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Background and Objective: The pharmacokinetics of mycophenolic acid (MPA) are complex, with large interindividual variability over time. There are also well documented interactions with cyclosporin, and assessment of MPA exposure is therefore necessary when reducing or stopping cyclosporin therapy. Here we report on the pharmacokinetic and pharmacodynamic behaviour of MPA in renal transplant patients on standard dose, reduced dose and no cyclosporin.Study Design: The CAESAR study, a prospective 12-month study in primary renal allograft recipients, was designed to determine whether mycophenolate mofetil-based regimens containing either low-dose cyclosporin or low-dose cyclosporin withdrawn by 6 months could minimize nephrotoxicity and improve renal function without an increase in acute rejection compared with a mycophenolate mofetil-based regimen containing standard-dose cyclosporin.Patients and Methods: A subset of patients from the CAESAR study contributed to this pharmacokinetic analysis of MPA exposure. Blood samples were taken over one dosing interval on day 7 and at months 3, 7 and 12 post-transplantation. The sampling time points were predose, 20, 40 and 75 minutes and 2, 3, 4, 6, 8 and 12 hours after mycophenolate mofetil dosing. Assessments included plasma concentrations of MPA and mycophenolic acid glucuronide (MPAG) and cyclosporin trough concentrations. The area under the plasma concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) for MPA was the primary pharmacokinetic parameter, and the AUC(12) for MPAG was the secondary parameter.Results: In total, 536 de novo renal allograft recipients were randomized in the CAESAR study. Of these, 114 patients were entered into the pharmacokinetic substudy and 110 patients contributed to the pharmacokinetic analysis. There was a rapid rise in MPA concentrations (median time to peak concentration 0.72-1.25 hours). At day 7 and month 3, the MPA AUC(12) values were similar in the cyclosporin withdrawal and low-dose cyclosporin groups (patients with the same cyclosporin target concentrations to month 6), while at 7 and 12 months, the values in the cyclosporin withdrawal group were higher than in the low-dose group (19.9% and 30.2% higher, respectively). MPA AUC(12) values in the standard-dose cyclosporin group were lower than in the other groups at all time points and increased over time. At all time points, the MPA peak plasma concentration was similar in all groups, and the MPAG concentrations rose more slowly than MPA concentrations. The ratio of the AUC from 6 to 12 hours/AUC(12) suggests that an increasing AUC in the cyclosporin withdrawal group is due to an increase in the enterohepatic recirculation.Conclusion: These findings are consistent with the hypothesis that cyclosporin inhibits the biliary secretion and/or hepatic extraction of MPAG, leading to a reduced rate of enterohepatic recirculation of MPA. Several concurrent mechanisms, such as cyclosporin-induced changes in renal tubular MPAG excretion and enhanced elimination of free MPA through competitive albumin binding with MPAG, can also contribute to the altered MPAG pharmacokinetics observed in the presence and absence of cyclosporin. [ABSTRACT FROM AUTHOR]

Background: Daclizumab, a humanized monoclonal antibody against the interleukin-2 receptor, reduced the risk of rejection without increasing the risk of infection among renal-transplant recipients and, in a single-center trial, among cardiac-transplant recipients. We conducted a multicenter, placebo-controlled, double-blind study to confirm these results in cardiac-transplant patients.Methods: We randomly assigned 434 recipients of a first cardiac transplant treated with standard immunosuppression (cyclosporine, mycophenolate mofetil, and corticosteroids) to receive five doses of daclizumab or placebo. The primary end point was a composite of moderate or severe cellular rejection, hemodynamically significant graft dysfunction, a second transplantation, or death or loss to follow-up within six months.Results: By six months, 104 of 218 patients in the placebo group had reached the primary end point, as compared with 77 of the 216 patients in the daclizumab group (47.7 percent vs. 35.6 percent, P=0.007), a 12.1 percent absolute risk reduction and a 25 percent relative reduction. The rate of rejection was lower in the daclizumab group than in the placebo group (41.3 percent vs. 25.5 percent). Among patients reaching the primary end point, the median time to the end point was almost three times as long in the daclizumab group as in the placebo group during the first 6 months (61 vs. 21 days) and at 1 year (96 vs. 26 days). More patients in the daclizumab group than in the placebo group died of infection (6 vs. 0) when they received concomitant cytolytic therapy.Conclusions: Daclizumab was efficacious as prophylaxis against acute cellular rejection after cardiac transplantation. Because of the excess risk of death, concurrent or anticipated use of cytolytic therapy with daclizumab should be avoided. [ABSTRACT FROM AUTHOR]

