PMID- 20171422 OWN - NLM STAT- MEDLINE DCOM- 20100514 LR - 20221207 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 32 IP - 1 DP - 2010 Jan TI - Bioequivalence and pharmacokinetic comparison of two mycophenolate mofetil formulations in healthy Chinese male volunteers: an open-label, randomized-sequence, single-dose, two-way crossover study. PG - 171-8 LID - 10.1016/j.clinthera.2010.01.013 [doi] AB - BACKGROUND: Mycophenolate mofetil (MMF) is an ester prodrug of mycophenolic acid (MPA), so clinical studies measure the circulating plasma MPA concentration instead of MMF. MPA is extensively glucuronidated by several uridine diphosphate glycosyltransferases into an inactive 7-O-glucuronide and a pharmacologically active acylglucuronide. Considering the effect of racial differences and genetic factors on the pharmacokinetic (PK) properties of drugs, it is necessary to study them in Chinese populations. OBJECTIVES: The aim of this study was to compare the clinical bioequivalence and PK properties of a test (dispersible tablets) and reference (capsules) formulation of MMF 1.0 g in healthy Chinese volunteers. We also established a validated HPLC method for the determination and quantification of MPA in human plasma. The study was required to obtain Chinese regulatory approval for the test formulation. METHODS: This open-label, randomized-sequence, single-dose, 2-way crossover study was conducted at the First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 1.0-g dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The plasma concentration of MPA, which is the active metabolite of MMF, was determined using a validated HPLC method. For analysis of PK properties, blood samples were collected at 0, 10, 20, 30, and 45 minutes, and 1, 1.5, 3, 5, 8, 11, 18, 36, and 48 hour(s). The PK parameters, including C(max), T(max), t((1/2)), AUC(0-48), and AUC(0-infinity), were determined from the plasma concentrations of the 2 formulations by noncompartmental analysis. Tolerability was assessed at baseline (be- fore administration) and at 30 minutes and 1, 5, 18, and 48 hours after administration by monitoring vital signs. Laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) were performed for the identification of adverse events (AEs) (eg, leukopenia, thrombocytopenia, anemia). Patient interviews were conducted to assess the occurrence of AEs such as diarrhea, abdominal pain, nausea, vomiting, and secondary infections. The formulations were considered to meet the regulatory requirements of bioequivalence if the log-transformed ratios of C(max) and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). RESULTS: Eighteen healthy Chinese male volunteers (mean [range] age, 23.5 [22-30] years; weight, 63.3 [56-68] kg; height, 171 [165-184] cm) were enrolled and completed the study. The main PK parameters of the MMF test and reference formulations were as follows: mean (SD) T(max), 0.68 (0.21) and 0.81 (0.18) hour, respectively; C(max), 25.58 (4.79) and 26.47 (3.67) mg/L; AUC(0-48), 59.19 (9.23) and 58.32 (9.28) mg/L/h; t((1/2)), 15.12 (3.17) and 16.04 (4.22) hours; AUC(0-infinity)), 63.28 (10.23) and 62.41 (10.28) mg/L/h. The mean (SD) relative bioavailability was 101.5% (10.3%). No statistically significant differences were found based on ANOVA. The ratios of C(max) (0.97) and AUC (1.01) for the test and reference formulations were within the FDA bioequivalence definition intervals of 80% to 125%. No AEs were reported by subjects or found on analysis of vital signs or laboratory tests. CONCLUSIONS: In this study in healthy Chinese male volunteers, results from the PK analysis suggested that a single dose of the test and reference formulations of MMF 1.0 g met the regulatory requirements of bioequivalence, based on the FDA regulatory definition (rate and extent of absorption). Both formulations were well tolerated. FAU - Zhang, Qian AU - Zhang Q AD - Pharmaceutical Department, First Hospital of Nanjing Medical University, Nanjing, China. FAU - Tao, Yifu AU - Tao Y FAU - Zhu, Yubing AU - Zhu Y FAU - Zhu, Dingchun AU - Zhu D LA - eng PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Capsules) RN - 0 (Immunosuppressive Agents) RN - 0 (Tablets) RN - HU9DX48N0T (Mycophenolic Acid) SB - IM MH - Administration, Oral MH - Adult MH - Area Under Curve MH - Asian People MH - Biological Availability MH - Capsules MH - China MH - Chromatography, High Pressure Liquid MH - Cross-Over Studies MH - Humans MH - Immunosuppressive Agents/administration & dosage/blood/*pharmacokinetics MH - Male MH - Mycophenolic Acid/administration & dosage/*analogs & derivatives/blood/*pharmacokinetics MH - Reference Values MH - Tablets MH - Tandem Mass Spectrometry MH - Therapeutic Equivalency MH - Time Factors MH - Young Adult EDAT- 2010/02/23 06:00 MHDA- 2010/05/15 06:00 CRDT- 2010/02/23 06:00 PHST- 2009/10/08 00:00 [accepted] PHST- 2010/02/23 06:00 [entrez] PHST- 2010/02/23 06:00 [pubmed] PHST- 2010/05/15 06:00 [medline] AID - S0149-2918(10)00014-7 [pii] AID - 10.1016/j.clinthera.2010.01.013 [doi] PST - ppublish SO - Clin Ther. 2010 Jan;32(1):171-8. doi: 10.1016/j.clinthera.2010.01.013.