150378-17-9

Crixivan was launched in Australia, Switzerland, the UK and the US as an orally-bioavailable HIV-1 protease inhibitor. The compound can be prepared by coupling an optically active piperazine derivative with an epoxide derivative (now commercially available). The synthesis of the proteins, reverse transcriptase, integrase, structural proteins and a protease, required by the virus to complete its lifecycle, can be interupted if the protease enzyme is not capable of cleaving a proform polypeptide chain into these components. lndinavir inhibits this process and is more potent than the first approved protease inhibitor saquinavir. This effect was noted by the increase in CD4⁺ cells and a decrease in HIV RNA levels. Since indinavir is metabolized by the CYP3A4 isozyme, care must be taken with patients with hepatic insufficiency and to sex-related differences in the level of this enzyme. Other than nephrolithiasis (5%), indinavir is relatively safe and well tolerated.

Monohydrate: Crystallizes from wet ethyl acetate or isopropyl acetate. Loss of water below 100°C and recrystallization yields the anhydrate, melting point 153-154°C; the second anhydrate melts at 167.5-168°C. Solubility in water (mg/ml): 0.015 (without buffer), >1.5 (pH 4.0). [α]D22+24.1. (C=0.0133, chloroform). Indinavir Sulfate: C36Ha7N5O4?H2SO4. [157810-81-6]. Appears as a monoethanolate. Crystallizes from anhydrous ethanol, softening point 135°C, melting point 150-153°C (decomposition). Hydrates form upon loss of ethanol or exposure to moisture.

Merck (USA)

Indinavir is a member of the novel hydroxyaminopentane amide class of HIV-1 protease inhibitors. Indinavir is used as an antiviral.

ChEBI: Indinavir is a N-(2-hydroxyethyl)piperazine, a piperazinecarboxamide and a dicarboxylic acid diamide. It has a role as a HIV protease inhibitor.

Indinavir (Crixivan) is a potent inhibitor of HIV reverse transcriptase. It produces the side effects common to all protease inhibitors and also may produce nephrolithiasis, urolithiasis, and possibly renal insufficiency or renal failure. This problem occurs more frequently in children (approximately 30%) than adults (approximately 10%) and can be minimized by drinking at least 1.5 L of water daily. Additional side effects include asymptomatic hyperbilirubinemia, alopecia, ingrown toenails, and paronychia. Hemolytic anemia rarely occurs. Rifampin should not be given with indinavir.

Crixivan

The major mutations in the protease enzyme associated with loss of the antiretroviral activity occur at positions 46, 82 and 84. Generally, the level of resistance rises with the number of point mutations.

When administered with a high-fat diet, indinavir(Crixivan) achieves a maximum serum concentration of77% of the administered dose. The drug is 60% bound inthe plasma. It is extensively metabolized by CYP3A4, andseven metabolites have been identified. Oral bioavailabilityis good, with a t_max of 0.8±0.3 hour. The half-life ofelimination is 1.8 hour, and the elimination products aredetectable in feces and urine. Indinavir also causes dyslipidemia.The available dosage forms are capsules of 200 mg,333 mg, and 400 mg.

A synthetic compound formulated as the sulfate for oral administration.

Oral absorption: c. 65%v C_max 800 mg thrice daily: c. 8.97 mg/L
C_min 800 mg thrice daily: c. 0.15 mg/L
Plasma half-life: c. 2 h
Volume of distribution: c. 0.4–1.74 L/kg
Plasma protein binding: c. 60%
Absorption and distribution
It is rapidly absorbed and not significantly affected by intake with food. Distribution in the body has not been fully characterized. It penetrates well into the CNS. The semen:plasma ratio is 1.9. It is distributed into breast milk.
Metabolism and excretion
Seven major metabolites have been described, including a glucuronide conjugate and six oxidative metabolites. Around 83% of the dose is recovered in feces and 18% in urine, 10% as unchanged drug. The effect of renal impairment has not been studied. It should be used with caution in the presence of hepatic impairment, particularly if severe.

