Pharmacokinetics and Dosing Recommendations of Tenofovir Disoproxil Fumarate in Hepatic or Renal Impairment

Patients and 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 300mg 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%.