Background: Glycopyrronium tosylate (GT; Qbrexza ® [glycopyrronium] cloth, 2.4%) is a topical anticholinergic approved (USA) for primary axillary hyperhidrosis in patients aged ≥ 9 years., Objective: The objective of this study was to compare the pharmacokinetics and safety of GT to oral glycopyrrolate (phase I study) and assess the relationship between glycopyrronium pharmacokinetics and anticholinergic-related adverse events or efficacy with population pharmacokinetics using data from two phase II studies., Methods: In the phase I study, study staff applied GT to axillae of patients with primary axillary hyperhidrosis (aged 9-65 years) once daily (5 days); oral glycopyrrolate was administered to healthy adults (aged 18-65 years) every 8 hours (15 days). In the phase II studies (NCT02016885 [20 December, 2013], NCT02129660 [2 May, 2014]), adults with primary axillary hyperhidrosis applied topical glycopyrronium (0.8-3.2%) or vehicle to axillae once daily (4 weeks). Pharmacokinetic and adverse event data were collected in all studies., Results: Glycopyrronium pharmacokinetic parameters were similar between adult and pediatric patients treated with GT; there was no evidence of accumulation. Systemic absorption of glycopyrronium was lower with GT vs oral glycopyrrolate. No anticholinergic-related adverse events occurred with GT in the phase I study, while dry mouth and nasal dryness occurred with oral glycopyrrolate; anticholinergic adverse events occurred in the phase II studies. In the population pharmacokinetic analysis, frequency/severity of anticholinergic-related adverse events increased with higher glycopyrronium concentration; no relationship was observed between efficacy and pharmacokinetic measures., Conclusions: These studies indicate limited absorption of GT compared to oral glycopyrrolate and a low risk of anticholinergic adverse events with proper GT administration when following instructions for use (wipe each underarm once with same cloth, wash hands, avoid ocular contact).

Background: Glycopyrronium tosylate is a topical anticholinergic approved in the USA for primary axillary hyperhidrosis in patients aged ≥ 9 years (Qbrexza™ [glycopyrronium] cloth, 2.4%)., Objective: This 44-week open-label extension study assessed glycopyrronium tosylate safety and descriptive efficacy in patients completing one of two, phase III, double-blind, vehicle-controlled, 4-week trials (NCT02530281; NCT02530294)., Methods: Patients aged ≥ 9 years with primary axillary hyperhidrosis were randomized 2:1 (glycopyrronium tosylate: vehicle, once daily) in the double-blind trials. Completers could receive open-label glycopyrronium tosylate for up to an additional 44 weeks. Treatment-emergent adverse events and local skin reactions were assessed. Descriptive efficacy assessments were gravimetrically measured sweat production, Hyperhidrosis Disease Severity Scale responder rate (≥ 2 grade improvement), and Dermatology Life Quality Index/children's Dermatology Life Quality Index., Results: Of 651 patients completing the double-blind trials, 564 (86.6%) entered the open-label extension; 550 were analyzed. Most patients experiencing treatment-emergent adverse events had mild or moderate events (> 90%). Discontinuation because of treatment-emergent adverse events remained low and relatively stable, with a cumulative rate of 8.0% (44/550) over 44 weeks. Common treatment-emergent adverse events (> 5%) were dry mouth (16.9%), vision blurred (6.7%), application-site pain (6.4%), nasopharyngitis (5.8%), and mydriasis (5.3%). Most patients (67.5%) had no local skin reactions; those occurring were predominantly mild/moderate. Glycopyrronium tosylate efficacy was maintained throughout the trial; at week 44, the Hyperhidrosis Disease Severity Scale responder rate was 63.2%, and improvements from baseline (double blind) in sweat production were - 71.3% and 8.7 ± 6.2/6.2 ± 4.9 for Dermatology Life Quality Index/children's Dermatology Life Quality Index., Conclusions: Daily long-term application of glycopyrronium tosylate for up to 48 weeks (double blind plus open label) was generally well tolerated and efficacy was maintained. No new safety signals emerged., Trial Registry: Clinicaltrials.gov NCT02553798.

Introduction: Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome., Methods: Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC₀₋₁₂. Free MPA AUC values were available for a subgroup of patients (n = 269)., Results: The overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus- (21%) treated patients. The incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. The total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections., Conclusion: Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.

Background: To better define subpopulations in which achieving adequate mycophenolic acid (MPA) concentrations quickly would be important, a post hoc exploratory analysis on the fixed-dose concentration-controlled database was performed, comparing high- versus low-risk renal transplant patients., Methods: Renal transplant patients were treated with mycophenolate mofetil, corticosteroids, and cyclosporine A or tacrolimus. Patients were defined as "high risk" if they had one or more of the following characteristics: delayed graft function, second or third transplantation, panel reactive antibodies >15%, four or more human leukocyte antigen mismatches, or were of black race., Results: A total of 549 patients (61%) were classified as high risk, of whom 284 were on cyclosporine A treatment and 265 on tacrolimus. In high-risk patients, the difference in rejection incidence was 14.3% in the MPA-area under the concentration (AUC) less than 30 mg hr/L vs. 7.8% in the MPA-AUC more than or equal to 30 mg hr/L groups (P=0.025) during the first month after transplantation; whereas, in low-risk patients, there were similar rejection rates (5.7% vs. 4.5%). In the subgroup of high-risk tacrolimus-treated patients, the difference in acute rejection incidence in the first month between patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was most pronounced: 16 of 67 patients (23.9%) vs. 18 of 173 patients (10.4%); P=0.012., Conclusions: The incidence of acute rejection is higher in high-risk patients if MPA-AUC0-12 is below 30 mg hr/L. In contrast, a difference in acute rejection incidence in low-risk patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was not observed. This supports the use of a higher mycophenolate mofetil starting dose in selected patient populations early after transplantation.

Background: Exposure to mycophenolic acid (MPA), the primary active metabolite of mycophenolate mofetil (MMF), is correlated with therapeutic efficacy of MMF but varies depending on the concomitantly administered immunosuppressive drugs., Methods: A 3-month pharmacokinetic substudy of the prospective, randomized, multicentre, open-label Symphony study was performed. Eighty-three adult renal transplant patients received standard-dose cyclosporine, MMF 2 g/day and corticosteroids, or daclizumab induction, MMF 2 g/day and corticosteroids plus low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The area under the concentration-time curve (AUC(0-12)) of MPA and its metabolites between treatment groups was compared. Pharmacokinetic sampling was performed before MMF administration and at 20, 40, 75 min; 2, 3, 6, 8, 10 and 12 h post-dose on Day 7 and Months 1 and 3., Results: Compared with standard-dose cyclosporine, patients receiving low-dose tacrolimus or low-dose sirolimus had significantly higher AUC(0-12) values for MPA at Day 7 and Month 1 and for free MPA at Day 7, and significantly lower AUC(0-12) values for 7-O-MPA-glucuronide (MPAG) at Month 1 and for acyl-glucuronide at Months 1 and 3 (P < 0.05). AUC(0-12) of MPA and free MPA was significantly greater with low-dose tacrolimus and low-dose sirolimus than with low-dose cyclosporine in the first month (P < 0.05). The ratio of MPA to MPAG exposure was significantly higher in the three low-dose groups than in the standard-dose cyclosporine group (P < 0.05)., Conclusions: Standard- and low-dose cyclosporine reduces the exposure of MPA and free MPA compared to low-dose tacrolimus or low-dose sirolimus in patients given the same dose of MMF.

