Crixivan Indinavir

In some circumstances, the FDA processes drug reviews under the accelerated scheme. This mechanism is to review and approve drugs speedily for cases where effective therapies are lacking or in situations of rare diseases. One of the fastest approval times to date is the case of imatinib mesylate (Gleevec, Novartis—Exhibit 7.3) for the treatment of chronic myeloid leukemia (CML) it was approved in less than 3 months after the filing of an NDA with the FDA. Another example is the new AIDS drug indinavir (Crixivan, Merck), which was approved in a mere 42 days. 

Imipenem (Primaxin) Indapamide (Lozol) Indinavir (Crixivan)... 

Indinavir (Crixivan) is a potent inhibitor of HIV reverse transcriptase. It produces the side effects common to aU protease inhibitors and also may produce nephrolithiasis, urolithiasis, and possibly renal insufficiency or renal failure. This problem occurs more fre-... 

Figure 2.2. Timeline of fast-track development of an HIV protease inhibitor, indinavir Crixivan) by Merck through a project research team approach. Adapted from Merck s account on Crixivan development.

The key goals of the reaction network from indene to as- (IS, 2 J )-indanediol, an intermediate via as-aminoindanol to indinavir (Crixivan ), Merck s HIV protease inhibitor, are to enhance toluene dioxygenase over monooxygenase activity, and to avoid degradation of cis-(lS,2J )-indanediol. Still to achieve are a low enough by-product spectrum and commercially attractive yields. 

In Chapter 13, Section 13.3.3, we discussed indinavir (Crixivan ), Merck s HIV protease inhibitor, which is currently manufactured via a chemical synthesis route. An alternative biocatalytic route, at least to intermediates, briefly discussed in Sec-... 

Indinavir/Crixivan (IDV) 200, 333, or 400mg capsules 800 mg q. 8h or 800 mg b.i.d. with ritonavir Nephrolithiasis, Gl intolerance, hyperbihrubinemia, metabolic complications 108... 

Indinavir. When administered with a high fai diet, indinavir (Crixivan) achieves a maximum serum concentration of V< ul the administered dose. The drug is 60% bound in the plasma. It is extensively metabolized by CYP 3A4, and seven metabolites have been identified. Oral bioavail-abiiity is good, with a of 0.8 0.3 hour. The half-life of elimination is 1.8 hour, nnd the elimination products are delectable in feces and urine. Indinavir also causes dyslipide-mm. The available dosage forms are capsules of 200, 333, and dOO mg. 

James, J. Indinavir (Crixivan) Access and Distribution. AIDS Treatment News, 5 April 1996. 

Figure 35.22 Compound optimization. Four compounds are evaluated for characteristics including the IC50 (the compound concentration required to reduce HIV replication to 50% of its maximal value), log P, and c ax (the maximal concentration of compound present) measured in the serum of dogs. The compound shown at the bottom has the weakest inhibitory power (measured by IC50) but by far the best bioavailability (measured by Cmax)- f compound was selected for further development, leading to the drug indinavir (Crixivan).

The development of practical routes to the title compound has been the focus of intensive research effort since cis-aminoindanol was identified as a critical component of the highly effective HIV protease inhibitor indinavir (Crixivan ).7,8 Reported routes include racemate synthesis followed by resolution via diastereomeric salts,8 enzymatic resolution,9 and asymmetric hydroxylation.10 However, the use of a modified Ritter... 

PI disables protease, a protein that HIV needs to make more copies of itself. Drugs within this category include Amprenavir (Agenerase, APV), Atazanavir (Reyataz, ATV), Fosamprenavir (Lexiva, FPV), Indinavir (Crixivan, IDV), Lopinavir, Ritonavir (Kaletra, LPV/r), Nelvinavir (ViracepL NFV), Ritonavir, (Norvir, RTV), and Saquinavir (Fortovase, SQV Invirase). 

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