Publications by authors named "James Keirns"

44 Publications

Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

J Clin Pharmacol 2020 01 5;60(1):125-139. Epub 2019 Aug 5.

ERT, Rochester, New York, USA.

The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean C on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.
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http://dx.doi.org/10.1002/jcph.1502DOI Listing
January 2020

Population pharmacokinetics of immediate- and prolonged-release tacrolimus formulations in liver, kidney and heart transplant recipients.

Br J Clin Pharmacol 2019 08 7;85(8):1692-1703. Epub 2019 Jun 7.

Formerly Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA.

Aims: Develop a population pharmacokinetics model of tacrolimus in organ transplant recipients receiving twice-daily, immediate-release (IR-T; Prograf) and/or once-daily, prolonged-release (PR-T; Advagraf or Astagraf XL) tacrolimus.

Methods: Tacrolimus concentration-time profiles were analysed from 8 Phase II studies in adult and paediatric liver, kidney and heart transplant patients receiving IR-T and/or PR-T. A tacrolimus population pharmacokinetic model, including identification of significant covariates, was developed using NONMEM.

Results: Overall, 23,176 tacrolimus concentration records were obtained from 408 patients. A 2-compartment model with first-order absorption and elimination described the concentration-time profiles. Tacrolimus absorption rate was 50% slower with PR-T vs IR-T. Tacrolimus apparent oral clearance was 44.3 L/h in Whites and 59% higher in Asians. Tacrolimus central volume of distribution was 108 L in males and 55% lower in females; trough concentrations were similar between formulations. Tacrolimus relative bioavailability was similar between formulations (geometric mean ratio PR-T:IR-T 95%, 90% confidence intervals: 89%, 101%). Asians had 83% and 51% higher relative bioavailability than Whites and Blacks, respectively, for IR-T and PR-T. Whites had 49% and 77% higher relative bioavailability than Blacks for PR-T and IR-T, respectively. Blacks had 52% lower relative bioavailability than Whites and Asians for IR-T and PR-T. Type of organ transplanted and patient population (adult/paediatric) did not have a significant effect on tacrolimus pharmacokinetics.

Conclusions: This population pharmacokinetic model described data from transplant recipients who received IR-T and/or PR-T. Tacrolimus trough concentrations and relative bioavailability were similar between formulations, supporting 1 mg:1 mg conversion from Prograf to Advagraf/Astagraf XL in clinical practice.
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http://dx.doi.org/10.1111/bcp.13952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624387PMC
August 2019

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.

Adv Ther 2017 12 13;34(12):2612-2624. Epub 2017 Nov 13.

Division of Clinical Pharmacology, University of Miami, Miami, FL, USA.

Introduction: Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir.

Methods: These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment.

Results: In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated.

Conclusion: The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5-2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance FUNDING: Astellas Pharma.
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http://dx.doi.org/10.1007/s12325-017-0643-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709452PMC
December 2017

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

Adv Ther 2017 12 13;34(12):2625-2637. Epub 2017 Nov 13.

Astellas Pharma Inc., Tokyo, Japan.

Introduction: Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants.

Methods: Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days.

Results: Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUC) and C . After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUC increased by about 90%. In the bioavailability study, AUC and C were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported.

Conclusion: Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUC almost doubling when amenamevir was administered with food. The concentration versus time profile of the tablet was slightly lower than that of the capsule; the relative bioavailability of the tablet versus the capsule was 86%. Amenamevir was safe and well tolerated in the dose range investigated.

Funding: Astellas Pharma.

Trial Registration: ClinicalTrials.gov identifiers NCT02852876 (15L-CL-002) and NCT02796118 (15L-CL-003).
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http://dx.doi.org/10.1007/s12325-017-0642-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709458PMC
December 2017

The Effect of Verapamil, a P-Glycoprotein Inhibitor, on the Pharmacokinetics of Peficitinib, an Orally Administered, Once-Daily JAK Inhibitor.

Clin Pharmacol Drug Dev 2017 Nov 16;6(6):548-555. Epub 2017 Mar 16.

Astellas Pharma Global Development Inc., Northbrook, IL, USA.

Peficitinib is an orally administered, once-daily Janus kinase inhibitor currently in development for the treatment of rheumatoid arthritis. It has been shown to be a P-glycoprotein (P-gp) substrate in vitro. The effects of verapamil, an inhibitor of the efflux pump P-gp, on the pharmacokinetic profile of peficitinib were assessed in this open-label, single-center, single-sequence, crossover drug-interaction study. Twenty-four healthy volunteers received a single 150-mg dose of peficitinib on days 1 and 12 of a 14-day treatment period and received verapamil 80 mg 3 times daily on days 5-14. Repeated-dose administration of verapamil increased mean peficitinib AUC , AUC , and C by 27%, 27%, and 39%, respectively, and also increased the mean AUC and C of peficitinib metabolites H1, H2, and H4. Coadministration of verapamil with peficitinib 150 mg was generally well tolerated. Overall, the most commonly reported adverse event was headache, which occurred in 5 subjects (21%); all reported adverse events were grade 1 severity, with the exception of 1 grade 2 incident of vomiting.
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http://dx.doi.org/10.1002/cpdd.344DOI Listing
November 2017

Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects.

