saquinavir or other HIV drugs.

• Pre-existing Conditions: Liver problems, heart issues, diabetes (a persistent metabolic condition distinguished by elevated levels of blood glucose), bleeding disorders, mental or mood disorders. History of pancreatitis (pancreas inflammation), high cholesterol, triglycerides, and kidney problems.

• Current Medications: List all prescribed and non-prescribed medications, vitamins, and herbal supplements. Inform the doctor about other HIV medications and drugs that may interact with Saquinavir mesylate.

• Pregnancy and Breastfeeding: Inform the doctor if one is pregnant, planning pregnancy, or breastfeeding, and discuss with the doctor. Saquinavir mesylate's safety during pregnancy is uncertain and weighs potential risks. HIV-positive mothers are generally advised against breastfeeding due to transmission risks.

• Contraception: For childbearing-age individuals, discuss contraception methods to prevent unintended pregnancies.

• Liver Function: Disclose any history of liver problems or hepatitis (inflammation of the liver), as Saquinavir is metabolized in the liver.

• Heart Health: Report any history of heart issues, especially prolonged QT intervals or irregular heartbeats.

• Alcohol and Substance Use: Inform about alcohol consumption and recreational drug use, as they may interact with Saquinavir mesylate.

• Routine Check-ups: Regularly update the doctor on health status, new symptoms, or side effects during Saquinavir mesylate treatment.

How Is Saquinavir Mesylate Administered?

Saquinavir mesylate and Ritonavir should be taken within two hours after a meal. For patients who cannot swallow capsules, open the Saquinavir mesylate capsules and transfer the contents into an empty container. Combine with 15 mL (milliliters) of sugar syrup or sorbitol syrup (for those with type 1 diabetes or glucose intolerance) or three teaspoons of jam in the container. Stir the contents with a spoon for 30 to 60 seconds. Administer the entire prepared dose. Ensure that suspensions are at room temperature before giving them.

What Are the Side Effects of Saquinavir Mesylate?

Common Side Effects of Saquinavir Mesylate:

• Nausea, vomiting, diarrhea (loose stools), abdominal pain, tiredness, pneumonia (a respiratory infection), and changes in body fat are common side effects.

Saquinavir Mesylate and Diabetes:

• Some individuals taking protease inhibitors, like Saquinavir mesylate, may experience new or worsening diabetes or high blood sugar.

• Inform the healthcare provider if the patient observes increased thirst or frequent urination while on Saquinavir mesylate.

Liver Problems:

• Those with liver issues such as hepatitis B or C (viral infections that primarily affect the liver), cirrhosis (an advanced phase of liver scarring characterized by fibrosis), or a history of alcoholism may experience worsening liver problems.

• Contact the healthcare provider immediately if one notices signs like loss of appetite, jaundice, dark-colored urine, pale stools, itchy skin, or abdominal pain.

Increased Bleeding (Hemophilia):

• People with hemophilia (a genetic bleeding disorder) may experience increased bleeding with protease inhibitors, including Saquinavir mesylate.

Elevated Blood Fat Levels:

• Saquinavir mesylate may lead to increased cholesterol and triglyceride levels.

• The healthcare provider will monitor the blood for high-fat levels before and during Saquinavir mesylate treatment.

Changes in Body Fat:

• Taking HIV-1 medicine, like Saquinavir mesylate, may result in changes in body fat distribution, including fat accumulation in specific areas.

• The long-term health effects are currently unknown.

Immune System Changes:

• Starting HIV-1 medicines may strengthen the immune system, leading to the revelation of and fighting against hidden infections.

• Notify the healthcare provider of any new or worsening infection symptoms after starting HIV-1 medicine.

Dietary Considerations:

As such, there is nothing specific, but it is crucial to follow a balanced diet.

Missed Dose:

Missed doses of Saquinavir mesylate can lead to an increase in the HIV (viral load) in the blood, causing further damage to the immune system. A few skipped doses may render Saquinavir ineffective due to the development of resistance, which could extend to other antiretrovirals with a similar mechanism of action.

Consequently, missed Saquinavir doses may limit future treatment options. Consistent Saquinavir intake is crucial, even if feeling unwell. If a Saquinavir dose is missed, take it promptly. However, if the next scheduled dose is imminent or closer, avoid doubling up; simply continue with the regular dosing schedule.