Background: The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results., Methods: De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL)., Results: Low-dose Tac was significantly superior for renal function, acute rejection, and graft survival at 12 months. Median trough levels of CsA, Tac, or SRL were toward the high end of target ranges in all groups, and 50% to 60% were within target. During weeks 1 to 8, only 6.5% to 11.0% of patients were consistently within target. At week 8, the range of concentrations encompassing 75% of patients on standard-dose CsA was 141 to 321 ng/mL; for low-dose CsA, 62 to 159 ng/mL; for low-dose Tac, 4.3 to 10.0 ng/mL, and for low-dose SRL, 4.4 to 11.2 ng/mL. The protocol-defined target levels were approximately, but not fully achieved., Conclusions: To replicate the Symphony study results in clinical practice, the protocol-defined drug concentration targets should be aimed for, but the concentrations actually achieved may be regarded as acceptable. Future clinical studies should include measures of how well target drug levels were achieved to better guide further attempts to develop new regimens designed to reduce or eliminate calcineurin inhibitors.

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels

Background: Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant., Methods: Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation., Results: Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively)., Conclusions: There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.

Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patients. In this study, we have found no influence of the -840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation. There also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for AcylMPAG has been suggested.

Objective: Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation., Methods: A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12., Results: Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36)., Conclusion: We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial., ((c) 2007 AASLD.)

Aims: Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects., Methods: One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation., Results: The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL., Conclusions: By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.

Background: There are no data on the effects of mycophenolate mofetil (MMF) on the incidence of bronchiolitis obliterans syndrome (BOS) in lung-transplant patients. This study attempted to determine whether MMF reduces the incidence of BOS in de novo lung transplant recipients compared with azathioprine (AZA)., Methods: This prospective, randomized, open-label, multicenter study compared the effects of MMF with AZA in combination with induction therapy, cyclosporine (Neoral) and corticosteroids in patients receiving their first lung transplant. Primary endpoint was incidence of BOS at 3 years. Secondary endpoints were incidence of acute rejection, time to first rejection event, and survival., Results: The incidence of acute rejection and the time to first rejection event at 1 and 3 years did not differ between groups (54.1% vs. 53.8% and 56.6% vs. 60.3% for MMF and AZA respectively). Survival at 1 year tended to be better in patients receiving MMF (88 vs. 80%, P = 0.07). At year 3, there was no difference in survival or in the incidence, severity or time to acquisition of BOS between the two groups. Treatment was generally well tolerated, however more patients withdrew from AZA treatment than from MMF (59.6% vs. 46.5%, P = 0.02). As a result, there was an imbalance in the observation times of the two groups (876 +/- 395 vs. 947 +/- 326 days)., Conclusions: No differences were seen in the incidence of acute rejection or BOS in lung transplant recipients treated with MMF or AZA. This null result may have been influenced by the shorter observation time for AZA patients.

A roundtable meeting to discuss the use of therapeutic drug monitoring (TDM) to guide immunosuppression with mycophenolate mofetil was held in New York in December 2004. Existing recommendations for the initial months after transplantation were updated. After ensuring adequate levels of mycophenolic acid (MPA, the active metabolite of mycophenolate mofetil) immediately after transplantation, optimal efficacy may require only a few dose adjustments, because intrapatient variability in exposure seems low. Recommendations based on current knowledge were made for posttransplantation sampling time points and for target MPA concentrations. Algorithms for estimating MPA exposure using limited sampling strategies were presented, and a new assay for MPA discussed. It was agreed that because of interpatient variability and the influence of concomitant immunosuppressants, TDM might help optimize outcomes, especially in patients at higher risk of rejection. The value of TDM in the general transplant population will be assessed from large, ongoing, randomized studies.

Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

The purpose of this study was to identify the pharmacokinetics of Amphotericin B Colloidal Dispersion in patients undergoing bone marrow transplantations with systemic fungal infections and to assess the influence of ABCD on renal function. Seventy-five patients (42 females, 33 males) with a median age of 34.5 years and median weight of 70.0 kg were enrolled in the study. The plasma concentration data was available in 51/75 patients and was best described by a two-compartment model; both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Serum creatinine values over the duration of therapy were available in 59/75 patients. Overall, there was no net change in renal function over the duration of therapy.

Purpose: Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS)., Patients and Methods: Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes., Results: Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin., Conclusion: Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.

