Topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 phase 3 randomized controlled trials.

BACKGROUND: Glycopyrronium tosylate (GT) is a topical anticholinergic developed for once-daily treatment of primary axillary hyperhidrosis. OBJECTIVE: Assess the efficacy and safety of GT for primary axillary hyperhidrosis. METHODS: ATMOS-1 and ATMOS-2 were replicate randomized, double-blind, vehicle-controlled, 4-week phase 3 trials. Patients were randomized 2:1 to GT 3.75% or vehicle applied once daily to each axilla for 4 weeks. Coprimary endpoints were responder rate (≥4-point improvement from baseline) on item 2 (severity of sweating) of the Axillary Sweating Daily Diary (ASDD), which is a newly developed patient-reported outcome measure, and absolute change from baseline in axillary gravimetric sweat production at week 4. Safety evaluation included treatment-emergent adverse events. RESULTS: Pooled data, which are consistent with the individual trial results, show that significantly more GT-treated patients achieved an ASDD-Item 2 response than did those treated with vehicle (59.5% vs 27.6%), and they had reduced sweat production from baseline (-107.6 mg/5 min vs -92.1 mg/5 min) at week 4 (P < .001 for both coprimary end points). Most treatment-emergent adverse events were mild or moderate and infrequently led to discontinuation. LIMITATIONS: Short trial duration and inherent challenges in gravimetrically assessing sweat production. CONCLUSIONS: GT applied topically on a daily basis over 4 weeks reduced the severity of sweating as measured by ASDD-Item 2, reduced sweat production as measured gravimetrically, and was generally well tolerated in patients with primary axillary hyperhidrosis.

How delayed graft function impacts exposure to mycophenolic acid in patients after renal transplantation.

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.

Limited Systemic Exposure with Topical Glycopyrronium Tosylate in Primary Axillary Hyperhidrosis.

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).

Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia.

PURPOSE: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients.

The pharmacokinetics of mycophenolate mofetil (MMF) in liver transplant recipients may change because of pharmacokinetic interactions with coadministered immunosuppressants or because changes in the enterohepatic anatomy may affect biotransformation of MMF to mycophenolic acid (MPA) and enterohepatic recirculation of MPA through the hydrolysis of mycophenolate acid glucuronide to MPA in the gut. In the latter case, the choice of formulation (oral versus intravenous) could have important clinical implications. We randomized liver transplant patients (n = 60) to standard (10-15 ng/mL) or reduced (5-8 ng/mL) trough levels of tacrolimus plus intravenous MMF followed by oral MMF (1 g twice daily) with corticosteroids. Pharmacokinetic sampling was performed after the last intravenous MMF dose, after the first oral MMF dose, and at selected times over 52 weeks. The efficacy and safety of the 2 regimens were also assessed. Twenty-eight and 27 patients in the tacrolimus standard-dose and reduced-dose groups, respectively, were evaluated. No significant differences between the tacrolimus standard-dose and reduced-dose groups were seen in dose-normalized MPA values of the time to the maximum plasma concentration (1.25 versus 1.28 hours), the maximum plasma concentration (15.5 +/- 7.93 versus 13.6 +/- 7.03 microg/mL), or the area under the concentration-time curve from 0 to 12 hours (AUC(0-12); 53.0 +/- 20.6 versus 43.8 +/- 15.5 microg h/mL) at week 26 or at any other time point. No relationship was observed between the tacrolimus trough or AUC(0-12) and MPA AUC(0-12). Exposure to MPA after oral and intravenous administration was similar. Safety and efficacy were similar in the two treatment groups. In conclusion, exposure to MPA is not a function of exposure to tacrolimus. The similar safety and efficacy seen with MMF plus standard or reduced doses of tacrolimus suggest that MMF could be combined with reduced doses of tacrolimus.

The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy.

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.

Design and Conduct Considerations for First-in-Human Trials.

A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations. An emphasis is placed on FIH trial design considerations, including starting dose selection, study size and population, dose escalation scheme, and implementation of adaptive designs. In light of the recent revision of the European Medicines Agency (EMA) guideline on FIH trials to promote safety and mitigate risk, we also discuss new measures introduced in the guideline that impact FIH trial design.

A 44-Week Open-Label Study Evaluating Safety and Efficacy of Topical Glycopyrronium Tosylate in Patients with Primary Axillary Hyperhidrosis.

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.

Daclizumab to prevent rejection after cardiac transplantation.

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.

Comparison of the Pharmacokinetics of Ketorolac Tromethamine After Continuous Subcutaneous Infusion and Repeat Intramuscular Bolus Injections in Healthy Adult Subjects.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that exhibits analgesic activity with no sedative or anxiolytic properties. Twelve healthy male subjects were enrolled in a study to receive either of 2 treatments over 2 periods in an open-label, randomized, 2-way crossover design: (A) 120 mg of ketorolac tromethamine administered as a continuous subcutaneous infusion over a 24-hour period; or (B) an identical total daily dose administered as 4 intramuscular bolus injections of 30 mg each given every 6 hours (current labeled treatment regimen). The pharmacokinetic and safety profiles were evaluated for both treatments. Both modes of administration have similar values for area under the curve (AUC) and half-life (t1/2 ), suggesting that continuous subcutaneous infusion and repeated intramuscular bolus injections have similar bioavailability. The peak plasma concentration (Cmax ) was 40% lower when ketorolac was administered as a continuous subcutaneous infusion compared with repeat intramuscular bolus injections. The concentration at steady-state (Css ) for continuous subcutaneous infusion was between the Cmax and Ctrough values obtained following the 4 intramuscular injections. Both treatment arms were well tolerated.

Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients.

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.

Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib.

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.

From mechanisms to long-term benefits.

Mycophenolate mofetil (MMF), a widely used immunosuppressant in solid organ transplantation, is a prodrug to deliver mycophenolic acid (MPA). MMF has been shown to decrease rejection rates and to improve graft survival, and probably accomplishes this through a variety of mechanisms. Its most prominent mechanism is to inhibit lymphocyte proliferation by inhibition of inosine monophosphate dehydrogenase. However, just as important to its overall beneficial effects are other mechanisms that include inhibition of proliferation of smooth muscle and fibroblasts, inhibition of antibody production, inhibition of lymphocyte adhesion and migration, and inhibition of nitric oxide synthase.

Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients.

BACKGROUND: This study reports the 36-month results of a randomized, double-blind, active-controlled trial of mycophenolate mofetil (MMF) vs azathioprine (AZA) in heart transplant patients. METHODS: Patients were randomized at the time of transplant to receive MMF (1,500 mg twice a day, N = 327) or AZA (1.5 to 3 mg/kg in 4 daily doses, N = 323) in addition to cyclosporine and corticosteroids; 289 patients in each group received study drug. Data were analyzed in all randomized patients (enrolled) and in patients who received study medications (treated). Clinical and graft assessments continued for 36 months. RESULTS: For the co-primary end-point, 53 of 289 (18.3%) AZA-treated patients either died or received another transplant compared with 34 of 289 (11.8%) MMF-treated patients (p < 0.01). Time to re-transplantation or patient death was significantly shorter for AZA- than MMF-treated patients (p = 0.029). In patients undergoing intravascular ultrasound, the change in mean maximal intimal thickness was less for the MMF group than for the AZA group (0.06 +/- 0.03 mm vs 0.13 +/- 0.03 mm, respectively; p = 0.056). No significant differences between treatments were observed in quantitative coronary angiographic measurements of transplant coronary vasculopathy. Congestive heart failure, atrial arrhythmia and leukopenia were more common in the AZA group, whereas diarrhea, esophagitis, Herpes simplex, Herpes zoster and cytomegalovirus (CMV) tissue invasion were more common in MMF-treated patients. CONCLUSION: MMF reduces mortality and graft loss up to 36 months after transplantation.

Evaluation of the effect of food and gastric pH on the single-dose pharmacokinetics of cabozantinib in healthy adult subjects.

Cabozantinib is a small molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Cabozantinib exhibits a pH-dependent solubility profile in vitro. Two phase 1 clinical pharmacology studies were conducted in healthy subjects to evaluate whether factors that may affect cabozantinib solubility and gastric pH could alter cabozantinib bioavailability: a food effect study (study 1) and a drug-drug interaction (DDI) study with the proton pump inhibitor (PPI) esomeprazole (study 2). Following a high-fat meal (study 1), cabozantinib Cmax and AUC were increased (40.5% and 57%, respectively), and the median tmax was delayed by 2 hours. Cabozantinib should thus not be taken with food (patients should not eat for at least 2 hours before and at least 1 hour after administration). In the DDI study (study 2), the 90% confidence intervals (CIs) around the ratio of least-squares means of cabozantinib with esomeprazole versus cabozantinib alone for AUC0-inf were within the 80%-125% limits; the upper 90%CI for Cmax was 125.1%. Because of the low apparent risk of a DDI, concomitant use of PPIs or weaker gastric pH-altering agents with cabozantinib is not contraindicated.

Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid.

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.

Mycophenolic acid exposure after administration of mycophenolate mofetil in the presence and absence of cyclosporin in renal transplant recipients.

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.

The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study.

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.

AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism.

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.

CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients.

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.