Overdose:

There is limited experience with Saquinavir overdose. In one instance, no acute toxicities or consequences were observed when a subject ingested eight grams of Saquinavir mesylate as a single dose; emesis (the act of vomiting) induction occurred within two to four hours after ingestion. Another subject ingested 2.4 grams of Saquinavir mesylate combined with 600 mg of Ritonavir, experiencing throat pain for six hours, which subsequently resolved.

In an exploratory Phase II study involving oral dosing of Saquinavir mesylate at 7200 mg per day (1200 mg every 4 hours), no serious toxicities were reported within the initial 25 weeks of treatment. In cases of Saquinavir overdose, management should involve general supportive measures, including monitoring vital signs and the ECG (electrocardiogram) and observing the patient's clinical status. Due to Saquinavir's high protein binding, dialysis (a medical procedure used to filter and remove waste) is unlikely to significantly remove the active substance.

Storage:

Store capsules and tablets at 25 degrees Celcius (77 degrees Fahrenheit) with excursions allowed to 15 to 30 degrees Celcius (59 to 86 degrees Fahrenheit).

Disposal:

The disposal of Saquinavir mesylate, or any medication, should be done following local guidelines and regulations. Typically, it involves returning unused or expired medication to a pharmacy or using designated drug take-back programs. Try not to dispose of medications by flushing them down the toilet unless instructed to do so to prevent environmental impact. It is advisable to consult with healthcare professionals or local authorities for guidance on the proper disposal of Saquinavir mesylate.

For Doctors:

Description:

Chemical Composition:

• Saquinavir mesylate is the brand name for Saquinavir mesylate, which functions as a suppressor of the protease enzyme associated with human immunodeficiency virus type 1.

• The chemical name for Saquinavir mesylate is N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2­quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide methanesulfonate.

• It has a molecular formula of C38H50N6O5·CH4O3S and a molecular weight of 766.96, with the free base weighing 670.86.

• Saquinavir mesylate is a white to off-white, very fine powder with an aqueous solubility of 2.22 mg per mL at 77 degrees Fahrenheit (25 degrees Celcius).

Inactive Ingredients:

• Capsules: Lactose, microcrystalline cellulose, povidone K30, sodium starch glycolate, talc, and magnesium stearate. The capsule shell includes gelatin, water, red iron oxide, yellow iron oxide, black iron oxide, FD and C Blue #2, and titanium dioxide.

• Tablets:Tabletscontain lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, and magnesium stearate. The film coat includes hypromellose, titanium dioxide, talc, iron oxide yellow, red, and triacetin.

Dose:

The standard dose is Saquinavir 1000 mg combined with Ritonavir 100 mg, taken twice daily.

Consider the following points when initiating Saquinavir mesylate therapy:

• The twice-daily administration of Saquinavir mesylate with Ritonavir is backed by safety data from the MaxCmin 1 trial.

• The effectiveness of Saquinavir mesylate with Ritonavir has yet to be compared to the efficacy of currently established antiretroviral regimens.

• The number of baseline primary protease inhibitor mutations influences the virologic response to Saquinavir mesylate or Ritonavir.

Dosing Considerations:1. Renal Impairment:

• Saquinavir's impact on renal impairment is likely minimal, as only one percent is excreted in urine.

• The consequences of significant renal impairment or end-stage renal disease (ESRD) are unknown, and caution is advised due to potential elevated Saquinavir concentrations.

2. Hepatic Impairment:

• A study showed a 30 percent reduction in Saquinavir exposure in moderate hepatic impairment.

• No dose alteration is required for patients with mild and moderate hepatic impairment, but caution is necessary.

3. Gender, Race, and Age:

• Females may have higher Saquinavir exposure than males.

• There is no evidence linking age or body weight to gender differences.

• There are no investigations on the impact of race on Saquinavir pharmacokinetics.

• There are no evaluations of the pharmacokinetics of Saquinavir in older people.

4. Pediatric Subjects:

• Pediatric subjects (two to less than six years) receiving Saquinavir showed variable exposures.

• There is limited data for subjects less than two years old and there is no dosing recommendation for this age group.

• No pharmacokinetic data is available for subjects ages six to 16 years.

What Are the Pharmacological Aspects of Saquinavir Mesylate?