Amphotericin B colloidal dispersion (ABCD) is a new formulation of conventional amphotericin B designed to minimize drug distribution in the kidney and reduce nephrotoxicity. We studied the safety and efficacy of ABCD in 133 renally compromised patients with invasive fungal infections. Patients had either nephrotoxicity from amphotericin B or preexisting renal disease. Intravenous treatment with ABCD (4 mg/kg of body weight daily) was administered for up to 6 weeks. Evaluations included clinical response to treatment and adverse events, with emphasis on changes in serum creatinine levels. ABCD did not appear to have an adverse effect on renal function: mean serum creatinine level tended to decrease slightly with days on therapy, and increases were not dose related. Complete or partial response to treatment was reported for 50% of the 133 intent-to-treat patients and 67% of the 58 evaluable patients.

To assess the efficacy and safety of amphotericin B colloidal dispersion (ABCD), 82 patients with proven or probable aspergillosis who were treated in clinical trials with ABCD were compared retrospectively with 261 patients with aspergillosis who were treated with amphotericin B at six cancer or transplant centers from January 1990 to June 1994. The groups were balanced in terms of underlying disease; ABCD recipients were younger and more likely to have preexisting renal insufficiency than were amphotericin B recipients (40.7% vs. 8.7%, respectively), and amphotericin B recipients were more likely to be neutropenic at baseline than were ABCD recipients (42.5% vs. 15.9%, respectively). Response rates (48.8%) and survival rates (50%) among ABCD-treated patients were higher than those (23.4% and 28.4%, respectively) among amphotericin B-treated patients (P < .001 for both comparisons). Renal dysfunction developed less frequently in ABCD recipients than in amphotericin B recipients (8.2% vs. 43.1%, respectively; P < .001). Multivariate analysis revealed that treatment group was the best predictor of response, mortality, and nephrotoxicity (ABCD: relative risk [RR] = 3.00, P = .002; RR = 0.35, P < .001; and RR = 0.13, P = .001; respectively). This retrospective study suggests that in the treatment of aspergillosis ABCD causes fewer nephrotoxic effects than amphotericin B and the efficacy of ABCD is at least comparable with that of amphotericin B.

Purpose: To determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy., Methods: Fifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks., Results: Nineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorubicin. Patients obtained clinical benefits such as flattening of lesions (48%), improved lesion color (56%), relief of pain (45%), and loss of edema (83%). Forty-nine percent of patients had more than one clinical benefit. The most common adverse effect was leukopenia, which occurred in 40% of patients. Only 15% of patients had nausea and/or vomiting, none of which was severe; 9% experienced alopecia, also generally mild., Conclusion: Pegylated-liposomal doxorubicin offers a new alternative for treatment of patients who have experienced failure of standard chemotherapy for AIDS-KS.

Amphotericin B colloidal dispersion (ABCD; Amphocil) was evaluated in a phase I dose-escalation study in 75 marrow transplant patients with invasive fungal infections (primarily Aspergillus or Candida species) to determine the toxicity profile, maximum tolerated dose, and clinical response. Escalating doses of 0.5-8.0 mg/kg in 0.5-mg/kg/patient increments were given up to 6 weeks. No infusion-related toxicities were observed in 32% of the patients; 52% had grade 2 and 5% had grade 3 toxicity. No appreciable renal toxicity was observed at any dose level. The estimated maximum tolerated dose was 7.5 mg/kg, defined by rigors and chills and hypotension in 3 of 5 patients at 8.0 mg/kg. The complete or partial response rate across dose levels and infection types was 52%. For specific types of infections, 53% of patients with fungemia had complete responses, and 52% of patients with pneumonia had complete or partial responses. ABCD was safe at doses to 7.5 mg/kg and had tolerable-infusion-related toxicity and demonstrable antifungal activity.

