Lower Calcineurin Inhibitor Doses in Older Compared to Younger Kidney Transplant Recipients Yield Similar Troughs

Abstract

The number of older adults undergoing kidney transplantation has increased, yet little is known about calcineurin inhibitor (CNI) metabolism in this group. We studied CNI troughs and doses to determine if there were age related differences in metabolism and dose requirements. We studied 348 young (18–34 years), 1831 middle (35–64 years) and 374 older (65–84 years) adult kidney transplant recipients enrolled in a 7-center prospective study. Troughs were obtained from each patient 2x/week in weeks 1–8 and 2x/month in months 3–6. A multivariable linear mixed model examined the effect of age on log dose and weight normalized troughs. Older recipients had higher normalized tacrolimus troughs than middle or young age adults despite receiving doses a median of 1–2 mg/day lower. Age and CYP3A5*1 genotype had the largest effect on tacrolimus troughs. Older recipients also had higher normalized cyclosporine troughs than middle or young adults despite receiving median doses 100 mg/day lower. After normalization for dose and weight, CNI troughs were more than 50% higher in older adults than young adults. These data support age related changes in CNI metabolism. Further studies are needed to determine optimal dosing of CNIs in the elderly.

Aging and the immune response to organ transplantation

“…Aged male C57BL/6 mice (18 months of age) treated with tacrolimus require only half the weight-adjusted dose to achieve trough levels found in young (2-3 months of age) murine skin recipients (46). These results are consistent with a prior prospective clinical study that found that recipients older than 65 years required half the body weight-adjusted dose to achieve therapeutic tacrolimus trough levels (92). CD4 + T cells isolated from the in aged mice (78).…”

Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients

“…Jacobson et al [65] also found a similar trend. Elder recipients had higher normalized cyclosporine pre-dose concentrations than middle aged or young adults, despite receiving median doses that were 100 mg/day lower, and recipient age had the largest effect on cyclosporine troughs [65]. These data suggest that in the elderly patient it might be better to reduce the starting dosage and aim at lower whole blood cyclosporine target concentrations.…”

“…In addition, the effect of age within a given genotype was still substantial. In recipients with the CYP3A5 * 3/ * 3 genotype (CYP3A5 non-expressers), dose and weight normalized predose concentrations were 45% higher in the elder subjects compared to the younger adults; meanwhile, a similar increase in predose concentration with increasing age was also observed in individuals with the CYP3A5 * 1/ * 1 or * 1/ * 3 genotype (CYP3A5 expressers) [65]. These data suggest that the dose requirement of tacrolimus in elderly patients might be much less than the younger patients when aiming for the same target concentration range.…”

“…In addition, elderly patients had a 44% higher intracellular T-lymphocyte-to-whole blood cyclosporine concentration ratio than younger patients [70], which may explain why older recipients not only have a lower frequency of acute rejection but also suffer more frequently from the toxic effects of cyclosporine [21,25,30]. Jacobson et al [65] also found a similar trend. Elder recipients had higher normalized cyclosporine pre-dose concentrations than middle aged or young adults, despite receiving median doses that were 100 mg/day lower, and recipient age had the largest effect on cyclosporine troughs [65].…”

“…The dose requirement of patients expressing CYP3A5 (those carrying the A nucleotide, defined as the *1 allele) is around 50 % higher than that of non-expressers (those homozygous for the G nucleotide, defined as the *3 allele) [59]. The study that has up until now provided the best available evidence for age-related differences in Tac exposure among renal transplant recipients is the one conducted by Jacobson et al This study showed that the dose/bodyweight-normalized tacrolimus predose concentrations in elderly recipients (65-84 years) were 17% higher than middle aged (35-64 years) adults and 68% higher than young (18-34 years) adults, with age and CYP3A5 genotype having the largest effect [65]. In addition, the effect of age within a given genotype was still substantial.…”