Clin Pharmacokinet 2017 07;56(7):747-757

Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, 60062, USA.

Background And Objective: Peficitinib is an orally administered, once-daily Janus kinase inhibitor in development for the treatment of rheumatoid arthritis. Peficitinib and its major metabolite H2 inhibit the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. This article reports a clinical study evaluating the effects of peficitinib on the pharmacokinetics of rosuvastatin, a substrate for the OATP1B1 transporter, and vice versa.

Methods: In an open-label, single-sequence clinical study, 24 healthy adults of East Asian and non-East Asian origin received a single dose of rosuvastatin 10 mg on days 1 and 10. On days 5-13, subjects received a daily dose of 150 mg peficitinib. Serial blood samples for pharmacokinetic assessment of rosuvastatin were collected up to 96 h post-dose on days 1 and 10, and for peficitinib were collected up to 24 h post-dose on days 9 and 10.

Results: Co-administration of peficitinib with rosuvastatin increased rosuvastatin area under the concentration-time curve (AUC) and maximum plasma concentration (C ) by 18 and 15%, respectively and increased peficitinib AUC and C by 16 and 28%, respectively. In East Asian (n = 6) vs. non-East Asian subjects (n = 18), peficitinib mean AUC for a dosing interval was 45 and 21% higher, and mean C was 67 and 34% higher, when administered alone or with rosuvastatin. Peficitinib was well tolerated with few adverse events overall.

Conclusion: In this study, once-daily oral administration of peficitinib had no clinically significant effect on the pharmacokinetics of rosuvastatin, a probe substrate for OATP1B1. Therefore, it is unlikely that peficitinib will have a clinically significant effect on the exposure of other substrates for OATP1B1. CLINICALTRIALS.

Gov Number: NCT01959399.
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http://dx.doi.org/10.1007/s40262-016-0474-4DOI Listing
July 2017

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T-Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients.

Clin Pharmacol Drug Dev 2016 Sep 28;5(5):408-25. Epub 2016 Mar 28.

Astellas Pharma Global Development, Northbrook, IL, USA.

ASP2408 is a next-generation anti-cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was 36.3%-56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single-dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose-dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose-limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12-lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.
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http://dx.doi.org/10.1002/cpdd.251DOI Listing
September 2016

Can Bias Evaluation Provide Protection Against False-Negative Results in QT Studies Without a Positive Control Using Exposure-Response Analysis?

J Clin Pharmacol 2017 01 7;57(1):85-95. Epub 2016 Jul 7.

iCardiac Technologies, Inc, Rochester, NY, USA.

The revised ICH E14 document allows the use of exposure-response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when this cannot be achieved, there may be a need for metrics to protect against false-negative results. The objectives of this study were to create bias in electrocardiogram laboratory QT-interval measurements and define a metric that can be used to detect bias severe enough to cause false-negative results using exposure-response analysis. Data from the IQ-CSRC study, which evaluated the QT effect of 5 QT-prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying electrocardiogram algorithm (COMPAS). The slope estimate of the Bland-Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately -20 milliseconds over a QTcF range of 100 milliseconds to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. With the random methods, the rate of false-negatives was ≤5% with bias severity < -10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false-negative predictions with exposure-response analysis.
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http://dx.doi.org/10.1002/jcph.779DOI Listing
January 2017

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

Clin Transplant 2016 08 18;30(8):901-11. Epub 2016 Jun 18.

Transplant Genomics Inc., Brookline, MA, USA.

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus.
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http://dx.doi.org/10.1111/ctr.12763DOI Listing
August 2016

Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects.

Clin Pharmacol Drug Dev 2016 Nov 30;5(6):435-449. Epub 2016 Jun 30.

Astellas Pharma Global Development, Northbrook, IL, USA.

Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUC ) by 27%. Mean peak JAK inhibition increased with dose, from 6% at 4 hours (median) following ASP015K 3 mg to 93% (range, 89%-98%) at 2 hours (median) after ASP015K 300 mg. In the multiple-dose study, ASP015K plasma exposure reached steady state by day 3. On day 14, mean ASP015K peak concentration was 38%-65% higher than after the first dose; peak JAK inhibition following 100 or 200 mg twice daily was >85%. The most common adverse events (AEs) were neutropenia, headache, and abdominal pain; no serious AEs occurred. The safety findings at pharmacologically effective doses of ASP015K support further clinical development.
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http://dx.doi.org/10.1002/cpdd.273DOI Listing
November 2016

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14.

