Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?

Abstract

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at https://ichgcp.net/clinical-trials-registry/NCT00490412.).

Figures

Fig 1

Plasma tenofovir and intracellular tenofovir diphosphate concentration by time following administration of tenofovir disoproxil fumarate. (A) Plasma tenofovir concentration by time postdose. (B) Intracellular tenofovir diphosphate concentration by time postdose.

Fig 2

Changes in Vitamin D binding protein and free 1,25-OH(2) vitamin D by quintile of plasma tenofovir concentration. (A) Vitamin D binding protein by TDF use and plasma tenofovir concentration. Shown is the increase in vitamin D binding protein by quintile of plasma tenofovir concentration (TFVQ1 to TFVQ5). P = 0.023 for the overall difference in vitamin D binding protein by quintile of plasma tenofovir, and P = 0.018 for the difference between quintile 1 and quintile 5. (B) Free 1,25-OH(2) vitamin D by TDF use and plasma tenofovir concentration. Shown is the decrease in free 1,25-OH(2) vitamin D by quintile of plasma tenofovir concentration. P = 0.001 for the overall difference in vitamin D binding protein by quintile of plasma tenofovir, and P = 0.008 for the difference between quintile 1 and quintile 5. Values for participants treated with tenofovir disoproxil fumarate or left untreated (TDF and no TDF, respectively) overall are shown for comparison in both panels.

Fig 3

Potential differential endocrine effects of plasma tenofovir and intracellular tenofovir diphosphate. TDF, tenofovir disoproxil fumarate (prodrug); TFV, tenofovir (metabolite in plasma); TFV-DP, tenofovir diphosphate (active intracellular metabolite); VDBP, vitamin D binding protein; free 1,25-OH(2)D, free 1,25 dihydroxy vitamin D3; PTH, parathyroid hormone; FGF23, fibroblast growth hormone 23. (A) Plasma tenofovir may be linked to increased parathyroid hormone through the mechanism of increased vitamin D binding protein and albumin, which causes decreased free 1,25 OH(2)D. (B) The association of higher tenofovir diphosphate and lower fibroblast growth hormone 23 may occur through a mechanism that remains to be explained.