The purpose of this study was to evaluate the pharmacokinetics of amphotericin B colloidal dispersion and its effect on creatinine clearance in bone marrow transplant patients with systemic fungal infections. Seventy-five patients (42 females and 33 males) with a median age of 34.5 years and a median weight of 70.0 kg were enrolled in the study. Patients received 1 of 15 dose levels (range, 0.5 to 8.0 mg/kg of body weight) daily for a mean duration of 28 days and a mean cumulative dose amount of 8 g. Plasma samples for amphotericin B determination (median number, 4; range, 2 to 30) and daily serum creatinine values were obtained for each patient. Iterative two-stage analysis, one of several approaches to population pharmacokinetic and pharmacodynamic modelling, was employed for the pharmacokinetic analysis. The plasma data were available for 51 of 75 patients and were best described by a two-compartment model. Both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Of the covariates studied, only body weight and dose size were significant. Serum creatinine values over the duration of therapy were available for 59 of 75 patients. Overall, there was no net change in renal function over the duration of therapy; 12 patients had > 30% increases in creatinine clearance, whereas 13 had > 30% decreases. No measure of amphotericin B colloidal dispersion exposure, demographic values, or concomitant treatment with other medications was related to changes in the creatinine clearance.

A specific system of transport for p-aminohippurate (PAH) is demonstrated in rabbit renal basal-lateral membrane vesicles. The PAH uptake into an intravesicular space is inhibited by probenecid in concentrations above 0.2 mM. The transport is saturable and is also temperature-dependent with an optimum between 37 and 45 degrees C. Divalent cations are able to enhance the uptake 2- to 3-fold. The stimulatory effect of the divalent cations diminishes in the following order: Mg++ = Mn++, Ba++, Ca++ and Sr++. Maximum stimulation occurs between 2.5 and 5 mM Mg++. The divalent cation stimulatory effect is not the result of changes in the size of the vesicles, in the degree of vesiculation, in the net charge of the membrane or of a transient potential difference across the membrane. Several inhibitors, more inhibitory than probenecid, were found. These are: lithium diiodosalicylate; 4-acetamido-4'-isothiocyano 2,2'-disulfonic acid stilbene; the mercurials, mersalyl acid, p-chloromercuriphenyl sulfonate and Hg++; and 5,5'-dithiobis(nitrobenzoate). Among these, mersalyl acid is the most potent inhibitor for PAH uptake. Its inhibitory effect is probably a combination of its reactivity toward sulfhydryl groups and its anionic character. The results with sulfhydryl reagents indicate that the PAH transport system contains sulfhydryl groups which are essential for the uptake activity. These sulfhydryl groups are probably buried in a hydrophobic region within the lipoprotein matrix of the basal-lateral membrane.

Recent clinical investigations and reports of theoretical models have provided considerable insight into mechanisms of hepatic drug elimination and into derangements that may occur in drug absorption and disposition in patients with hepatic disease. Carefully conducted and well controlled clinical studies have demonstrated that hepatic disease may alter substantially one or more pharmacokinetic parameters of drug absorption and disposition. Physiological models of hepatic drug elimination have emphasised the importance of physiological variables such as hepatic blood flow, protein binding and intrinsic clearance of the liver on hepatic drug elimination. Both clinical investigations and theoretical considerations have indicated that the influence of hepatic disease on the pharmacokinetics of a drug may be complex and may result in either unchanged, retarded or even accelerated drug elimination. Changes in response to drugs in patients with hepatic impairment add to this complexity. Although general guidelines may be formulated now to assist clinicians in constructing dosage regimens of several important drug classes (notably the benzodiazepines and barbiturates) in hepatic disease, it is not now possible to predict in an individual the influence of a specific hepatic disease on the disposition of a drug, with the exception that the oral availability of drugs with high hepatic extraction ratios is increased in patients with cirrhosis and protacaval shunting of blood. Attempts to correlate concentrations of endogenous substances (such as bilirubin), or the pharmacokinetics of model drugs (such as antipyrine), with the pharmacokinetics of drugs that are useful in patients with hepatic impairment have not resulted in clinically useful tests of hepatic drug elimination. Following the administration of a drug to a patient with hepatic impairment, careful monitoring of the patient and also monitoring of plasma or blood drug concentrations remain important considerations.

