Pharmacokinetics Of Mycophenolic Acid Research Articles

Therapeutic drug monitoring of mycophenolic acid and clinical outcomes of lupus nephritis: a systematic review and meta-analysis.

Mycophenolic acid (MPA) is a primary immunosuppressive agent used in the treatment of lupus nephritis (LN). While therapeutic drug monitoring (TDM) of MPA is well established in organ transplantation, its role in LN treatment remains uncertain. Our objective was to review and summarise current knowledge on TDM of MPA in the LN treatment. A systematic search was conducted in the online databases, specifically targeted patients diagnosed with LN receiving MPA treatment. The included studies had to report both MPA pharmacokinetic parameters and renal outcomes. A random-effects model meta-analysis was conducted to assess the relationship between clinical responses and MPA pharmacokinetics. A total of 1507 studies were initially screened, resulting in the inclusion of 16 studies for meta-analysis, encompassing 433 patients. The response group exhibited significantly higher MPA area under the concentration-time curve (AUC) compared with the non-response group (51.44±21.73 mg·h/L vs 30.30±16.24 mg·h/L). The weighted mean difference (WMD) of MPA-AUC between responders and non-responders was 16.83 mg·h/L (95% CI 10.59 to 23.06; p<0.001). Similarly, trough concentration (C0) of MPA showed a strong association with renal response, evidenced by C0 values of 2.50±1.73 mg/L in the response group vs 1.51±1.33 mg/L in the non-response group (WMD 1.37 mg/L; 95% CI 0.77 to 1.97; p<0.001). There was no significant relationship identified between MPA-AUC and adverse events. This meta-analysis emphasised the meaningful correlation between MPA AUC and C0 with renal response in LN treatment. Randomised controlled trials are necessary to validate this approach and determine its superiority over fixed dosing in the context of LN treatment.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study.

Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15-20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m2, 1.0 m2, 1.5 m2) and dosing (400 mg/m2, 600 mg/m2, 900 mg/m2 twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on Vd/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m2 twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice.

Population pharmacokinetics of mycophenolic acid and dose optimisation in adult Chinese kidney transplant recipients

1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimise the dosage for adult kidney transplant recipients. 2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix® NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimise the dosage regimen. 3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalised therapy of MPA for kidney transplant patients.

Association Between Mycophenolic Acid (MPA) Pharmacokinetics and In Vitro MPA Glucuronide (MPAG) Turnover by Gut Microbiota of Kidney Transplant Recipients

Association Between Mycophenolic Acid (MPA) Pharmacokinetics and In Vitro MPA Glucuronide (MPAG) Turnover by Gut Microbiota of Kidney Transplant Recipients

Mycophenolic acid therapeutic drug monitoring using area under the curve in pediatric heart transplant recipients.

Pharmacokinetics of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10-fold difference of exposure in individual patients under a fixed-dose regimen. MPA trough level (C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA AUC. Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤21years old who underwent MPA AUC between 2011 and 2021. Median age was 4years (IQR .6-12.1). Median time from transplant to MPA AUC sampling was 15days (IQR 11-19). MMF doses (mg or mg/day) had low, negative Pearson correlation coefficients (r) while doses adjusted for weight or body surface area had low correlation with Trapezoidal MPA AUC0-24h (r=.3 and .383, respectively). MPA C0 had weak association (r=.451) with Trapezoidal MPA AUC0-24h . LSS with two pharmacokinetic sampling time points at 90 (C3 ) and 360 (C5 )min after MMF administration (estimated AUC0-24h =32.82+4.12×C3 +11.53×C5 ) showed strong correlation with Trapezoidal MPA AUC0-24h (r=.87). MMF at fixed or weight-adjusted doses, as well as MPA trough levels, correlate poorly with MPA AUC0-24h . We developed novel LSSs to estimate Trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs should be completed in a separate cohort of pediatric HTx recipients.

Gut Microbiota-Mediated Pharmacokinetic Drug-Drug Interactions between Mycophenolic Acid and Trimethoprim-Sulfamethoxazole in Humans.

Mycophenolic acid (MPA) and trimethoprim-sulfamethoxazole (TMP-SMX) are commonly prescribed together in certain groups of patients, including solid organ transplant recipients. However, little is known about the pharmacokinetic drug-drug interactions (DDIs) between these two medications. Therefore, the present study aimed to determine the effects of TMP-SMX on MPA pharmacokinetics in humans and to find out the relationship between MPA pharmacokinetics and gut microbiota alteration. This study enrolled 16 healthy volunteers to take a single oral dose of 1000 mg mycophenolate mofetil (MMF), a prodrug of MPA, administered without and with concurrent use of TMP-SMX (320/1600 mg/day) for five days. The pharmacokinetic parameters of MPA and its glucuronide (MPAG) were measured using high-performance liquid chromatography. The composition of gut microbiota in stool samples was profiled using a 16S rRNA metagenomic sequencing technique during pre- and post-TMP-SMX treatment. Relative abundance, bacterial co-occurrence networks, and correlations between bacterial abundance and pharmacokinetic parameters were investigated. The results showed a significant decrease in systemic MPA exposure when TMP-SMX was coadministered with MMF. Analysis of the gut microbiome revealed altered relative abundance of two enriched genera, namely the genus Bacteroides and Faecalibacterium, following TMP-SMX treatment. The relative abundance of the genera Bacteroides, [Eubacterium] coprostanoligenes group, [Eubacterium] eligens group, and Ruminococcus appeared to be significantly correlated with systemic MPA exposure. Coadministration of TMP-SMX with MMF resulted in a reduction in systemic MPA exposure. The pharmacokinetic DDIs between these two drugs were attributed to the effect of TMP-SMX, a broad-spectrum antibiotic, on gut microbiota-mediated MPA metabolism.

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 stableKTRs 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 (AUC0-12h ), clearance (CL), and CL/body mass index (BMI) with 0-h troughs. MPA enterohepatic recirculation (EHR), MPA-AUC6-12h /MPA-AUC0-12h , and MPA glucuronide (MPAG)-AUC0-12h /MPA-AUC0-12h 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-AUC6-12h /MPA-AUC0-12h (p=0.049) and increased MPAG-AUC0-12h /MPA-AUC0-12h (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 AUC0-12h : 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 AUC0-12h 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 AUC0-12h 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.

Influence of SLCO1B1 Polymorphisms on the Pharmacokinetics of Mycophenolic Acid in Renal Transplant Recipients.

This study was designed to analyze the correlation between single nucleotide polymorphisms (SNP) related to drug metabolism and pharmacokinetics of mycophenolic acid (MPA) during long-term follow-up. A retrospective cohort study involving 71 renal transplant recipients was designed. Blood samples were collected to extract total DNAs, followed by target sequencing based on next-generation sequencing technology. The MPA area under the curve (AUC) was calculated according to the formula established in our center. The general linear model and linear regression model were used to analyze the association between SNPs and MPA AUC. A total of 689 SNPs were detected in our study, and 90 tagger SNPs were selected after quality control and linkage disequilibrium analysis. The general linear model analysis showed that 9 SNPs significantly influenced MPA AUC. A forward linear regression was conducted, and the model with the highest identical degree (r2=0.55) included 4 SNPs (SLCO1B1: rs4149036 [P < 0.0001], ABCC2: rs3824610 [P = 0.005], POR: rs4732514 [P = 0.006], ABCC2: rs4148395 [P = 0.007]) and 6 clinical factors (age [P < 0.0001], gender [P < 0.0001], the incident of acute rejection (AR) [P = 0.001], albumin [P < 0.0001], duration after renal transplantation [P = 0.01], lymphocyte numbers [P = 0.026]). The most relevant SNP to MPA AUC in this model was rs4149036. The subgroup analysis showed that rs4149036 had a significant influence on MPA AUC in the older group (P = 0.02), high-albumin group (P = 0.01), male group (P = 0.046), and both within-36-month group (P = 0.029) and after-36-month group (P = 0.041). The systematic review included 4 studies, and 2 of them showed that the mutation in SLCO1B1 resulted in lower MPA AUC, which was contrary to our study. A total of 4 SNPs (rs4149036, rs3824610, rs4148395, and rs4732514) were identified to be significantly correlated with MPA AUC. Rs4149036, located in SLCO1B1, was suggested to be the most relevant SNP to MPA AUC, which had a stronger influence on recipients who were elder, male, or with high serum albumin. Furthermore, 6 clinical factors, including age, gender, occurrence of acute rejection, serum albumin, time from kidney transplantation, and blood lymphocyte numbers, were found to affect the concentration of MPA.

Clinical Evidence on the Purported Pharmacokinetic Interactions between Corticosteroids and Mycophenolic Acid.

Corticosteroids (steroids) are commonly used concurrently with mycophenolic acid (MPA) as the first-line immunosuppression therapy for the prevention of rejection in solid organ transplantations. Steroids are also commonly administered with MPA in various autoimmune disorders such as systemic lupus erythematosus and idiopathic nephrotic syndrome. Despite various review articles having suggested the presence of pharmacokinetic interactions between MPA and steroids, definitive data have not yet been demonstrated. The aim of this Current Opinion is to critically evaluate the available clinical data and propose the optimal study design for characterising the MPA-steroid pharmacokinetic interactions. The PubMed and Embase databases were searched for relevant clinical articles in English as of September 29, 2022, where a total of 8 papers have been identified as supporting and 22 as non-supporting the purported drug interaction. To objectively evaluate the data, novel assessment criteria to effectively diagnose the interaction based on known MPA pharmacology were formulated, including the availability of independent control groups, prednisolone concentrations, MPA metabolite data, unbound MPA concentrations, and the characterisations of entero-hepatic recirculation and MPA renal clearance. Overall, the majority of the identified corticosteroid data were pertaining to prednisone or prednisolone. Our assessment indicated that no conclusive mechanistic data supporting the interaction are available in the current clinical literature, and further studies are required to quantify the effects/mechanisms of steroid-tapering or withdrawal on MPA pharmacokinetics. This current opinion provides justification for further translational investigations, as this particular drug interaction has the potential to exert significant adverse outcomes in patients prescribed MPA.

Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis

BackgroundMycophenolate mofetil (MMF), a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is difficult to administer because of the pharmacokinetic complexity of MPA. Although dosage adjustment according to the 12-h area under the concentration–time curve (AUC0-12) is thought to be desirable, multiple blood samplings for AUC calculation may pose a clinical challenge. A limited sampling strategy (LSS) would provide a solution; however, little is known about MPA pharmacokinetics in lupus nephritis patients, especially in those with Asian backgrounds, or few, if any, LSSs are reported for them.MethodsThirty-four adult Japanese patients receiving MMF for lupus nephritis were examined retrospectively. MPA pharmacokinetics were investigated, and a PPK model was developed using Phoenix® NLME™ software. Single and double blood sampling strategies from Bayesian estimation using the PPK model and from multiple linear regression were compared. Tolerability was also evaluated.ResultsIn the pharmacokinetic analysis, renal function and serum albumin had significant effects on dose-normalized AUC0-12; and serum albumin, concomitant proton pump inhibitor (PPI) and iron/magnesium oxide did on dose-normalized maximum concentration. As a PPK model, a two-compartment model was developed with a transit absorption model and first-order elimination, in which creatinine clearance and serum albumin were covariates for MPA clearance. The double sampling strategy at 1 and 4 h by multiple linear regression showed the best agreement with the observed AUC0-12 (r2 = 0.885). Of the single sampling strategies, the one at 6 h by Bayesian estimation performed best (r2 = 0.769). The tolerability evaluation showed that correlations were suggested for gastrointestinal involvement.ConclusionsThe present study developed the first PPK model of MPA for Japanese lupus nephritis patients. As for LSSs, a double sampling strategy at 1 and 4 h by multiple linear regression would work best; when only a single blood sampling is allowed, a strategy at 6 h by Bayesian estimation using the PPK model developed in this study would be best. The LSSs good enough for clinical use may facilitate safer, more effective, and individualized therapy.