Pharmacodynamics:

Researchers studied how Saquinavir mesylate affects the heart in 59 healthy adults. They measured the QTcS interval, which shows the time it takes for the heart to recharge between beats, using electrocardiogram tests on Day 3.

1. QTcS Interval Changes:

• For people taking Saquinavir mesylate with Ritonavir 1000 per 100 mg twice daily, the QTcS interval increased by 18.9 ms compared to a placebo.

• The increase was even more for those taking a higher dose of 1500 per 100 mg twice daily, at 30.2 ms.

• The maximum increase was observed about 12 to 20 hours after taking the medicine.

2. Cmax (Maximum Concentration):

• For the higher dose (1500 per 100 mg twice daily), the Day 3 Cmax of Saquinavir mesylate was about 1.4 times higher than the approved therapeutic dose in healthy volunteers.

3. QTcS in Healthy Subjects:

• The QTcS interval for males and females was calculated using a formula similar to Fridericia’s correction.

4. PR and QRS Interval Prolongations:

• Saquinavir mesylate and Ritonavir caused prolongations in the PR and QRS intervals on Day 3.

• For the 1000 per 100 mg twice daily dose, the increase in PR interval was 28.6 ms, and for the higher dose, it was 38.4 ms.

• The increase in QRS interval was 2.9 ms for the lower dose and 4.4 ms for the higher dose.

5. PR Interval Prolongation (More Than 200 ms):

• About 40 percent and 47 percent of people taking Saquinavir mesylate with Ritonavir at the two doses experienced PR interval prolongation of more than 200 ms on Day 3.

• In comparison, only three percent of people in the active control Moxifloxacin group and five percent in the placebo group had similar PR prolongation.

Mechanism

• Saquinavir inhibits HIV-1 protease, an enzyme necessary for processing viral proteins.

• It acts as a substrate analog, binding to the protease active site and preventing enzyme activity.

• Inhibition stops the cleavage of viral polyproteins, forming immature, noninfectious viral particles.

Pharmacokinetics

Researchers studied how Saquinavir mesylate, a medicine used in HIV treatment, works in both HIV-1-infected and healthy subjects.

• Comparison in Healthy and HIV-1-infected Subjects: In healthy subjects, the levels of Saquinavir mesylate in the blood (AUC, Cmax, and Cmin) are about 50 percent higher than in HIV-1-infected subjects when taken twice daily.

• Absorption and Bioavailability in Adults: Saquinavir mesylate's effectiveness is similar whether taken as a tablet or a capsule with low-dose Ritonavir under fed conditions. The absorption increases when 600 mg of Saquinavir mesylate is taken with a high-fat meal. The bioavailability of Saquinavir (the active ingredient) could be higher, likely due to incomplete absorption and extensive first-pass metabolism.

• Comparison of Different Doses: Saquinavir mesylate with Ritonavir 1000 per 100 mg twice daily provides similar Saquinavir levels as Saquinavir soft gel capsules with Ritonavir 1000 per 100 mg twice daily and higher levels than Saquinavir soft gel capsules 1200 mg three times daily.

• Food Effect: Taking Saquinavir mesylate with Ritonavir within two hours after a meal is recommended. Food increases Saquinavir levels in the blood, especially with a high-calorie meal.

• Distribution: Saquinavir is distributed into tissues, and about 98 percent is bound to plasma proteins. It shows negligible concentrations in cerebrospinal fluid.

• Metabolism and Elimination: Saquinavir is mainly metabolized by the liver enzyme CYP3A4. After oral administration, most of the radioactivity is recovered in feces (88 percent) and a small amount in urine (one percent). Extensive first-pass metabolism occurs. Systemic clearance is rapid, and Saquinavir has a short residence time in the body.

Non-Clinical Toxicity:Carcinogenesis:

• Saquinavir showed no signs of causing cancer in rats and mice over a two-year study.

• Limited bioavailability in animals resulted in exposures lower than those in humans at the recommended clinical dose of Ritonavir.

Mutagenesis:

• Saquinavir demonstrated no mutagenic activity in various tests, including Ames and Chinese hamster lung V79 or HPRT tests.

• No chromosomal or primary DNA (deoxyribonucleic acid) damage was observed.

