Mycophenolate, clinical pharmacokinetics, formulations, and methods for assessing drug exposure

This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 (Clin J Am Soc Nephrol. 2010;5:341-358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations.

Summary points

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Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal clinical outcomes.

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Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent.

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The area under the concentration-time curve (AUC_0-12) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC_0-12, trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose.

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Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC_0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS.

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Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal impairment (creatinine clearance <25 mL/min) to guide dosage estimation, especially because renal function changes over time after transplant, while recognizing that robust prospective studies to show the clinical advantage of measuring free MPA exposure are still required.

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Lower total measured MPA exposure in patients with hypoalbuminemia may still indicate sufficient free MPA exposure. Mycophenolate free concentration measurement and estimation of exposure are likely to be beneficial in patients with a serum albumin less than or equal to 31 g/L to guide interpretation of MPA exposure.

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A 1.5-g twice-daily starting dose of MMF rather than a 1-g twice-daily starting dose of MMF is more likely to achieve the minimum target MPA exposure in adult transplant recipients receiving concomitant cyclosporine therapy. Because the cyclosporine dose is progressively tapered following transplantation, MPA exposure should be measured repeatedly and MMF should be doses adjusted accordingly to achieve optimal clinical outcome.

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Mycophenolate exposure should be measured in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year with appropriate dosage adjustment, as AUC is likely to increase over time. After 1 year, if dosage requirement has stabilized, MPA exposure can be assessed each time the immunosuppressive regimen is changed or a potentially interacting drug is introduced or withdrawn.

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Assessment of UGT1A9 single nucleotide polymorphisms (−275T>A, −2152C>T, −440C>T, −331T>C) should be considered before transplantation to assist in dosing decisions to achieve optimal MPA exposure immediately after transplant.

Consideration of the points summarized above should lead to more effective dosage adjustment based on sound applied pharmacokinetic and pharmacodynamic principles.     

Clinical trials design: structure modifying agents for osteoarthritis. Future guidelines: areas for development.

Clinical trials guidelines should offer evidence-based recommendations, and, where evidence is lacking or absent, should reflect the considered opinion of experts in the field. Recent OsteoArthritis Research Society International (OARSI) guidelines encompass these principles and are the result of a Task Force Workshop involving representatives from academia, regulatory authorities and industry. Areas for continued development for trials of Structure Modifying Osteoarthritis Drugs (STMOAD) include patient selection, study duration, sample size estimation, outcome assessment, imaging, response definition and pharmoeconomics. As developments occur in these and related areas, guideline documents will require revision to reflect this evolution. Notwithstanding these issues, there is opportunity to identify STMOAD class agents using current methodologies.     

Yield of imaging and scintigraphy assessing biochemical failure in prostate cancer patients

A retrospective study was undertaken to determine the diagnostic yield of computed tomography (CT) and bone scan in patients with biochemical failure after definitive therapy for prostate cancer. The records of the Radiation Oncology Division were screened for patients presenting with prostate cancer between January 1, 1993, and December 31, 1996. Of 198 patients, 44 developed biochemical failure postoperatively (n = 24) or postradiotherapy (n = 20), and were not treated with hormones prior to restaging. Review was made of restaging studies performed at the time of biochemical failure. Postoperatively, 5% (1 of 20) of bone scans and 11% (2 of 18) of CT scans were positive. Postradiotherapy, 30% (6 of 20) of bone scans and 30% (3 of 10) of CT scans were positive. Our study showed that imaging studies are of low utility in the evaluation of patients with biochemical failure after definitive therapy of prostate cancer given that most patients begin hormonal therapy irrespective of the results of restaging studies. If salvage therapy is considered, imaging results may have a role in the decision-making process.     

