Age associations with tacrolimus and mycophenolic acid pharmacokinetics in stable Black and White kidney transplant recipients: Implications for health inequities

Abstract

Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and is dosed empirically in elderly kidney transplant recipients (KTRs) resulting in health inequities. Limited immunosuppressive pharmacokinetics are available comparing adult ages. This secondary analysis compared TAC and MPA pharmacokinetics and adverse effects (AEs) among young, middleaged, and elderly Black and White KTRs. The 12-h TAC and MPA pharmacokinetics with AE evaluation were conducted in 67 stable KTRs greater than or equal to 6 months post-transplant. TAC regimens were adjusted to target troughs. MPA regimens were adjusted using clinical response. Participants were: young: less than or equal to 40 years; middle age: greater than 40 to 60 years, and elderly greater than 60 years. Noncompartmental pharmacokinetic analysis determined area under the concentration-time curve 0-12 h (AUC 0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC 6-12h /MPA-AUC 0-12h , and MPA glucuronide (MPAG)-AUC 0-12h / MPA-AUC 0-12h were determined. Univariate analysis of variance (ANOVA) was conducted using SAS version 9.4. No group differences were noted for estimated glomerular filtration rate, MPA, and TAC doses. EHR was reduced in elderly with decreased MPA-AUC 6-12h /MPA-AUC 0-12h (p = 0.049) and increased MPAG-AUC 0-12h /MPA-AUC 0-12h (p = 0.036). MPA troughs (p = 0.045) were reduced in the elderly. TAC CL/BMI (p = 0.043) was reduced in the elderly. For therapeutic MPA AUC 0-12h : 30-60 mg•h/L, 34.3% KTRs achieved this target with 55.2% greater than the therapeutic range. 77.6% KTR were in the TAC AUC 0-12h target: 100-190 ng•h/mL and 19.4% were below this range with no age relationship. In 44% young, 26% middle-age and 7.8% elderly subjects achieved target AUC 0-12h for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age-related

HDL-C and creatinine levels at 1 month are associated with patient 12-month survival rate after kidney transplantation

“…Violette Gijsen investigated the effect of age on tacrolimus pharmacokinetics and reported similar results [21]. Another study found that the blood clearance rate of tacrolimus in the elderly is lower than that in the young, the possible reason is that liver aging leads to the decline of liver function, which affects the blood concentration of tacrolimus in the body [22]. Until more recently kidney transplantation was not recommended for elderly patients, but evidence has shown that older people who receive kidney transplantation have higher rates and lengths of survival than younger people [23].…”

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross‐Sectional Study

“…39). Elderly KT recipients are characterized by higher TAC dose‐ and weight‐adjusted blood exposure, 40,41 notably explained by a reduced drug clearance itself resulting from the decline in liver function 42 . Therefore, age is a valuable factor integrated in some models of TAC population PKs 28,29,43 .…”

“…Elderly KT recipients are characterized by higher TAC dose-and weight-adjusted blood exposure, 40,41 notably explained by a reduced drug clearance itself resulting from the decline in liver function. 42 Therefore, age is a valuable factor integrated in some models of TAC population PKs. 28,29,43 Additionally, the gut microbiota composition evolves with advancing age due to, among others, the deterioration of dentition (and subsequent changes in dietary habits) and the lowering of intestinal motility.…”