Quantitation of didanosine in human plasma and urine by high-performance liquid chromatography

Knupp, Catherine A.; Stancato, Frank A.; Papp, E; Barbhaiya, Rashmi H.

doi:10.1016/s0378-4347(00)82215-x

Cited by 52 publications

(22 citation statements)

References 11 publications

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“…The excess CL of cidofovir above the level of glomerular filtration must have been a consequence of active tubular secretion of the drug in the kidney. Similar renal tubular secretion has been reported for structurally related antiviral nucleoside analogs, including stavudine (6) and didanosine (7).…”

Section: Discussionsupporting

confidence: 76%

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

Cundy

Petty

Flaherty

et al. 1995

Antimicrob Agents Chemother

178

107

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The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean ؎ standard deviation terminal half-life of 2.6 ؎ 1.2 h (n ‫؍‬ 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean ؎ standard deviation total clearance of the drug from serum (148 ؎ 25 ml/h/kg; n ‫؍‬ 25) approximated renal clearance (129 ؎ 42 ml/h/kg; n ‫؍‬ 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 ؎ 21 ml/h/kg; n ‫؍‬ 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.Cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) is an acyclic nucleotide analog with potent activity against a broad spectrum of herpesviruses, including cytomegalovirus (CMV). The in vivo and in vitro antiviral activities of cidofovir have been reviewed (1). Unlike ganciclovir and other nucleoside analogs currently used for clinical therapy of human herpesvirus infections, cidofovir does not depend on phosphorylation by viral nucleoside kinases to exert its antiviral effect (2). Instead, the drug is phosphorylated to its active form by cellular enzymes. In vitro studies have suggested that the resulting active metabolites are cleared slowly from the intracellular space (2).Preclinical pharmacokinetic studies with radiolabelled cidofovir in rats and mice (10) and in rabbits and monkeys (3) have demonstrated that the majority of the drug is distributed to the kidneys and is excreted in the urine within 24 h of intravenous administration. In monkeys, a fraction of the radioactive dose (approximately 10%) was excreted in a slow elimination phase, with a terminal elimination half-life of 24 to 35 h. This slower excretion phase may reflect the long intracellular half-life of the phosphorylated metabolites of cidofovir (2). In both monkeys and rabbits, approximately 98% of the excreted radioactive dose was present in the urine as unchanged drug. The oral bioavailability of the drug was estimated to be 3% i...

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Section: Discussionsupporting

confidence: 76%

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

Cundy

Petty

Flaherty

et al. 1995

Antimicrob Agents Chemother

178

107

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“…The excess CL of adefovir above the level of glomerular filtration must have been a consequence of active tubular secretion of the drug in the kidney. Similar renal tubular secretion has been reported for structurally related antiviral nucleotide and nucleoside analogs, including cidofovir (9), stavudine (12), and didanosine (15).…”

Section: Discussionsupporting

confidence: 73%

Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients

Cundy

Barditch‐Crovo

Walker

et al. 1995

Antimicrob Agents Chemother

127

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The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean ؎ standard deviation terminal half-life of 1.6 ؎ 0.5 h (n ‫؍‬ 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean ؎ standard deviation total serum clearance of the drug (223 ؎ 53 ml/h/kg; n ‫؍‬ 25) approximated the renal clearance (205 ؎ 78 ml/h/kg; n ‫؍‬ 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 ؎ 18 ml/h/kg; n ‫؍‬ 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 ؎ 76 ml/kg; n ‫؍‬ 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n ‫؍‬ 8) and 3.0 mg/kg/day (n ‫؍‬ 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was <12% (n ‫؍‬ 5) on the basis of the concentrations in serum or 16.4% ؎ 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% ؎ 8.3% (n ‫؍‬ 5) on the basis of concentrations in serum or 84.8% ؎ 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.

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“…DDI and 3TC plasma concentrations were determined with a modified version of a validated reverse-phase high-performance liquid chromatography (HPLC) assay based on ultraviolet wave absorbance. The limits of quantification were 0.01 mg/l for DDI, 14,15 0.025 mg/l for 3TC, 16 and 0.5 mg/l for efavirenz.…”

Section: Pharmacokinetic Studymentioning

confidence: 95%

Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial

Nacro

Zouré

Hien

et al. 2011

Bull. World Health Organ.

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Quantitation of didanosine in human plasma and urine by high-performance liquid chromatography

Cited by 52 publications

References 11 publications

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients

Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial

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