Indinavir development

A 37-year-old HIV-infected woman receiving stavudine, lamivudine, and indinavir developed epigastric pain, anorexia, and vomiting. She had lactic acidosis (serum lactate 4.9 mmol/1), raised liver enzymes, and an increased prothrombin time. She had hepatomegaly and tachypnea and required mechanical ventilation. Her progress was complicated by pancreatitis and acute respiratory distress syndrome. Antiviral medication was stopped and she was treated with co-enzyme Q, carnitine, and vitamin C. The serum lactic acid and transaminases returned to normal over 4 weeks and she was weaned off the ventilator after 4 months. 

In a retrospective analysis of 198 normotensive patients in a protease inhibitor comparison study, 30% of those who took indinavir developed stage I or worse hypertension, compared with none of the patients who took nelfinavir, ritonavir, or saquinavir (2). 

HIV-positive/AIDS patients using indinavir develop rashes early in treatment, a finding that is familiar with various other drugs used in this condition. This problem has been quantified in a study using data from postmarketing surveillance (27). Of 110 HIV/AIDS patients with a rash, 67% reported that it had occurred within 2 weeks of the start of indinavir therapy. The rash was initially localized in aU cases, but in the majority it went on to spread to other body areas, involving aU parts of the body in no less than 44%. It was usually pruritic but not accompanied by fever. Relief was often obtained by use of topical antihistamines or oral or topical glucocorticoids. More than half the patients decided to continue therapy despite the rash. 

In 1995 the FDA approved saquinavir, the first protease inhibitor, for use in combination with other nucleoside analogue medications. In 1999 a soft gel capsule formulation of saquinavir with considerably improved absorption characteristics was developed. Ritonavir and indinavir have been approved for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Nelfinavir is the first protease inhibitor labeled for use in children. Amprenavir is the newest of the protease inhibitors. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because the fat content may decrease the absorption of the drug. The most disturbing adverse reactions to protease inhibitors consist of the lipodystrophy syndrome with severe hyperlipidemia and unpredictable fat redistributions over the body... 

Indinavir sulfate may be analyzed by TLC using E. Merck silica gel 60F-254 high performance thin layer chromatographic plates, and eluted with a mobile phase of 8 1 1 (v/v/v) ethyl acetate methanol ammonium hydroxide [8], Visualization was performed by developing the plate with iodine stain, and viewing under short-wave UV (254 nm) light. When using this method, the Rf of indinavir sulfate is approximately 0.6 [8]. 

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.

Indinavir is a protease inhibitor used in the management of HIV infection. CYP3A4 mediates the biotransformation of indinavir in vitro (85,86), and in vivo, indinavir has been shown to be a potent competitive and mechanism-based inhibitor of CYP3A4 (85,87). Piscitelli and coworkers (80) examined the effect of St. John s wort (300 mg t.i.d. x 14 days) administration on indinavir (800 mg q.i.d. x 8 hr x four doses) exposure in eight healthy volunteers (two females). The administration of St. John s wort for 14 days resulted in a significant 54 /o reduction in the indinavir eight-hour area under the concentration-time curve, from 35.8 13.0 to 15.6 5.8 pg X hr/mL. The authors conclude that the magnitude in the reduction in indinavir concentrations may result in the development of antiretroviral resistance and subsequent treatment failure. 

In rats, high doses of indinavir are associated with development of thyroid adenomas. 

A retrospective analysis of the development of diabetes in 1011 patients has been summarized (163). All were nondiabetic when antiretroviral treatment was started. Over 10 months, diabetes was diagnosed in 16 patients (2.06 per 100 person-years). Older age (HR = 1.1, 1.06-1.16) was associated with a higher risk. In multivariate analysis adjusted for age and sex, the onset of diabetes was not related to CD4 cell count, viral load, or type of antiviral therapy (with or without protease inhibitors). However, patients taking stavudine or indinavir were at significantly higher risks (stavudine HR = 16, 95% Cl — 3, 84 indinavir HR = 4.0,95% Cl = 1.3,13). The strong association of stavudine with diabetes is surprising and needs further confirmation. 

Two case reports have suggested that when a protease inhibitor is used with a glucocorticoid the tendency to adverse corticosteroid effects is potentiated (969,970). Two HIV-positive patients developed severely disfiguring skin striae within 3 months of starting indinavir therapy (971). 

Buffalo neck was described in a middle-aged man taking indinavir who developed a lipomatous formation in the retrocervical area abdominal fat also increased in volume, while the subcutaneous fat on the lower limbs decreased (995). 

HIV-1 genetic resistance to protease inhibitors occurs via specific mutations. Genotypic analysis of the HIV protease gene from isolates selected in vitro indicated that Gly48Val and Leu90Met mutants had reduced susceptibility to saquinavir (Ohta, 1997). Indinavir and ritonavir resistance maps to residue 82, whereas for amprenavir the key mutation is at residue 50 (I50V) and confers a threefold decline in viral sensitivity to amprenavir. Two additional mutations at residues 46 and 47 follow development of mutation at position 50, resulting in a 20-fold de-... 

The most common adverse effects are indirect hyperbilirubinemia and nephrolithiasis due to crystallization of the drug. Nephrolithiasis can occur within days after initiating therapy, with an estimated incidence of 3-15%, and may be associated with renal failure. Consumption of at least 48 oz of water daily is important to maintain adequate hydration and prevent nephrolithiasis. Thrombocytopenia, elevations of serum aminotransferase levels, nausea, diarrhea, and irritability have also been reported. There have also been rare cases of acute hemolytic anemia. In rats, high doses of indinavir are associated with development of thyroid adenomas. 

The single enantiomer of indinavir has five stereogenic centers, four of which are derived either directly or indirectly from epoxide (27). Synthesis of indinavir sulfate developed by Merck is shown in Scheme-3. 

A 34-year-old man with AIDS took risperidone 4 mg/ day for a Tourette-like tic disorder. Ritonavir and indinavir were added, and 1 week later he developed significantly impaired swallowing, speaking, and breathing, and worsening of his existing tremors. 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

Failure of antiretroviral drug therapy has been attributed to an interaction of carbamazepine with indinavir in a 48-year-old man taking indinavir, zidovudine, and lamivudine his HIV-RNA viral load became undetectable after less than 2 months and he developed a Herpes zoster infection (87). Lower doses of carbamazepine are also required during co-administration of ritonavir, as has been shown in two recent cases. 

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