Cell and tissue therapy regulation: worldwide status and harmonization.

Rapid developments in scientific and technological aspects in stem cell biology and tissue engineering have led to the increased use of human cells and tissues for the treatment of various diseases and injuries. The regulatory environment for CTT products is rapidly evolving and drug regulatory agencies are working towards establishment of a risk-based system with some common features. Various drug regulatory agencies in many countries/regions have implemented regulatory controls in the last few years. This article will highlight some of works done till date to regulate CTT products in Australia, Canada, Europe, Japan, Korea, Singapore and United States of America.

Mechanism-based enterohepatic circulation model of mycophenolic acid and its glucuronide metabolite: assessment of impact of cyclosporine dose in Asian renal transplant patients.

Mycophenolic acid (MPA) is mainly metabolized to MPA-glucuronide (MPAG), which may be reconverted to MPA following enterohepatic circulation (EHC). A physiologically realistic EHC model was proposed to estimate and assess the impact of cyclosporine (CsA) dose on the extent of EHC of MPA and MPAG. After the first oral dose of mycophenolate mofetil (MMF), the MPA and MPAG plasma concentration-time data of 14 adult renal transplant patients (12 receiving concomitant CsA and prednisolone and 2 receiving only concomitant prednisolone without CsA) were analyzed by individual pharmacokinetic modeling using a proposed 5-compartment drug and metabolite EHC model with a time-varying gallbladder emptying process. Simulations were performed to assess the influence of the time of bile release after dosing (T(bile)) and the gallbladder emptying interval (tau(gall)) on the EHC process. The extent of EHC for both MPA and MPAG tended to be lower in the group receiving CsA coadministration and decreased with increasing total body weight-adjusted CsA dose. Simulations revealed that T(bile) and tau(gall) influenced the time of occurrence and maximum concentration of the second peak, as well as the extent of EHC, for MPA and MPAG.

Is a standard fixed dose of mycophenolate mofetil ideal for all patients?

BACKGROUND: A standard fixed dose of 2 g/day of mycophenolate mofetil (MMF), irrespective of total body weight (TBW), is recommended when used in combination with cyclosporine and corticosteroids in renal transplantation. METHODS: To determine the optimal MMF dose in a population with wide variation in TBW, steady-state pharmacokinetics of mycophenolic acid (MPA) was performed in 53 Asian (Chinese, Malay, Indian, Eurasian) renal transplant recipients (RTX) receiving MMF [250-1000 mg twice daily (BD)] for at least 3 months. Blood samples were collected at 0, 0.5, 1, 1.5, 2 and 6 h after the MMF dose and total MPA quantified using HPLC. RESULTS: Drug exposure, as evaluated by AUC(ss, 0-12), demonstrated a significant positive correlation with TBW-adjusted MMF dose (outliers omitted: r(2) = 0.49, P < 0.0005). An AUC(ss, 0-12) of 45 mg h/l could be attained with an MMF dose of 12 mg/kg BD. CONCLUSION: This study proposes that MMF should be dosed based on TBW rather than a fixed dose regimen in RTX.

Simple reversed-phase liquid chromatographic assay for simultaneous quantification of free mycophenolic acid and its glucuronide metabolite in human plasma.

A reversed-phase HPLC-UV method, involving simple instrumental setup and mobile phase without ion-pairing reagent, was developed and validated for direct simultaneous quantification of free mycophenolic acid (MPA) and its major metabolite MPA-glucuronide (MPAG) in human plasma. Both free MPA and MPAG were isolated from plasma samples using ultrafiltration prior to analysis. Each chromatographic run was completed within 13 min. The optimized method showed good performance in terms of specificity, linearity (r(2)=0.9999), sensitivity (limit of quantitation (LOQ): 0.005 mg/L for MPA; 1 mg/L for MPAG), and intra- and inter-day precision (R.S.D.<7%). This assay was successfully applied to free MPA and MPAG measurements in clinical samples.

Randomized trial of Alemtuzumab for prevention of graft rejection and preservation of renal function after kidney transplantation.

BACKGROUND: A randomized, multicenter, controlled trial was undertaken to evaluate the safety and efficacy of Alemtuzumab, a powerful lytic agent for both T and B lymphocytes, in the prophylaxis of rejection in renal transplantation (RTx). METHODS: Thirty patients were randomized to receive Alemtuzumab together with low-dose cyclosporine (CsA) monotherapy (CAMPATH, n = 20) or to full doses of CsA with azathioprine and corticosteroids (Standard, n = 10). CsA was administered at doses to achieve whole-blood trough CsA levels of 90 to 110 ng/mL and 180 to 225 ng/mL in CAMPATH and Standard groups, respectively. RESULTS: Per protocol, CsA trough levels were lower in patients assigned to CAMPATH post-RTx (median trough level of 119 vs. 166 ng/mL at 6 months, CAMPATH vs. Standard; 95% confidence interval, -92 to -34). At 6 months post-RTx, serum creatinine, graft and patient survivals, incidence of biopsy proven acute rejection (25% vs. 20%, CAMPATH vs. Standard), overall treatment failure, and severe and moderate infections were comparable. Whereas all patients receiving Standard therapy required maintenance corticosteroids at 6 months, of the 17 of 20 patients with functioning grafts in CAMPATH, 15 (88%, 95% confidence interval, 53%-97%) were steroid free. CONCLUSION: These results suggest that Alemtuzumab is an effective induction agent that permits low-dose steroid-free immunosuppression in RTx.

Simple reversed-phase ion-pair liquid chromatography assay for the simultaneous determination of mycophenolic acid and its glucuronide metabolite in human plasma and urine.

A simple and reproducible reversed-phase ion-pair high-performance liquid chromatographic (HPLC) method using isocratic elution with UV absorbance detection is presented for the simultaneous quantitation of mycophenolic acid (MPA) and MPA-glucuronide (MPAG) in human plasma and urine. The sample preparation procedures involved simple protein precipitation for plasma and 10-fold dilution for urine. Each analytical run was completed within 15min, with MPAG and MPA being eluted at 3.8 and 11.4min, respectively. The optimized method showed good performance in terms of specificity, linearity, detection and quantitation limits, precision and accuracy. This assay was demonstrated to be applicable for clinical pharmacokinetic studies.

Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population.

STUDY OBJECTIVE: To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis (MDRTB) after undergoing solid organ transplantation. DESIGN: Retrospective analysis. SETTING: Community outpatient clinic. PATIENTS: Forty-eight recipients of solid organ transplants beginning prophylaxis for MDRTB during August 1999 after possible exposure to a single index case of multidrug-resistant Mycobacterium tuberculosis within our community INTERVENTION: Prophylaxis consisted of pyrazinamide 30 mg/kg/day plus levofloxacin 500 mg/day, administered for 1 year. MEASUREMENTS AND MAIN RESULTS: Thirteen (27.1%) of the 48 patients completed therapy; 27 (56.3%) discontinued therapy within 4 months due to adverse drug events. Gastrointestinal intolerance was the major adverse event resulting in early discontinuation. CONCLUSION: Prophylaxis of MDRTB with levofloxacin and pyrazinamide was associated with limited tolerability due to the high frequency of adverse events. While we search for a better tolerated prophylactic regimen, close monitoring for adverse reactions is recommended.