Impairment of Fertility:

• In rats, no negative impact on reproductive capabilities or performance was noted in the study.

• However, bioavailability differences in animals meant exposures were about 26 percent of those in humans at the recommended clinical dose with Ritonavir.

Clinical Studies:

In a study, the combination of Saquinavir mesylate and Zalcitabine proved more effective in reducing disease progression in Zidovudine-experienced HIV-1-infected adults compared to monotherapies. Another study showed that Saquinavir mesylate, Zidovudine, and Zalcitabine together led to greater CD4+ cell count increases than alternative combinations in advanced HIV-1 infection with a history of prolonged Zidovudine treatment. The HIV treatment regimens used in these trials are no longer standard care. In the MaxCmin1 trial, Saquinavir gel capsule with Ritonavir demonstrated positive outcomes in a diverse group of HIV-1-infected subjects, with 61 percent achieving and sustaining an HIV-1 RNA of less than 400 copies per mL after 48 weeks of treatment.

What Are the Contraindications of Saquinavir Mesylate?

Saquinavir mesylate has several contraindications, and individuals with certain conditions or using specific medications should avoid its use. Contraindications for Saquinavir mesylate include

1. Hypersensitivity: Do not use Saquinavir mesylate in individuals with a clinically significant hypersensitivity reaction to Saquinavir mesylate, or any of its ingredients.

2. Concomitant Medications: Saquinavir mesylate, especially when administered with Ritonavir, is contraindicated with drugs that are CYP3A substrates, as increased plasma levels may result in serious or life-threatening reactions. Specific drugs contraindicated with Saquinavir and Ritonavir combination include but are not limited to:

• Alfuzosin (alpha 1-adrenoreceptor antagonist).

• Amiodarone, Bepridil, Dofetilide, Flecainide, Lidocaine, Propafenone, and Quinidine (antiarrhythmics).

• Trazodone (antidepressant).

• Rifampin (antimycobacterial agent).

• Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine (Ergot derivatives).

• Cisapride (GI motility agent).

• Lovastatin, Simvastatin (HMG-CoA reductase inhibitors).

• Pimozide (neuroleptic).

• Sildenafil (PDE5 inhibitor).

• Triazolam is orally administered, as is Midazolam (sedative or hypnotic).

Warnings and Precautions:

• Drug Interactions: The combination of Saquinavir mesylate-Ritonavir is a potent CYP3A inhibitor, significantly increasing exposure to drugs metabolized by CYP3A. Some medications are contraindicated due to potentially life-threatening adverse events or significant interactions (mentioned in drug interactions).

• PR Interval Prolongation: Saquinavir with Ritonavir prolongs the PR interval, posing risks for atrioventricular block. ECG monitoring is recommended, especially for patients with underlying heart conditions.

• QT Interval Prolongation: Saquinavir and Ritonavir cause dose-dependent QT prolongation, and caution is advised in patients with specific conditions. ECG monitoring is crucial, and drugs that increase the QT interval should not be combined.

• Diabetes Mellitus or Hyperglycemia: New-onset diabetes or exacerbations have been reported during protease inhibitor therapy. Monitoring and adjustments to insulin or oral hypoglycemic agents may be necessary.

• Hepatotoxicity: Worsening liver disease reports exist in patients with underlying liver conditions.

• Hemophilia: Spontaneous bleeding in hemophiliac patients treated with protease inhibitors has been reported. Additional factor VIII may be required.

• Hyperlipidemia: Elevated cholesterol and triglyceride levels may occur, requiring monitoring and management.

• Lactose Intolerance: Each capsule contains lactose, but intolerance symptoms are not expected.

• Fat Redistribution: Body fat redistribution may occur, and its long-term consequences are unknown.

• Immune Reconstitution Syndrome: Inflammatory responses to opportunistic infections may develop during initial antiretroviral treatment.

• Resistance and Cross-Resistance: Cross-resistance among HIV-1 protease inhibitors may occur, emphasizing the importance of viral suppression maintenance during Saquinavir mesylate therapy.

What Are the Drug Interactions of Saquinavir Mesylate?

The combination of Saquinavir mesylate-Ritonavir acts as a potent inhibitor of CYP3A, potentially leading to a significant increase in the exposure of drugs primarily metabolized by CYP3A.