Multicenter clinical trials and their value in assessing total joint arthroplasty

Multicenter clinical trials (MCT) have an important role in the assessment of total joint arthroplasty. The primary reason for such MCT is the need to have access to a large number of patients. In Sweden, failure after total hip arthroplasty has been recorded prospectively since 1979. Medical records from every reoperation are documented and computer analyzed. This MCT has shown that patient-related, surgical, and implant-related parameters are of importance to rates of failure. There were an increasing number of revisions after total hip arthroplasty in Sweden between 1979 and 1986. Male gender and young age increase the risk of revision. The primary diagnosis is very important for type of failure. The risk of deep infection is small but increases with the number of previous operations. Aseptic loosening has emerged as the main problem and is the cause for 74% of all revisions. Prosthetic design is of utmost importance for the rate of failure, and significant differences exist among different prosthesis types with respect to long-term survival. Finally, this MCT has shown that revisions for total hip arthroplasty in patients younger than 70 years of age eventually have failed in Sweden whenever the cemented technique has been used.     

Current status of clinical trials assessing oncolytic virus therapy for urological cancers

Oncolytic virus therapy has recently been recognized as a promising new option for cancer treatment. Oncolytic viruses replicate selectively in cancer cells, thus killing them without harming normal cells. Notably, T‐VEC (talimogene laherparepvec, formerly called OncoVEX^GM‐CSF), an oncolytic herpes simplex virus type 1, was approved by the US Food and Drug Administration for the treatment of inoperable melanoma in October 2015, and was subsequently approved in Europe and Australia in 2016. The efficacies of many types of oncolytic viruses against urological cancers have been investigated in preclinical studies during the past decade, and some have already been tested in clinical trials. For example, a phase I trial of the third‐generation oncolytic Herpes simplex virus type 1, G47Δ, in patients with prostate cancer was completed in 2016. We summarize the current status of clinical trials of oncolytic virus therapy in patients with the three major urological cancers: prostate, bladder and renal cell cancers. In addition to Herpes simplex virus type 1, adenoviruses, reoviruses, vaccinia virus, Sendai virus and Newcastle disease virus have also been used as parental viruses in these trials. We believe that oncolytic virus therapy is likely to become an important and major treatment option for urological cancers in the near future.     

The clinical and biochemical effects of two combination oral contraceptive agents.

A comparison of the effects of two low-dose oral contraceptives on lipid metabolism was undertaken in an open-group comparative design study at the Family Planning Clinic, Groote Schuur Hospital, Cape Town. Sixty healthy women aged 18-35 years requesting oral contraception were allocated alternately to use a monophasic oral contraceptive containing 30 micrograms ethinyloestradiol and 150 micrograms desogestrel (Marvelon, group A), or a triphasic oral contraceptive containing 30-40 micrograms ethinyloestradiol and 50-125 micrograms levonorgestrel (Triphasil, group B). The changes in the lipoprotein profile elicited by the two preparations differed significantly. Group A subjects had a much greater triglyceridaemic response (42.4%) than group B (14.6%) and had a significant increase in high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo-A1). In group B, HDL-C decreased and Apo-A1 showed little change. Non-HDL-C (NHDL-C) and Apo-B levels hardly changed in either group. The atherogenic ratios, NHDL-C/HDL-C and Apo-B/Apo-A1 were higher in group B. This study confirmed a significant difference in the response of plasma lipoproteins to the two oral contraceptive preparations. The evidence suggests that the desogestrel-containing oral contraceptive elicits a less atherogenic lipoprotein profile than does the levonorgestrel-containing preparation. Although unsupported by direct clinical evidence that changes in the lipoprotein pattern induced by oral contraceptives cause atherosclerosis, these effects should be considered when prescribing oral contraceptives for women who have risk factors for cardiovascular disease.     

The role of 111indium-capromab pendetide imaging for assessing biochemical failure after radical prostatectomy

