FIG. 2.

Correlation between apparent TFV clearance, plasma AUCs, and the development of PRTD. Animals had been on stable subcutaneous TFV dosage regimens for at least 4 months at the time of the pharmacokinetic studies. Symbols indicating whether PRTD (glucosuria and/or hypophosphatemia) occurred refer to the time frame after the pharmacokinetics study was performed. While some animals were previously on higher-dosage regimens (see Table 1), the dosages indicated refer to the time of the pharmacokinetic studies. Because clearance is calculated as dose/AUC, hyperbolas are predicted at a specific dose. The quadrants define where differences and changes in TFV CL/F are physiologic (i.e., due to individual variation and the effect of aging) versus pathological (i.e., nephrotoxicity). The available data suggest that the cutoff values for the different quadrants are approximately AUCs of 20 μg·h/ml and clearance values of 400 ml/h/kg. Quadrant A is the zone where no PRTD was observed; quadrant B is a pre-PRTD stage; quadrants C and D area are associated with clinical PRTD. Glucosuria was detected once for animal 33091 after the pharmacokinetic values were at the intersection of these quadrants; the glucosuria resolved following dosage reduction (which was associated with an increase in TFV clearance [quadrant A]). (Inset) Empirical model for the pathogenesis of PRTD during high-dose TFV regimens. At high TFV exposures (quadrant B), the gradual development of PRTD reduces TFV clearance; this reduced clearance, by further increasing drug exposure (i.e., AUCs), aggravates renal toxicity and drives the animals' pharmacokinetic parameters further and further into quadrant C; only following drastic dosage reductions can values move from quadrant C toward quadrant D.