• Potential for Other Drugs to Influence Saquinavir Mesylate: The metabolism of Saquinavir, facilitated mainly by CYP3A, and its status as a P-glycoprotein (P-gp) substrate indicate that drugs affecting CYP3A and/or P-gp may alter Saquinavir's pharmacokinetics. For instance, concurrent use with potent CYP3A inducers, such as Phenobarbital, Phenytoin, or Carbamazepine, could reduce Saquinavir plasma concentrations, impacting therapeutic efficacy.

• Established and Other Potentially Significant Drug Interactions: Saquinavir mesylate-Ritonavir has shown dose-dependent prolongations of QT and PR intervals, warranting caution with certain drug classes. Additive effects on QT and/or PR interval prolongation may occur with antiarrhythmics, neuroleptics, antidepressive agents, PDE5 inhibitors (for pulmonary arterial hypertension), antimicrobials, antihistaminics, and others, potentially elevating the risk of ventricular arrhythmias.

The following drugs are to be avoided while taking Saquinavir mesylate:

• Alfuzosin.

• Amiodarone.

• Bepridil.

• Cisapride.

• Dofetilide

• Ergot-containing medicines, including Dihydroergotamine mesylate, Ergonovine, Ergotamine tartrate, and others.

• Flecainide.

• Lidocaine.

• Lovastatin.

• Midazolam hydrochloride oral syrup.

• Pimozide.

• Propafenone.

• Quinidine.

• Rifampin.

• Sildenafil.

• Simvastatin.

• Trazodone.

• Triazolam.

Specific Considerations:

• Pregnancy: Saquinavir mesylate, based on reproductive studies in rats and rabbits, has demonstrated no embryotoxicity or teratogenicity. However, due to limited bioavailability and dosing constraints, plasma exposures (AUC values) in rats and rabbits were approximately 29 percent and 21 percent of those observed in humans at the recommended clinical dose boosted with Ritonavir. Clinical experience in pregnant women is limited, and the use of Saquinavir in pregnant individuals should be contemplated using Saquinavir only if the anticipated advantages surpass the potential risks to the fetus. A registry for antiretroviral use during pregnancy has been created to oversee the maternal-fetal outcomes of expectant women exposed to antiretroviral medications, including Saquinavir mesylate.

• Nursing Mothers: HIV-infected mothers are advised by the Centers for Disease Control and Prevention not to breastfeed to prevent postnatal transmission of HIV-1. The excretion of Saquinavir mesylate in human milk is unknown. Due to the potential risks of transmission of HIV-1 and the occurrence of severe adverse reactions in breastfeeding infants, mothers receiving Saquinavir mesylate should refrain from breastfeeding.

• Pediatric Use: Saquinavir's safety and efficacy were assessed in 68 pediatric subjects aged four months to less than 16 years treated with Saquinavir mesylate boosted with Ritonavir or Lopinavir or Ritonavir in two clinical trials. While saquinavir boosted with Ritonavir provided significantly higher plasma levels than observed in adults, long-term data from the HIVNAT 017 trial indicated favorable outcomes in pediatric subjects.

Steady-state Saquinavir exposures in pediatric trials were notably higher than in adults, raising concerns about dose-dependent QTc and PR prolongation. Reducing the saquinavir mesylate dose to minimize QT prolongation risk may compromise antiviral efficacy. Reliable and safe pediatric dose recommendations below QT and PR prolongation thresholds could not be established.

• Geriatric Use: Clinical trials lacked sufficient subjects aged 65 and over to determine whether elderly individuals respond differently. Caution should be exercised when dosing Saquinavir mesylate in elderly patients, considering potential differences in hepatic, renal, or cardiac function and the prevalence of concomitant diseases or drug therapies.

• Impaired Renal Function: Renal clearance is a minor elimination pathway for Saquinavir, and patients with renal impairment do not require an initial adjustment in dosage. However, caution is advised in cases of severe renal impairment or end-stage renal disease (ESRD), as such populations have not been studied.

• Impaired Hepatic Function: Patients infected with HIV-1 and experiencing mild or moderate hepatic impairment do not necessitate a dosage adjustment. However, caution is necessary for patients with underlying liver conditions, as there have been reports of worsening liver disease. Saquinavir mesylate with Ritonavir is contraindicated in severe hepatic impairment.