Loss of Function ABCG2 c.421C>A (rs2231142) Polymorphism Increases Steady-State Exposure to Mycophenolic Acid in Stable Renal Transplant Recipients: An Exploratory Matched Cohort Study.

Polymorphism ABCG2 c.421C>A (rs2231142) results in reduced activity of the important drug efflux transporter breast cancer-resistance protein (BCRP/ABCG2). One study has suggested that it may affect enterohepatic recirculation of mycophenolic acid (MPA). We evaluated the effect of rs2231142 on steady-state exposure to MPA in renal transplant recipients. Consecutive, stable adult (age ≥ 16years) renal transplant recipients on standard MPA-based immunosuppressant protocols (N = 68; 43 co-treated with cyclosporine, 25 with tacrolimus) underwent routine therapeutic drug monitoring after a week of initial treatment, and were genotyped for ABCG2 c.421C>A and 11 polymorphisms in genes encoding enzymes and transporters implicated in MPA pharmacokinetics. ABCG2 c.421C>A variant versus wild-type (wt) patients were matched with respect to demographic, biopharmaceutic, and genetic variables (full optimal combined with exact matching) and compared for dose-adjusted steady-state MPA pharmacokinetics [frequentist and Bayes (skeptical neutral prior) estimates of geometric means ratios, GMR]. Raw data (12 variant versus 56 wt patients) indicated around 40% higher total exposure (frequentist GMR = 1.45, 95% CI 1.10-1.91; Bayes = 1.38, 95% CrI 1.07-1.81) and around 30% lower total body clearance (frequentist GMR = 0.66, 0.58-0.90; Bayes = 0.71, 0.53-0.95) in variant carriers than in wt controls. The estimates were similar in matched data (11 variant versus 43 wt patients): exposure GMR = 1.41 (1.11-1.79) frequentist, 1.39 (1.15-1.81) Bayes, with 90.7% and 85.5% probability of GMR >1.20, respectively; clearance GMR = 0.73 (0.58-0.93) frequentist, 0.71 (0.54-0.95) Bayes. Sensitivity analysis indicated low susceptibility of the estimates to unmeasured confounding. Loss-off-function polymorphism ABCG2 c.421C>A increases steady-state exposure to MPA in stable renal transplant patients.

Population Pharmacokinetics of Mycophenolic Acid in Haploidentical Transplant Recipients Receiving Post-Transplant Cyclophosphamide Based GvHD Prophylaxis

