title: Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment.
abstract: BACKGROUND
  Tenofovir disoproxil fumarate is the prodrug of the acyclic nucleotide reverse transcriptase inhibitor tenofovir that is indicated for use in the treatment of HIV. Tenofovir is eliminated as unchanged drug in the urine, with a significant component of active tubular secretion. The aim of this study was to evaluate the pharmacokinetics of tenofovir in subjects with renal or hepatic impairment, both of which are common in HIV-infected individuals.
  
  
  METHODS
  HIV seronegative and otherwise healthy subjects with varying degrees of renal or hepatic function were recruited, and tenofovir pharmacokinetics were evaluated over 48 hours (hepatic impairment study) and 96 hours (renal impairment study) following a single tenofovir disoproxil fumarate 300 mg dose. Subjects with hepatic dysfunction were categorised based upon Child-Pugh-Turcotte score, and subjects with renal impairment were categorised based upon their calculated creatinine clearance (CL(CR)) using the Cockcroft-Gault method.
  
  
  RESULTS
  As expected for a renally eliminated drug, subjects with and without hepatic impairment displayed similar tenofovir systemic exposures without evidence of substantial alterations in drug disposition, and therefore no dosage adjustments were warranted in these patients. In contrast, in subjects with renal impairment, two distinct groups were observed: (i) subjects with CL(CR)>/=50 mL/min in whom tenofovir pharmacokinetics were similar to subjects with normal renal function; and (ii) subjects with CL(CR) <50 mL/min (moderate or severe impairment) in which tenofovir renal clearance was substantially reduced and thus drug exposures increased. Subjects with end-stage renal disease (ESRD) demonstrated no extrarenal route of tenofovir elimination. Simulations of once-daily or modified dosing regimens demonstrated the need for tenofovir disoproxil fumarate dose-interval adjustment to prevent unnecessary drug accumulation. In patients with ESRD, high-flux haemodialysis efficiently removed tenofovir, with an elimination rate of 134 mL/min and an extraction coefficient of 54%.
  
  
  CONCLUSIONS
  No tenofovir disoproxil fumarate dose adjustment is warranted in the setting of hepatic impairment. Tenofovir disoproxil fumarate 300 mg every 48 hours in individuals with moderate renal impairment and twice weekly corresponding to every 72-96 hours in those with severe renal impairment is recommended in order to target steady-state tenofovir exposures consistent with those observed in subjects with normal renal function receiving tenofovir disoproxil fumarate 300 mg once daily. For subjects receiving thrice-weekly 4-hour maintenance haemodialysis sessions, tenofovir disoproxil fumarate 300 mg administered every 7 days after a haemodialysis session is recommended. HIV-infected patients with significant end-organ dysfunction should be monitored in accordance with clinical practice, including close management of their viral suppression and clinical chemistries.
authors.affiliation: Gilead Sciences Inc., Foster City, California 94404, USA. bkearney@gilead.com
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
authors.forename: Kitty
authors.initials: K
authors.lastname: Yale
authors.forename: Jaymin
authors.initials: J
authors.lastname: Shah
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhong
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism* / Q000628:therapy / Q000652:urine; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D012720:Severity of Illness Index; D000068698:Tenofovir
chemical_list: D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine