Systemic and Renal Pharmacokinetics of Adefovir and Tenofovir Upon Coadministration

Abstract

Adefovir and tenofovir are nucleotide analogs that undergo renal secretion by the human renal organic anion transporter. The pharmacokinetics of tenofovir and adefovir following the administration of tenofovir disoproxil fumarate and adefovir dipivoxil alone and together were determined in 24 healthy subjects in an 8-day, open-label, fixed-sequence study. Subjects received oral doses of adefovir dipivoxil on days 1 and 8 and oral doses of tenofovir disoproxil fumarate on days 2 to 8. Pharmacokinetic sampling was performed on days 1, 7, and 8. The plasma pharmacokinetics of tenofovir and adefovir were unaltered upon coadministration. Furthermore, the renal clearances (CLrenal) of tenofovir and adefovir were unaffected by their coadministration. The plasma Cmax values of tenofovir and adefovir were 33-fold and 340-fold lower than their Km values for the human renal organic anion transporter. These results demonstrate that coadministration of tenofovir disoproxil fumarate and adefovir dipivoxil does not result in substantial changes to their individual pharmacokinetic profiles.

Fatal Pancreatitis in Simian Immunodeficiency Virus SIV mac251 -Infected Macaques Treated with 2′,3′-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade

“…Also, the maximum plasma concentration of ddI can be increased when it is administered in combination with PMPA (tenofovir) (15), thus increasing ddI-related toxicity, including pancreatitis and lactic acidosis (24). A portion of ART-treated HIV-infected individuals develop pancreatitis accompanied by increased plasma lipase and diabetes, but ART-related pancreatitis is normally lower in incidence and symptoms are milder than what was observed here (17,19).…”

“…ART-related toxicity can result in pancreatitis and diabetes in both humans and macaques (1,15,17,19). Previously, in studies where the same antiretroviral regimen was given to the same animal model starting at 14 weeks postinfection, we have observed an incidence of diabetes of 18% staring at 25 to 30 weeks from ART initiation (see Table S1 in the supplemental material).…”

Renal Handling of Amphotericin B and Amphotericin B-Deoxycholate and Potential Renal Drug-Drug Interactions with Selected Antivirals

“…The incubation concentrations of adefovir, tenofovir, and cidofovir corresponded to the therapeutic plasma levels achieved in humans (42)(43)(44). Considerable in vitro interactions between AmB-DOC and all three antiviral agents at hOAT1 were demonstrated (Fig.…”

Adefovir dipivoxil-induced Fanconi syndrome and its predictive factors: A study of 28 cases

“…Several studies have reported that HOAT-1 has a strong affinity for adefovir dipivoxil, and that individuals who show high expression levels of HOAT-1 show a higher uptake of adefovir dipivoxil in the renal proximal tubule compared with individuals who show low expression of HOAT-1 or who are deficient (37,38); this was observed in cases with tenofovir-related kidney damage (39,40). Adefovir bisphosphonate, which is the effective metabolite of adefovir dipivoxil, tends to suppress the duplication of mitochondrial DNA, leading to mitochondrial DNA loss in the renal proximal tubule, thus affecting renal tubular reabsorption and secretion (36).…”