肾移植患者吗替麦考酚酯血药浓度监 测简

目的：探讨对吗替麦考酚酯进行治疗药物监测的临床必要性.方法：采用HPLC方法测定血浆中麦考酚酸的谷浓度和峰浓度,对2012 年10 – 12 月期间83 例肾移植患者血浆麦考酚酸浓度进行分析.结果：患者血浆麦考酚酸谷浓度在0.34 ～ 3.99 μg·mL-1范围内的共46例次,血浆麦考酚酸峰浓度在0.91～12.78 μg·mL-1范围内的有37例次.在固定给药剂量下,麦考酚酸血药浓度的个体差异较大.结论：对吗替麦考酚酯进行治疗药物监测具有重要的临床价值.     

肾移植术后吗替麦考酚酯替换硫唑嘌呤的临床分析

目的 :观察肾移植后吗替麦考酚酯 (MMF)替换硫唑嘌呤 (Aza)的安全性及其临床效果。方法 :回顾分析16例由Aza转换为MMF患者的临床资料。4例因肝功能损害而改用MMF,7例肾功能损害 ,5例应患者要求而换用MMF。结果 :4例肝功能损害者肝功能均恢复正常 ,7例肾功能损害者2例逆转 ,4例肌酐 (SCr)下降但未能恢复正常 ,1例继续恶化恢复血液透析。2例不良反应包括原有贫血明显加重 ,1例腹泻。结论 :Aza可以安全替换为MMF。因环孢素 (CsA)加Aza引起肝功能损害者 ,换用MMF ,减少CsA用量 ,肝功能可望恢复。MMF对部分慢性排斥反应可能有效     

Therapeutic drug monitoring of mycophenolate in adult solid organ transplant patients: an update

Introduction: Mycophenolate (MPA) therapeutic drug monitoring (TDM) in adult solid organ transplant recipients was summarized extensively in consensus reports published between 2009 and 2011. Thus, this review provides an update on the science of MPA TDM over the past 5 years.

Areas covered: PubMed and Google Scholar (January 2010-January 2016) were searched; relevant articles from bibliographies of identified articles were extracted for further review. New evidence on TDM-guided dosing in MPA efficacy and toxicity and best approaches for estimating MPA area-under-the-curve for TDM were retrieved.

Expert opinion: Since 2011, little advancement in consensus on MPA TDM has been established for any type of solid organ transplant. Lack of systematic studies validating or further defining MPA’s target range suggests that routine TDM is still unwarranted.

Accurate, precise, and user-friendly limited sampling strategies (LSSs) are available in specific patient populations taking mycophenolate mofetil but not enteric-coated mycophenolate sodium. In absence of outcome data, routine use of LSSs in MPA TDM still cannot be recommended.

Further research should attempt to define factors that modulate MPA’s pharmacokinetics to elucidate their impact on utility of TDM. Future studies should also validate LSSs in larger patient populations and demonstrate benefits of LSSs in improving patient outcomes.     

Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases

Aim

To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis.

Methods

MPA areas under the concentration–time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C₀) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients'' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed.

Results

In both autoimmune diseases, at PK assessment, median MPA C₀ for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l^–1 (IQR 0.9–2.1 mg l^–1) vs. 2.95 mg l^–1 (IQR 1.38–3.73 mg l^–1) for SLE (P = 0.048) and 1.55 mg l^–1 (IQR 0.98–2.18 mg l^–1) vs. 3 mg l^–1 (IQR 2.2–4.4 mg l^–1) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C₀ threshold of 2.5–3 mg l^–1 was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C₀ ≥ 2.5–3 mg l^–1 at inclusion had better clinical outcomes during the 12 months following PK assessment.

Conclusion

Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C₀ measured approximately 12 h post-dose.     

Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

AIMS

Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients.

METHODS

PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks.

RESULTS

Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r²= 0.812; IMPDH r²= 0.833). MPA AUC_0–12 of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC_0–12 28 µg*h ml⁻¹ (7–45) vs. 40 µg*h ml⁻¹ (16–130), P < 0.01), MPA AUC_0–12 of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC_0–12 65 µg*h ml⁻¹ (range 37–130) vs. 37 µg*h ml⁻¹ (range 7–120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC_0–12) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC_0–12 43 nmol*h mg⁻¹ protein h⁻¹[range 12–67) vs. 75 nmol*h mg⁻¹ protein h⁻¹ (range 15–371), P < 0.01].

CONCLUSIONS

Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC_0–4 and IMPDH AEC_0–4 in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC_0–12 from 30 to 60 µg*h ml⁻¹ seems to be appropriate in renal allograft recipients.     

The association between trough blood concentration and systemic exposure of tacrolimus: Comparison between once-daily (Advagraf®) and twice-daily (Prograf®) formulation in de novo kidney transplant recipients

Available data of early conversion from twice-daily tacrolimus (TAC-BID) to once-daily tacrolimus (TAC-OD) in de novo kidney transplant (KT) recipients are limited. We conducted a prospective study of early conversion to TAC-OD in de novo KT recipients. Eligible patients were enrolled to receive TAC-BID (Prograf®) and then converted to TAC-OD (Advagraf®) by 1:1 ratio, approximately 14 days after KT (range 9–22). Blood samples were investigated for pharmacokinetic parameters before and 7–14 days after the conversion. Fifteen patients were included and provided AUC_0-24 of 202.9 ± 44.4 ng h/mL for TAC-BID (pre-conversion) and 193.0 ± 63.4 ng h/mL for TAC-OD (post-conversion) (p = 0.41). Mean trough blood concentration (C_min) of TAC-BID and TAC-OD was 6.4 ± 1.4 ng/mL and 4.9 ± 1.6 ng/mL (p = 0.01). Correlation coefficient (r) between C_min and AUC_0-24 of TAC-BID and TAC-OD were 0.620 and 0.875. Additional analysis found that patients with a drop of C_min > 30% had a significant lower AUC_0-24 after conversion. Renal function remains stable. We conclude that early conversion to TAC-OD is safe and well tolerated with an indifferent systemic exposure. However, patients with a drop of C_min > 30% after conversion to TAC-OD will require additional dose adjustment.