Post-transplant Cyclophosphamide (PTCy) based Graft versus Host disease (GvHD) prophylaxis has improved the success of Haploidentical transplantation (HaploHCT) in recent years. Therapeutic drug monitoring (TDM) of Mycophenolic acid [MPA-active metabolite of Mycophenolate Mofetil (MMF)] has proved beneficial in solid organ transplantation; however, there are no TDM recommendations in the HCT setting yet. In the present study, we sought to create a population pharmacokinetic (POPPK) model of oral MMF in haploidentical HCT recipients receiving PTCy/MMF/CyclosporineA (CsA) based GvHD prophylaxis and to evaluate the feasibility of TDM by assessing the impact of MPA exposure on clinical outcomes. Thirty-six patients with various underlying diagnoses who underwent HaploHCT between October 2021 and June 2022 were enrolled. All patients received GvHD prophylaxis comprising of Cyclophosphamide (I.V. 50 mg/kg/day x 2days (day+3 & +4) and i.v. Cyclosporine (2.5mg/kg; Q12H) with oral MMF (15 mg/kg; Q8H) from day +5 post HCT. Plasma was separated from the peripheral blood collected at predetermined time points at day+8 post HCT. Plasma MPA was analyzed using a validated HPLC-UV method, and the concentration was expressed as ug/ml. MPA PK was estimated using nonlinear mixed effects modeling via Monolix (version 2021R2). The covariates tested for MPA PK were: age, sex, body weight, BSA, and Creatinine clearance. The PK parameters AUC, CL, V, and k were estimated on day+8 for MPA. The influence of MPA PK on GvHD and graft rejection was assessed by the Mann-Whitney test (GraphPad Prism 8). MPA levels were available for thirty-one patients. A one-compartment model with first-order absorption best described MPA PK. We observed a 5-fold inter-individual variation (IIV) in MPA exposure. None of the covariates explained IIV in MPA PK. Two patients died before engraftment, while graft rejection was noted in 3 patients (1 primary and 2 secondary). Fifteen patients experienced acute GvHD, and there were nine deaths (25%) at the last follow-up of 3.7 ± 2.4 months. Interestingly, POPPK analysis revealed that all the 31 patients had MPA underexposure [Median: 14.1 (4.5 - 24.0)ug*hr/ml lesser than the lower limit of the therapeutic range of 30ug*hr/ml]. No associations were observed with clinical outcomes, including acute GvHD (p=0.8) or graft rejection (p=0.6). The MPA underexposure in the present study could be attributed to potential drug-drug interaction (DDI) with concomitant CsA administration that inhibits MRP2-mediated enterohepatic circulation causing decreased systemic MPA exposure. Numerous transplant centers across the globe use cyclosporine and tacrolimus interchangeably (Ruggeri et al. TCT 2020). However, the available retrospective data comparing the two calcineurin inhibitors appears to be conflicting (Castagna et al. BMT 2016, de Lima VJT et al. Ann Hematol 2022). On the PTCy platform for haploidentical transplantation, our results highlight that concomitant administration of CsA reduces systemic exposure of MPA. The impact of this effect on the clinical outcomes needs to be studied further and may potentially affect the choice of the calcineurin inhibitor for the PTCy platform. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The combination of exposure to Tacrolimus, mycophenolic acid, Inosine 5'-Monophosphate Dehydrogenase activity and inhibition in the first week define early histological outcomes in renal transplant recipients.

Therapeutic drug monitoring is routine for Tacrolimus, while levels are not routinely monitored for mycophenolic acid (MPA). This study investigated the effect of early post-transplant pharmacokinetics (PK) of MPA and Tacrolimus along with the pharmacodynamics (PD) of MPA on biopsy-proven acute rejection (BPAR) after renal transplantation. A prospective PK/PD study with limited sampling (three blood samples) was conducted in renal transplant recipients on week 1, around Day 6 (n=42) and at the 3rd-month biopsy on Day 90 (n=23). The partial exposures (area under curve [AUC]0-3.5h ) of both MPA and Tacrolimus obtained during the first week were more predictive of rejection (combined clinical and subclinical rejection) by Day 90 than their trough concentrations or Day 90 exposures. Patients with rejection had significantly worse renal function (eGFR) and a comparatively lower exposure to MPA during the first post-transplant week. The lower MPA exposure was also associated with sub-optimal inosine monophosphate dehydrogenase (IMPDH) inhibition in patients with rejection, and the probability of rejection was higher in the presence of an increased pre-transplant IMPDH activity. A composite of parameters, including MPA exposure and IMPDH activity was found to predict acute rejection and may be beneficial along with tacrolimus monitoring early after renal transplantation.

Important lack of difference in tacrolimus and mycophenolic acid pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients.

