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

Cundy, Kenneth C.; Barditch‐Crovo, Patricia; Walker, Robert; Collier, Ann C.; Ebeling, Dorothea; Toole, John J.; Jaffe, Howard S.

doi:10.1128/aac.39.11.2401

Cited by 126 publications

(81 citation statements)

References 17 publications

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“…The histopathologies of the three animals that were euthanized after chronic dosing with PMPA at 30 mg/kg revealed renal tubular atrophy and degeneration as common lesions. This toxicity of PMPA is probably related to its renal clearance; studies with animals and humans indicate that PMPA and its related nucleotide analogs are excreted in unchanged form in urine through a combination of renal filtration and active tubular secretion (10,14,15,16). Thus, accumulation of drug in tubular epithelial cells (due to more drug uptake from plasma than secretion into the tubular lumen) may be the direct cause of these renal effects.…”

Section: Discussionmentioning

confidence: 99%

Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

Rompay

Brignolo

Meyer

et al. 2004

Antimicrob Agents Chemother

127

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The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.In recent years, the discovery of novel potent antiretroviral drugs has led to significant advances in the clinical management of human immunodeficiency virus (HIV)-infected patients (9). Although combination therapy is able to suppress virus replication in many patients, a number of problems, including incomplete suppression of virus replication, the emergence of drug-resistant viral mutants, the difficulty of patients' adherence to complicated dosage regimens, and the occurrence of intolerable side effects, preclude prolonged therapy. Relative to adult HIV infection, these problems associated with drug therapy are even more accentuated in pediatric HIV infection (60). Accordingly, there is an urgent need for better and safer antiviral drugs with less complex dosage regimens for use by children and adults.Simian immunodeficiency virus (SIV) infection of newborn and infant macaques is a practical animal model of pediatric HIV infection that allows researchers to test the efficacies of novel antiviral drugs. Studies with this animal model demonstrated that a once-daily dosage regimen of the acyclic nucleoside phosphonate 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was highly efficacious for prophylaxis and therapy, most remarkably, even in the presence of viral mutants with reduced susceptibility to PMPA in vitro (49-53, 55, 56).The focus of the pr...

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Section: Discussionmentioning

confidence: 99%

Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

Rompay

Brignolo

Meyer

et al. 2004

Antimicrob Agents Chemother

127

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“…Preliminary data in animals also indicates that the bioavailability of alamifovir may decrease when it is given with food. In contrast, the oral bioavailability of the broad-spectrum antiviral adefovir was approximately 4% in cynomolgus monkeys (5,17) and less than 12% in humans (4). Therefore, in comparison to adefovir, alamifovir has shown greater oral bioavailability.…”

mentioning

confidence: 86%

“…For study 1, serial venous blood samples (15 ml) for the determination of alamifovir, 602074, 602075, and 602076 concentrations in plasma were collected into glass tubes containing sodium heparin via an indwelling cannula. Blood samples were collected just prior to dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4,6,8,12,24,36,48, and 72 h postdose during each treatment period. Samples were immediately centrifuged for 10 min at 2,000 ϫ g and at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Clinical Pharmacokinetics of Alamifovir and Its Metabolites

Chan

Abu-Raddad

Golor³

et al. 2005

Antimicrob Agents Chemother

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Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclincal efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single-and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.2 to 80 mg), with a subset receiving 20 mg in a fed state. Study 2 subjects were dosed with 2.5 to 15 mg twice daily for 15 days. Plasma samples were collected over 72 h in study 1 and over 24 h on days 1 and 15 in study 2. Concentrations of alamifovir and its major metabolites were determined using liquid chromatography/tandem mass spectrometry methods. The data were analyzed using a noncompartmental technique. Although alamifovir was rapidly absorbed, there was limited systemic exposure due to its rapid hydrolysis and formation of at least three metabolites, suggesting that alamifovir acts as a prodrug. The major metabolites detected were 602074 and 602076, with 602075 detectable only in higher-dose groups. Maximum 602074 plasma concentration was achieved at approximately 0.5 h (T max ) and declined with a 1-to 2-h terminal half-life (t 1/2 ). Maximum concentrations of 602076 (C max ) averaged 10% of the 602074 C max and reached T max in 2.5 h with a 4-h t 1/2 . Food appeared to decrease the extent of absorption of the compound. Multiple dosing resulted in minimal accumulation, and the concentrations following multiple doses could be predicted using the single-dose data. Alamifovir was well tolerated and the pharmacokinetics were characterized in these studies.

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“…4,5 Its oral pro-drug is adefovir dipivoxil, which is a butyl ester of PMEA. Therefore, PMEA is used in the treatment of chronic hepatitis B.…”

Section: 3mentioning

confidence: 99%

The effects of ionic strength and temperature on the dissociation constants of adefovir and cidofovir used as antiviral drugs

Atabey¹,

Sarı

2014

Turk J Chem

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Abstract:The effects of ionic strength and temperature on the dissociation constants of adefovir (PMEA) and cidofovir (HPMPC) used as antiviral drugs were studied at 298 K, 308 K, and 318 K in aqueous media and at different ionic strength backgrounds of NaCl potentiometrically. The dissociation constants of the ligands were determined via the calculation of the titration data with the SUPERQUAD computer program. The thermodynamic parameters ( ∆G , ∆H , and ∆S) for all species were calculated. The dissociation order of nitrogen and oxygen atoms in the ligands according to proton affinities values were obtained using PM6 semiempirical methods. Moreover, p Ka values of the ligands were determined at 0.00, 0.10, 0.15, 0.20, and 0.5 mol dm −3 ionic strength (NaCl) at 298 K. Consequently, when the ionic strength and temperature in the titration cells were increased, the obtained dissociation constants of PMEA (p Ka3 , p Ka4 , and p Ka5) and HPMPC (p Ka2 and p Ka3) decreased.

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

Cited by 126 publications

References 17 publications

Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

Clinical Pharmacokinetics of Alamifovir and Its Metabolites

The effects of ionic strength and temperature on the dissociation constants of adefovir and cidofovir used as antiviral drugs

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