Treatment of adult HIV infection (in combination with other antiretroviral drugs)

The principal side effect is nephrolithiasis, including flank pain with or without hematuria. There is good evidence that indinavir directly causes nephrolithiasis as a result of crystallization in the urinary tract. Indirect hyperbilirubinemia occurs in about 10% of patients associated with inhibition of bilirubinconjugating activity occurring as a result of competitive inhibition of uridine diphosphate (UDP)-glucuronosyltransferase.
Ritonavir-boosted indinavir is associated with a dyslipidemia profile characteristic of those treated with other protease inhibitors boosted with a 200 mg dose of ritonavir per day. Insulin resistance and hyperglycemia have also been associated with ritonavir-boosted indinavir.

Potentially hazardous interactions with other drugs
Anti-arrhythmics: possibly increased amiodarone and flecainide concentration - avoid.
Antibacterials: rifampicin increases metabolism - avoid concomitant use; increased rifabutin concentration - avoid; avoid with telithromycin in severe renal and hepatic failure.
Anticoagulants: avoid with apixaban and rivaroxaban.
Antidepressants: concentration reduced by St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenytoin, primidone and phenobarbital, also concentration of carbamazepine, fosphenytoin and phenytoin increased.
Antifungals: itraconazole and ketoconazole inhibits metabolism - reduce dose of indinavir to 600 mg every 8 hours.
Antimalarials: use artemether/lumefantrine with caution; possibly increased quinine concentration.
Antipsychotics: possibly increased risk of ventricular arrhythmias with pimozide - avoid; possibly inhibits aripiprazole metabolism - reduce aripiprazole dose; possibly increases lurasidone and quetiapine concentration - avoid.
Antivirals: avoid with atazanavir; concentration reduced by efavirenz, nevirapine and possibly etravirine, avoid with etravirine; concentration of both drugs increased with darunavir; concentration of maraviroc increased, consider reducing maraviroc dose; concentration increased by ritonavir; saquinavir concentration increased.
Anxiolytics and hypnotics: increased risk of prolonged sedation with alprazolam and midazolam - avoid.
Avanafil: concentration of avanafil possibly increased - avoid.
Ciclosporin: concentration of ciclosporin increased.
Colchicine: possibly increases risk of colchicine toxicity, avoid in hepatic or renal impairment.
Cytotoxics: possibly increases concentration of axitinib, reduce dose of axitinib; possibly increases bosutinib, cabazitaxel and docetaxel concentration - avoid or reduce dose of bosutinib, cabazitaxel and docetaxel; possibly increases concentration of crizotinib and everolimus - avoid; possibly increases ibrutinib concentration, reduce dose of ibrutinib; avoid with olaparib and pazopanib; reduce dose of ruxolitinib.
Ergot alkaloids: risk of ergotism - avoid.
Guanfacine: possibly increases guanfacine concentration, halve dose of guanfacine.
5HT1 agonists: concentration of eletriptan increased - avoid.
Lipid-regulating drugs: avoid with lomitapide increased risk of myopathy with rosuvastatin and simvastatin - avoid; and possibly with atorvastatin.
Naloxegol: possibly increases naloxegol concentration - avoid.
Orlistat: absorption possibly reduced by orlistat.
Ranolazine: possibly increases ranolazine concentration - avoid.
Sildenafil: concentration of sildenafil increased - reduce initial sildenafil dose.
Vardenafil: concentration of vardenafil increased - avoid.

The usual oral dose for indinavir alone or in combination with other antiviral agents is one 800 mg capsule every 8 hours. The drug is well absorbed if given on an empty stomach or 1 hour before or 2 hours after a light meal with water. The dose is reduced to 600 mg every 8 hours if given concurrently with ketoconazole. Indinavir activity is increased when combined with RT inhibitors.