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

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, middle-aged, 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 0-12h (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 center dot 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 center dot 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(0-12)h for both medications (p = 0.036). Neurologic AEs were manifested in the elderly (p = 0.014). Immunosuppressive pharmacokinetics demonstrated age-related differences with reduced TAC CL/BMI and MPA EHR and increased neurologic AE in the elderly. This immunosuppressive regimen may require age-adjusted individualization to optimize allograft function. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tacrolimus (TAC) and mycophenolic acid (MPA) provide maintenance immunosuppression and are 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, middle-aged, and elderly Black and White KTRs. WHAT QUESTION DID THIS STUDY ADDRESS? This secondary analysis compared TAC and MPA pharmacokinetics and AEs among young, middle--aged, and elderly Black and White KTRs. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This secondary analysis reported age--related differences in the commonly prescribed TAC and MPA regimen in stable KTRs. Reduced TAC Clearance/BMI and MPA enterohepatic recirculation and increased neurologic AEs were reported in the elderly. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY AND TRANSLATIONAL SCIENCE? This report suggests that TAC and MPA immunosuppressive regimen may require age--adjusted individualization to achieve therapeutic exposure and the benefits of this approach must be confirmed in a larger KTR population.

Automated summary

This study compared the pharmacokinetics and adverse effects of Tacrolimus (TAC) and mycophenolic acid (MPA) in young, middle-aged, and elderly kidney transplant recipients. The results showed age-related differences in drug metabolism and neurologic adverse effects. This suggests the need for age-adjusted individualization of immunosuppressive regimens to optimize transplant outcomes.