The transport of organic anions by the kidney has been shown to be a carrier-mediated process. In an effort to learn more about this process, and examine the potential for two organic anions to compete for the same carrier site, studies were done which involved the transport of p-aminohippuric acid (PAH) and furosemide by vesicles made from basal-lateral membranes of rabbit kidney proximal tubules. Basal-lateral membranes were prepared by differential and ultracentrifugation. The transport was measured by using radiolabelled (3H) organic anions. The transport of each molecule was inhibited by probenecid, indicating that the carrier-mediated process for organic anion transport was functional in these studies. The results indicate that transport of PAH can be inhibited by furosemide in a concentration-dependent manner. This may indicate competition for the same carrier site. Inhibition of furosemide transport by PAH was not significant, perhaps due to much variability in the data. This variability may be due to nonspecific binding of furosemide to the vesicle, higher affinity of furosemide than of PAH for the receptor, or to the presence of more transport carriers for furosemide than for PAH. Experiments were done to determine the extent of nonspecific binding of furosemide. The results show that nonspecific binding of furosemide is extensive, indicating that this may contribute to the differences seen in the inhibition of transport. The data suggest that PAH and furosemide are transported by a common carrier-mediated process in the proximal tubule of the rabbit kidney.

The rapid kinetics of D-glucose uptake into membrane vesicles, prepared from the renal cortex of the rat, were measured. A vacuum manifold apparatus for the filtration of suspensions containing membrane vesicles and radiolabelled sugars was constructed to permit measurements of D-glucose accumulation within the vesicles at 8-s intervals. The rate of Na+-independent accumulation of D-glucose was nearly constant for the first 24 s while the rate for Na+-dependent uptake was always changing. While a linear relationship between Na+-dependent D-glucose accumulation and time could not be established for a time period as short as 8 s, the time for half maximum Na+-dependent D-glucose uptake could be estimated. A value of 4 s for half maximum accumulation D-glucose into membrane vesicles in the presence of sodium was obtained.

In renal basal-lateral membranous vesicles, the probenecid-sensitive p-aminohippurate uptake was stimulated by alloxan. This stimulation of uptake was observed only after a lag period of 15 seconds, and it reached a maximal value after one minute. Stimulation was increased by 1 mM to 5 mM alloxan in a linear fashion. The effect was maximal and constant between 5 mM and 20 mM alloxan. Alloxan affected neither the glucose space of the vesicle nor the rate of transport or diffusion of glutamate, another organic anion. The mechanism of stimulation by alloxan was not clear. Its effect was blocked by the sulfhydryl reagent N-ethylmaleimide and weakly mimicked by H2O2, an oxidizing reagent. However, ninhydrin, a structural analogue of alloxan which reacts with sulfhydryl groups, and glucose, a neutral structural analogue of alloxan, failed to stimulate probenecid-sensitive uptake.

Basal-lateral membranes from the renal cortex of the rabbit were isolated by sucrose gradient centrifugation in a zonal rotor which allows for a large-scale preparation of these membranes. A heterogeneous population of membranes (P4) which contained 29% of the (Na+ + K+)-ATPase found in the homogenate of renal cortex was prepared by differential centrifugation. When pellet P4 was subjected to centrifugation in a sucrose gradient the activity of (Na+ + K+)-ATPase, a marker for basal-lateral membranes, could be separated from enzymatic markers of other organelles. The specific activity of (Na+ + K+)-ATPase was enriched 12-fold at a density of 1.141 g/cm3. Membranes (P alpha) contained in the (Na+ + K+)-ATPase-rich fractions consisted primarily of closed vesicles which exhibited probenecid inhibitable transport of rho-aminohippurate. These membranes did not exhibit Na+-dependent, phlorizin-inhibitable D-glucose transport. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of proteins from P alpha revealed at least six major protein bands with molecular weights of 91000, 81000, 73000, 65000, 47000 and 38000. A small fraction of total alkaline phosphatase found in the homogenate was found in pellet P4. Membranes containing this alkaline phosphatase activity were distributed widely over the gradient, with peak activity found at a density of 1.141 g/cm3. In contrast, when brush borders were subjected to gradient centrifugation under the same conditions as P4, alkaline phosphatase was found in a narrow distribution, with peak activity at a density of 1.158 g/cm3. The principle subcellular localization of the alkaline phosphatase found in P4 could not be determined unambiguously from the data, but the activity did not seem to be primarily associated with classical brush borders.