To examine whether differences in tacrolimus and mycophenolic acid (MPA) pharmacokinetics contribute to the poorer kidney transplant outcomes experienced by Aboriginal Australians. Concentration-time profiles for tacrolimus and MPA were prospectively collected from 43 kidney transplant recipients: 27 Aboriginal and 16 Caucasian. Apparent clearance (CL/F) and distribution volume (V/F) for each individual were derived from concentration-time profiles combined with population pharmacokinetic priors, with subsequent assessment for between-group difference in pharmacokinetics. In addition, population pharmacokinetic models were developed using the prospective dataset supplemented by previously developed structural models for tacrolimus and MPA. The change in NONMEM objective function was used to assess improvement in goodness of model fit. No differences were found between Aboriginal and Caucasian groups or empirical Bayes estimates, for CL/F or V/F of MPA or tacrolimus. However, a higher prevalence of CYP3A5 expressers (26% compared with 0%) and wider between-subject variability in tacrolimus CL/F (SD=5.00 compared with 3.25 L/h/70 kg) were observed in the Aboriginal group, though these differences failed to reach statistical significance (p= .07 and p= .08). There were no differences in typical tacrolimus or MPA pharmacokinetics between Aboriginal and Caucasian kidney transplant recipients. This means that Bayesian dosing tools developed to optimise tacrolimus and MPA dosing in Caucasian recipients may be applied to Aboriginal recipients. In turn, this may improve drug exposure and thereby transplant outcomes in this group. Aboriginal recipients appeared to have greater between-subject variability in tacrolimus CL/F and a higher prevalence of CYP3A5 expressers, attributes that have been linked with inferior outcomes.

Therapeutic Drug Monitoring of Mycophenolic Acid as a Precision Medicine Tool for Heart Transplant Patients: Results of an Observational Pharmacokinetic Pilot Study.

In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) in 21 HTx recipients treated with MMF combined with cyclosporine (CsA) or tacrolimus (TAC) at a median time of 2.6 months post-transplant. The two treatment groups were compared. We described the main MPA-PK parameters in patients developing acute cellular rejection (ACR) and those who did not. Median dose-adjusted MPA-trough levels and MPA-AUC0–12h were higher in patients co-treated with TAC than with CsA (p = 0.0001 and p = 0.006, respectively). MPA-Cmax and Tmax were similar between the two groups, whereas the enterohepatic recirculation biomarker of MPA (MPA-AUC4–12h) was higher in the MMF and TAC group (p = 0.004). Consistently, MPA clearance was higher in the MMF and CsA group (p = 0.006). In total, 87.5% of ACR patients were treated with MMF and CsA, presenting a lower MPA-AUC0–12h (p = 0.02). This real-world study suggested the CsA interference on MPA-PK in HTx, evidencing the pivotal role of MPA TDM as a precision medicine tool in the early phase after HTx. A prospective study is mandatory to investigate this approach to HTx clinical outcomes.

Drug-Drug Interactions Between Mycophenolic Acid and Proton Pump Inhibitors: A Systematic Review and Meta-Analysis.

The objective of the present study was to determine the impact of proton pump inhibitors (PPIs) on the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA). PubMed, Embase, Web of Sciences, and Scopus were systematically searched to identify relevant studies reporting pharmacokinetic parameters [including trough concentration (C0), maximum concentration (Cmax), time to maximum concentration (Tmax), the dose-adjusted area under the concentration-time curve from time 0-12 hours (AUC0-12 h/D), and half-life (t1/2)], and pharmacodynamic outcomes of MPA (eg, acute graft rejection and adverse drug reactions), with and without PPI administration. Pooled effect estimates were calculated using a random-effects model. Twelve studies involving 473 participants were eligible for inclusion, 11 of which were included in the meta-analysis. PPI exposure was significantly associated with lower C0 [mean difference (MD) = -0.62 mg/L; P = 0.003] lower Cmax (MD = -4.71 mg/L; P = 0.01), and longer Tmax (MD = 0.30 hours; P = 0.0001) of MPA. However, no significant association was observed between PPI exposure and AUC0-12 h/D, t1/2, or any pharmacodynamic outcomes. Based on subgroup analysis, it can be suggested that a significant association between PPI exposure and altered MPA pharmacokinetics was mainly associated with mycophenolate mofetil but not enteric-coated mycophenolate sodium. Coadministration of PPIs and mycophenolate mofetil significantly altered the pharmacokinetics of MPA, particularly by decreasing MPA absorption. However, PPI-MPA interactions did not impact pharmacodynamic outcomes of MPA.

