FIG. 1.

Changes in TFV clearance: effects of age and dosage regimens. Twenty-four-hour pharmacokinetic studies with subcutaneous administration of TFV were performed. (A and B) Weight- and age-related changes in TFV CL/F, respectively, following a single-dose administration of 10 or 30 mg/kg (subcutaneously) to 23 healthy, uninfected macaques of different ages; 2 of these 23 animals (male 31007 and female 31456) were given two doses of TFV (10 mg/kg,= subcutaneously) 19 months apart. (C) TFV CL/F in animals that received prolonged TFV regimens (once daily subcutaneously; regimens are outlined in Table 1). Pharmacokinetic data were collected either from animals that never showed PRTD (blue) or from animals prior to (red) or after (black) the development of PRTD. Animal 33091 had glucosuria at a single time point when the TFV clearance was 400 ml/h/kg, but this disappeared when clearance increased again after dosage reduction. (D) An overlay of graphs B and C with animals grouped according to the presence of PRTD demonstrates that animals that received chronic TFV treatment and never showed signs of PRTD throughout their observation periods had apparent TFV clearances indistinguishable from those of animals that received a single dose. Based on the available data, the horizontal dotted line indicates the arbitrary cutoff value of reduced TFV clearance (<400 ml/h/kg) that was associated with PRTD in juvenile and adult animals.