Although most assays for measuring drug levels in serum determine the total concentration, effects from a drug are determined better by measuring the concentration of unbound (free) drug in serum. When the free fraction of a drug is constant, the total drug concentration may act as a good guide in predicting drug activity. However, if the free fraction is altered from normal, the serum concentration of the total drug may be misinterpreted. Quinidine has a high binding affinity for alpha-1-acid glycoprotein. We present the case of a woman who had a myocardial infarction; after cardiac surgery, she was found to have high concentrations of alpha-1-acid glycoprotein (228 mg/dL) and a low free fraction of quinidine (0.032). At that time the patient had a total concentration of quinidine of 33.9 mumol/L (11 micrograms/mL) but showed no signs or symptoms of toxicity because the concentration of free quinidine was not high. Physicians should be aware of the limitations of assays in determining the unbound concentration of drugs in serum. This awareness is particularly crucial with drugs that bind well to serum proteins, especially when pathologic conditions change the extent of binding.

Basal-lateral membranous vesicles prepared from rabbit renal cortex exhibited Mg2+-stimulated, probenecid-inhibitable transport of p-aminohippurate (PAH). This uptake could be completely eliminated by incubating the membranes with trypsin at a weight ratio of 1:700 (trypsin/membrane protein). The loss of PAH uptake activity occurred in two stages. Over the first ten minutes of the vesicles' exposure to trypsin, there was a nearly linear loss, with respect to time, of about 80% of the PAH uptake activity. The remaining 20% of activity was resistant to further trypsin digestion for the next ten minutes, but by twenty-five minutes a total inactivation of the uptake activity occurred. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of normal and trypsin-treated vesicles showed very little degradation of proteins. However, two minor polypeptides (Mr - 410,000 and 388,000) were degraded during the first ten minutes of the membranes' exposure to trypsin. After twenty minutes of exposure, two other polypeptides (Mr = 94,500 and 87,500) were degraded. Chymotrypsin and clostripain also caused a loss of PAH transport activity. However, compared to the effects of trypsin, the effects of these two proteases were less complete, slower in onset, and for clostripain, a much higher concentration of enzyme was required. Other functions or properties of the vesicles including morphological appearance, degree of vesiculation, glucose space or Na+-dependent L-glutamate transport and Na+,K+-ATPase activity were not altered by the concentration of trypsin which abolished 80% of the transport of PAH. Thus, it is possible that one or more of the degraded polypeptides detected by polyacrylamide gel electrophoresis comprises the PAH transporter.(ABSTRACT TRUNCATED AT 250 WORDS)

In basal-lateral membranes of the renal cortex, thiol substituted analogs of salicylate inhibited the uptake of p-aminohippurate (PAH). The mercury-containing analogs, thimerosal and mercaptide V (formed from 2 mol of thiosalicylate and 1 mol of Hg++), were highly inhibitory. Compared with probenecid, thimerosal and mercaptide V yielded dose-response curves of steeper slope and higher maximal effect. The dose-response curves of thimerosal and mercaptide V were similar in shape, although mercaptide V was more potent. The inhibition by thimerosal, mercaptide V and mersalyl acid, an anionic sulfhydryl reagent which also inhibits uptake of PAH ( Tse et al., J. Pharmacol. Exp. Ther. 226: 19-26, 1983), was found to be competitive with Ki values of 0.39 +/- 0.05, 0.12 +/- 0.06 and 0.05 +/- 0.02 mM, respectively. The inhibitory effects of thimerosal and mercaptide V were only partially reversible. Thimerosal and mercaptide V reacted 35 and 62%, respectively, with membrane sulfhydryl groups which may explain the nonreversibility of the inhibitor. The nonreversibility is probably not due to irreversible destruction of the vesicles, as the "glucose space" of the vesicles was not affected by these two compounds. That derivatives of salicylates capable of reacting with sulfhydryl groups were more inhibitory than thiosalicylate is consistent with a hypothesis that the PAH transporter contains a sulfhydryl group(s) essential for uptake. Based on the degree of inhibition, the degree of reversibility, the degree of membrane sulfhydryl group oxidation and the computer-generated three dimensional models of thimerosal, mercaptide V and mersalyl acid, a model of the PAH transporter is proposed.