TY - JOUR
T1 - Association of higher plasma vitamin d binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics
T2 - Cause of a functional Vitamin D deficiency?
AU - Havens, Peter L.
AU - Kiser, Jennifer J.
AU - Stephensen, Charles B.
AU - Hazra, Rohan
AU - Flynn, Patricia M.
AU - Wilson, Craig M.
AU - Rutledge, Brandy
AU - Bethel, James
AU - Pan, Cynthia G.
AU - Woodhouse, Leslie R.
AU - Van Loan, Marta D.
AU - Liu, Nancy
AU - Lujan-Zilbermann, Jorge
AU - Baker, Alyne
AU - Kapogiannis, Bill G.
AU - Gordon, Catherine M.
AU - Mulligan, Kathleen
PY - 2013/11
Y1 - 2013/11
N2 - 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 vitaminD[1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin Dbinding 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 vitaminDbinding protein and lower free 1,25-OH(2)D, suggesting a functional vitaminDdeficiency 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.
AB - 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 vitaminD[1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin Dbinding 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 vitaminDbinding protein and lower free 1,25-OH(2)D, suggesting a functional vitaminDdeficiency 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.
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U2 - 10.1128/AAC.01096-13
DO - 10.1128/AAC.01096-13
M3 - Article
C2 - 24002093
AN - SCOPUS:84885909493
VL - 57
SP - 5619
EP - 5628
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 11
ER -