Pharmacokinetics of free and total mycophenolic acid in paediatric and adult renal transplant recipients: Exploratory analysis of the effects of clinical factors and gene variants.

Clinical and genetic influencing factors on free fraction of mycophenolic acid (MPA) have rarely been discussed. The present study investigated whether the clinical and genetic factors could explain the variability in the pharmacokinetics of free MPA (fMPA) and total MPA (tMPA) in Chinese paediatric and adult renal transplant recipients. Twenty-eight paediatric and 31 adult patients were enrolled, and the concentrations of tMPA and fMPA were determined at 0 h (predose) and 0.5, 1, 1.5, 2, 4, 5, 8, 9, 10 and 12 h after mycophenolate mofetil administration. Genetic polymorphisms of UGTs (rs671448, rs1042597, rs2741049, rs62298861, rs7439366, rs12233719) and ABCC2 (rs717620) were simultaneously determined. The clinical and genetic data were analysed and reported. tMPA and fMPA concentrations adjusted for dose per body weight were consistently higher in adults than in paediatric patients. In the paediatric group, only albumin and time after transplantation correlated significantly with the MPA-free fraction variation, which could explain 32.4% of the variability. Besides, ABCC2 polymorphism, albumin and time after transplantation correlated significantly with the MPA-free fraction variation in adults, which could explain 56.9% of the variability. The influencing factors in the paediatric group are different from those in adults, which may be due to age-related transporter expression.

In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil.

The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-β-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular in vitro dissolution test for the fasting state and developing a predictive in vitro dissolution test with sufficient simulation of the GE dynamics and proximal small intestinal pH fluctuations for the fed state would be excellent surrogates for the in vivo BE test. Furthermore, a physiologically based predictive in vitro dissolution test under both fasting and fed conditions would be a new trend for the BE studies of all other HV drug products.

Population Pharmacokinetics of Mycophenolic Acid in Renal Transplant Patients: A Comparison of the Early and Stable Posttransplant Stages.

Mycophenolic acid (MPA) is an antimetabolic immunosuppressive drug widely used in solid organ transplantation and autoimmune diseases. Pharmacokinetics (PK) of MPA demonstrates high inter- and intra-variability. The aim of this study was to compare the population PK properties of MPA in adult renal transplant patients in the early and stable post-transplant stages and to simulate an optimal dosing regimen for patients at different stages. A total of 51 patients in the early post-transplant period (1 week after surgery) and 48 patients in the stable state (5.5–10 years after surgery) were included in the study. In the two-compartment population PK model, CL/F (23.36 L/h vs. 10.25 L/h) and V/F (78.07 vs. 16.24 L) were significantly different between the two stages. The dose-adjusted area under the concentration time curve (AUCss,12h/dose) for patients in the early stage were significantly lower than those for patients in the stable state (40.83 ± 22.26 mg h/L vs. 77.86 ± 21.34 mg h/L; p < 0.001). According to Monte Carlo simulations, patients with 1.0–1.5 g of mycophenolate mofetil twice daily in the early phase and 0.50–0.75 g twice daily in the stable phase had a high probability of achieving an AUCss,12h of 30–60 mg h/L. In addition, limited sampling strategies showed that two 4-point models (C0-C1-C2-C4 and C1-C2-C3-C6) performed well in predicting MPA exposure by both Bayesian estimate and regression equation and could be applied in clinical practice to assist therapeutic drug monitoring of MPA.

Pharmacokinetics of mycophenolic acid and external evaluation of two limited sampling strategies of drug exposure in patients with juvenile systematic lupus erythematosus

Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0-12h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance. Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC-UV). Individual AUC0-12h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults. We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0-12h. The external validation MPA AUC0-12h was conducted by selecting the concentration-time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: - 0.8mgh/L), (2) ADAPT resulted in a bias of 6.7mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively. According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0-12h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0-12h between 30 and 45mgh/L is proposed in jSLE but this requires additional validation.