Treatment of AIDS and AIDS-Related Complex with 2′,3′-Dideoxyinosine Given Once Daily

Cooley, Timothy P.; Kunches, Laureen M.; Saunders, Carol A.; Perkins, Christopher J.; Kelley, Susan L.; McLaren, Colin; McCaffrey, Ronald P.; Liebman, Howard A.

doi:10.1093/clinids/12.supplement_5.s552

Cited by 41 publications

(18 citation statements)

References 21 publications

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“…However, its oral therapy is associated with poor gastrointestinal (GI) tolerability, narrow therapeutic index, several dose dependent side effects, e.g., peripheral neuropathy, lactic acidosis and pancreatitis (11). In addition, oral administration of didanosine suffers from poor GI stability at pH < 3.0, first pass metabolism and variable absorption leading to poor bioavailability of 35-40% (12). This problem, together with the need for frequent dosing, low plasma protein binding (< 5%), brief plasma elimination half-life (30 min to 4 h) points to the need to develop a suitable alternative dosage form of didanosine.…”

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confidence: 99%

Mannan-coated gelatin nanoparticles for sustained and targeted delivery of didanosine: In vitro and in vivo evaluation

Kaur¹,

Jain²,

Tiwary³

2008

Acta Pharmaceutica

100

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confidence: 99%

Mannan-coated gelatin nanoparticles for sustained and targeted delivery of didanosine: In vitro and in vivo evaluation

Kaur¹,

Jain²,

Tiwary³

2008

Acta Pharmaceutica

100

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“…Intracellular 5'-triphosphate metabolites of ddl mediate anti-human immunodeficiency virus activity by inhibition of viral reverse transcriptase and by their incorporation into DNA chains, resulting in chain termination (3,8). The favorable in vitro activity-toxicity profile of ddl, as well as its long intracellular half-life of more than 12 h (1), has prompted a number of clinical trials of ddI as a potential anti-AIDS drug.Pharmacokinetic studies of ddl have been completed in mice (11), in rats (2, 9), and in patients with AIDS (4,5,7,12). Total systemic clearance and the elimination half-life in rodents were different from those in humans (elimination half-life ranged from 5 to 28 min in rodents and ranged from 38 min to 1.6 h in humans).…”

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confidence: 99%

“…Pharmacokinetic studies of ddl have been completed in mice (11), in rats (2, 9), and in patients with AIDS (4,5,7,12). Total systemic clearance and the elimination half-life in rodents were different from those in humans (elimination half-life ranged from 5 to 28 min in rodents and ranged from 38 min to 1.6 h in humans).…”

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confidence: 99%

“…The percentage of ddl excreted unchanged in the urine of humans is 36% (7), i.e., about 16% more than in monkeys. Pharmacokinetic analysis of the phase I ddI data (4,5,12) indicates a CLT of 0.686 liters/h/kg, a volume of distribution at steady state of 0.73 liters/kg, and an elimination half-life of approximately 1.4 h (6). These values agree closely with those in this study.…”

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confidence: 99%

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Pharmacokinetics of 2',3'-dideoxyinosine in monkeys

Qian

Finco

Swagler

et al. 1991

Antimicrob Agents Chemother

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Comparison of the pharmacokinetic parameters obtained for dideoxyinosine (ddl) in monkeys with those obtained for humans indicates that the monkey is an appropriate animal model for ddl pharmacokinetics in humans. Following intravenous administration of 20 mg of ddI per kg of body weight and measurement of ddl in plasma and urine by high-performance liquid chromatography, pharmacokinetic parameters were determined by noncompartmental analysis. Total systemic clearance was 0.74 liters/h/kg, volume of distribution was 0.92 liters/kg, and the elimination half-life of ddI was 1.22 h. The pharmacokinetics of ddl in five monkeys were determined following intravenous administration of 20 mg/kg and were found to be comparable to those obtained in patients with AIDS.2',3'-Dideoxyinosine (ddl) is a purine nucleoside analog that suppresses the infectivity and the cytopathic effect of human immunodeficiency virus in vitro (8). Intracellular 5'-triphosphate metabolites of ddl mediate anti-human immunodeficiency virus activity by inhibition of viral reverse transcriptase and by their incorporation into DNA chains, resulting in chain termination (3,8). The favorable in vitro activity-toxicity profile of ddl, as well as its long intracellular half-life of more than 12 h (1), has prompted a number of clinical trials of ddI as a potential anti-AIDS drug.Pharmacokinetic studies of ddl have been completed in mice (11), in rats (2, 9), and in patients with AIDS (4,5,7,12). Total systemic clearance and the elimination half-life in rodents were different from those in humans (elimination half-life ranged from 5 to 28 min in rodents and ranged from 38 min to 1.6 h in humans). The fractional urinary elimination and renal clearance of ddl have been reported in humans (7) but not in animals. Thus, at present there is not an abundance of pharmacokinetic data for ddl in animals, and of the species studied none appear to be suitable animal models for ddl pharmacokinetics in humans. Characterization of the pharmacokinetics of ddl in animals and hopefully, identification of an appropriate animal model will be useful in designing future studies, such as pharmacokinetic evaluations of drug interactions between anti-human immunodeficiency virus nucleosides. The current investigation was undertaken to determine the pharmacokinetics of ddl and to determine in what capacity monkeys would serve as an animal model for ddl pharmacokinetics. Five adult male monkeys (Macaca fascicularis), each weighing from 4.09 to 5.34 kg, were used for the pharmacokinetic study, after receiving approval from the University of Georgia Animal Care and Use Committee. Each animal was administered 20 mg of ddl prepared in sterile normal saline per kg of body weight intravenously (i.v.) into a leg vein over 1 min. For ddI administration and at blood collection times, animals were transferred to a device that provided access to the leg vein without anesthesia. Immediately following dosing, each animal was placed in a metabolism cage to facilitate

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“…13 It is not yet possible to determine the mechanism of ddl-induced hepatotoxic effects. The following theories have been proposed: (1) incorporation of the phosphorylated cytoplasmic form of ddl (ddATP [adenosine triphosphate]) into mitochondrial DNA might lead to mitochondrial dysfunction and resulting hepatotoxic effects 12 ; (2) ddlstimulated hepatic glycolysis in vitro might lead to a reduction in the hepatic glycogen stores with a decrease in glycolytic ATP production.…”

Section: Resultsmentioning

confidence: 99%