PURPOSE: Conventional imaging modalities, such as computerized tomography and magnetic resonance imaging, lack sensitivity and specificity for detecting recurrent prostate cancer after radical surgery. We evaluated the role of the indium-capromab pendetide scan, otherwise known as the ProstaScint (Cytogen Corp., Princeton, New Jersey) scan, in this setting. MATERIALS AND METHODS: A retrospective review was performed of 42 patients undergoing ProstaScint imaging for biochemical progression after radical prostatectomy. Of these patients 16 (38.1%) subsequently completed a course of salvage radiation therapy. RESULTS: Median prostate specific antigen (PSA) immediately prior to ProstaScint imaging was 1.2 ng/ml (range 0.2 to 4.8). Abnormal accumulation on the ProstaScint scan was detected in 36 patients (85.7%). Of the 16 patients undergoing salvage radiation therapy 15 had uptake isolated to the prostatic fossa on ProstaScint imaging. Ten of these 15 patients (66.7%) achieved undetectable PSA after radiation therapy, while 5 (33.3%) had little or no response. Using American Society for Therapeutic Radiology and Oncology criteria 3 of 10 responders had relapse after an average of 9 months. The remaining 7 patients remained biochemically free of disease at last followup. CONCLUSIONS: ProstaScint imaging is capable of detecting recurrent prostate cancer at low PSA levels. However, only 7 of 15 men (46.7%) with ProstaScint uptake isolated to the prostatic fossa showed a durable response to salvage radiation therapy. Based on these findings patients might be better treated based on the rate of increase in PSA rather than on routine scanning with this test.     

Comparison of conventional standing knee radiographs and magnetic resonance imaging in assessing progression of tibiofemoral joint osteoarthritis

OBJECTIVE: Although the current recommendation is to measure radiographic joint space width (JSW) to assess structural change in osteoarthritis (OA), there is increasing interest in direct measurement of cartilage volume from magnetic resonance imaging (MRI). We performed a longitudinal study to compare change in both JSW and articular cartilage volume in subjects with symptomatic knee OA. METHODS: JSW was measured in 28 subjects with knee OA (57% females, mean age 62.8+/-9.8 years) who had standing radiographs in full extension, where both radiographs had satisfactory alignment. Each subject had femoral, tibial and combined femoral and tibial cartilage volumes determined from T1-weighted fat saturated sagittal knee MRI. All subjects had a repeat of the knee radiograph and MRI 1.96+/-0.4 years later. RESULTS: At baseline there was a moderate, but statistically significant, correlation between JSW and femoral and tibial cartilage volumes in the medial tibiofemoral joint, which was strengthened by adjusting for medial tibial bone size (R=0.58-0.66, P=0.001). Although we observed a reduction in JSW and femoral and tibial cartilage volumes over the study period, there was no significant association between reduction in JSW and cartilage volume (R<0.13). There was a trend towards a significant association between change in medial tibiofemoral cartilage volume and joint replacement at 4 years (OR=9.0, P=0.07) but not change in medial tibiofemoral JSW (OR=1.1, P=0.92). CONCLUSIONS: Although there was a modest correlation between cartilage volume and JSW in the medial tibiofemoral compartment, there was no correlation between longitudinal change in these measures. Change in cartilage volume appears to be a better predictor of joint replacement. Further work in larger samples over a longer period of time will be needed to confirm these findings.     

无创评估容量反应性的临床应用进展

容量评估与干预是围术期患者安全管理的一项重要因素,可以影响患者最终转归。无创评估容量反应性具有简便、快速、创伤小、患者更易配合等特点,是进行个体化液体治疗的基础,近些年临床应用广泛。本文从基于心肺交互作用的评估指标、基于容量负荷的评估方法两方面对常用的无创评估容量反应性的方法进行阐述,为临床应用提供参考。     

应用三种方法治疗膝关节骨性关节炎的临床分析

目的比较三种方法治疗膝关节骨性关节炎的效果. 方法三组患者分别采用关节镜清理、玻璃酸钠注射及二者联合治疗. 结果根据关节痛、关节积液、关节活动程度及行走功能综合评分.随访2年以上,关节镜组:0.5～1年优良率86.7%,1～2年优良率76.3%,2年以上优良率66%.玻璃酸钠组:0.5～1年优良率80.6%,1～2年优良率72.8%,2年以上优良率56.2%.联合组:0.5～1年优良率96.8%,1～2年优良率87.2%,2年以上优良率78.2%. 结论三种方法均有疗效,关节镜清理并玻璃酸钠注射疗效最好,关节镜清理次之, 玻璃酸钠注射较差.