Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes

Venuto, Rocco C.; Meaney, Calvin J.; Chang, Shirley; Leca, Nicolae; Consiglio, Joseph D.; Wilding, Gregory E.; Brazeau, Daniel A.; Gundroo, Aijaz; Nainani, Neha; Morse, Sarah; Cooper, Louise; Tornatore, Kathleen M.

doi:10.1097/md.0000000000001315

Cited by 18 publications

(36 citation statements)

References 80 publications

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“…In our model, P‐gp may not have been adequately represented by using individual ABCB1 polymorphisms in the covariate analysis. Use of ABCB1 haplotypes may provide a more comprehensive investigation of this efflux transporter and the associated inter‐patient pharmacokinetic variability of tacrolimus …”

Section: Discussionmentioning

confidence: 99%

“…Use of ABCB1 haplotypes may provide a more comprehensive investigation of this efflux transporter and the associated inter-patient pharmacokinetic variability of tacrolimus. 51 Although this study included a small number of patients with no validation group included, the model developed has several advantages. This study was designed using intensive serial sampling strategy in clinically stable patients, which provides more accurate estimates of tacrolimus pharmacokinetic parameters.…”

Section: Discussionmentioning

confidence: 99%

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Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

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Mager

Brazeau

et al. 2018

The Journal of Clinical Pharma

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Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most black renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical, and genomic factors in stable black and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid ≥6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236C>T, 2677G>T/A, 3435C>T polymorphisms were characterized. Patients were classified as extensive, intermediate, and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with computer software (NONMEM 7.3, ICON Development Solutions; Ellicott City, Maryland). A 2-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P value < .05), which was faster in extensive (mean: 45.0 L/hr) and intermediate (29.5 L/hr) metabolizers than poor metabolizers (19.8 L/hr). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between black and white recipients with different CYP3A5 genotypes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

Campagne

Mager

Brazeau

et al. 2018

The Journal of Clinical Pharma

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“…The study was conducted at the UB Renal Research Unit at the Erie County Medical Center. Study design and methods have been previously described . Clinical stability was based on physical examination, comprehensive metabolic panel, fasting lipid panel and complete blood count at enrolment and on study morning.…”

Section: Methodsmentioning

confidence: 99%

“…Identifying pharmacokinetic factors contributing to AE manifestations is critical to guide tacrolimus dosing adjustment, improve treatment tolerance and reduce risk potential among these patients. A validated and standardized immunosuppressive extrarenal AE scoring system that includes physical findings, laboratory results and concomitant medications was aimed to minimize reporting bias of these manifestations . Previous associations between extrarenal AEs, sex and ABCB1 haplotypes have been reported, but the relationship between tacrolimus pharmacokinetics and these validated adverse events has not been investigated .…”

Section: Introductionmentioning

confidence: 99%

“…A validated and standardized immunosuppressive extrarenal AE scoring system that includes physical findings, laboratory results and concomitant medications was aimed to minimize reporting bias of these manifestations . Previous associations between extrarenal AEs, sex and ABCB1 haplotypes have been reported, but the relationship between tacrolimus pharmacokinetics and these validated adverse events has not been investigated . Several studies reported that tacrolimus‐related AEs were more frequent or severe at higher tacrolimus exposures .…”

Section: Introductionmentioning

confidence: 99%

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The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients

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Mager

Brazeau

et al. 2019

Brit J Clinical Pharma

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AIMSTacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUC ss,0-12h ). METHODSAll recipients receiving tacrolimus and mycophenolic acid ≥6 months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients. RESULTSDose-normalized tacrolimus AUC ss,0-12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose-normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error < 10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%). CONCLUSIONSSeveral AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUC ss,0-12h and clearance. Skin changes and acne were associated with dose-normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUC ss,0-12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2019) 85 516-529 516• Adverse effects (AEs) from tacrolimus immunosuppression are common and significantly contribute to morbidity in renal transplant patients. In addition, minimal investigations have reported use of standardized extrarenal AE criteria in stable transplant recipients. • The association between AEs and tacrolimus exposure is poorly understood in relation to trough blood concentrations, the most commonly measured exposure metric used for routine therapeutic drug monitoring. • Innovative therapeutic drug monitoring strategies are needed to predict and prevent tacrolimus AEs in the clinical arena. WHAT THIS STUDY ADDS• Several extrarenal AEs were associated with dose-normalized tacrolimus area under the curve and maximum concentration as well as apparent clearance. These extrarenal AEs were not associated with tacrolimus trough concentrations. • The developed limited sampling methods enabled accur...

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Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post–Renal Transplant

Meaney

Sudchada²,

Consiglio

et al. 2019

The Journal of Clinical Pharma

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Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration‐time curve from 0 to 12 hours (AUC0‐12h) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC0‐12h was 1.70‐fold greater with tacrolimus (68.9 ± 30.9 mg·h/L) relative to cyclosporine (40.8 ± 17.6 mg·h/L); P < .001. Target mycophenolic acid AUC0‐12h of 30–60 mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P < .001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6 ± 4.7 L/h) relative to cyclosporine (20.5 ± 10.0 L/h); P < .001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P < 0.001; with a 2.9‐fold greater mycophenolic acid glucuronide AUC0‐12h to mycophenolic acid AUC0‐12h ratio (P < .001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2‐fold higher with tacrolimus (P < .001) and more prominent in women (P = .017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P < 0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post–renal transplant, which could be attributed to differences in enterohepatic circulation.

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Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes

Cited by 18 publications

References 80 publications

Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

The impact of tacrolimus exposure on extrarenal adverse effects in adult renal transplant recipients

Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post–Renal Transplant

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