Drug Saf 2015 Sep;38(9):773-80

Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Karolinska Institutet, Stockholm, Sweden,

Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as an alternative to the E14 'thorough QT' study. This commentary shares and discusses the results of a recently conducted study with the objective to evaluate this approach. Six drugs with a well-characterized QT effect, five of which are known QT prolongers, were evaluated in a study design similar to a conventional single-ascending-dose study. Each drug was given to nine healthy subjects (six for placebo) in two dose levels, which for the positive drugs (ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide) were chosen with the intent to cause 10-12 ms and 15-20 ms QTc prolongation. Replicate 12-lead ECGs were extracted from continuous recordings pre-dose and serially after dosing and paired with drug concentration determinations. The ER criteria for the identification of a QT effect, a statistically significant positive ER slope and an effect above 10 ms, were met with all five positive drugs, and an effect exceeding 10 ms could be excluded at the supratherapeutic dose of the negative drug, levocetirizine. The study results thereby provided evidence to support that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study. Clinical and regulatory implications, as well as limitations of this approach, are discussed in the commentary.
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http://dx.doi.org/10.1007/s40264-015-0325-5DOI Listing
September 2015

Reproducibility of QTc interval changes after meal intake.

J Electrocardiol 2015 Mar-Apr;48(2):194-202. Epub 2015 Jan 8.

St. Paul's Cardiac Electrophysiology and Imperial College, London, England. Electronic address:

Background: Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established.

Methods: Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males. During each of the baselines, subjects were fasting in the morning and were served standardized lunch. Heart rates and QTc intervals were measured during repeated time-points throughout each study day. Two investigations were performed. In the first investigation, 3 heart rate and QTc measurements 1, 2, and 3h after lunch were averaged in each subject and corrected for the morning fasting baseline. Reproducibility of heart rate and QTc changes after the meal on different days X and Y was assessed by normalized repeatability coefficients 2*|MX-MY|/|MX+MY|, where MX and MY are measurements in the same subject on days X and Y, respectively. These were compared for heart rate and QTc changes after meal for different pairs of baseline days. In the second investigation, 36 females and 41 males were considered who received moxifloxacin during the source thorough QT study. The QTc increases after moxifloxacin were expressed by averaging 3 time-point values and corrected for placebo QTc values measured 25days apart. In the same subjects, QTc readings after lunch were also corrected for fasting baseline readings 25days apart. QTc responses to moxifloxacin and to meal intake were compared.

Results: Repeatability of QTc decreases after meal was significantly (p<0.0000001) poorer than that of heart rate increases after meal. Of the subjects receiving moxifloxacin during the study, 6% did not show QTc prolongation on moxifloxacin while 39% have not shown QTc shortening after lunch (p<0.00001).

Conclusion: The reproducibility of QTc changes after meal is limited. The power of proving QTc assay sensitivity by the detection of QTc changes after meal is poorer than the power of the standard moxifloxacin-based assay sensitivity.
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http://dx.doi.org/10.1016/j.jelectrocard.2015.01.006DOI Listing
November 2015

Are QTc interval changes after meal intake a reasonable method to prove assay sensitivity in thorough QT studies?

J Electrocardiol 2015 Mar-Apr;48(2):276-7. Epub 2015 Jan 6.

St. Paul's Cardiac Electrophysiology and Imperial College, London, England. Electronic address:

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http://dx.doi.org/10.1016/j.jelectrocard.2015.01.005DOI Listing
October 2015

Clinical pharmacokinetics and pharmacodynamics of the novel SGLT2 inhibitor ipragliflozin.

Clin Pharmacokinet 2014 Nov;53(11):975-88

Clinical Pharmacology, Global Development, Astellas Pharma Inc., Tokyo, Japan,

Ipragliflozin (Suglat(®)) is a potent and selective inhibitor of sodium-glucose cotransporter-2 that was recently launched in Japan. Its mechanism of action involves the suppression of glucose re-absorption in the kidney proximal tubules, causing excretion of glucose in the urine. The aim of this review is to provide a comprehensive overview of currently available pharmacokinetic and pharmacodynamic data on ipragliflozin, including studies in healthy subjects, patients with type 2 diabetes mellitus and special populations. In single- and multiple-dose studies, the maximum plasma concentration and area under the plasma concentration-time curve (AUC) for ipragliflozin increased in a dose-dependent manner. Although urinary excretion of ipragliflozin is low (approximately 1 %), tubular concentration of free ipragliflozin is adequate to provide pharmacological activities. No clinically relevant effects of age, gender or food on the exposure of ipragliflozin were observed. The AUC for ipragliflozin was 20-30 % greater in patients with moderate renal or hepatic impairment than in patients with normal renal or hepatic function. In drug-drug interaction studies, the pharmacokinetics of ipragliflozin and other oral antidiabetic drugs (metformin, sitagliptin, pioglitazone, glimepiride, miglitol and mitiglinide) were not significantly affected by their co-administration. Urinary glucose excretion (UGE) also increased in a dose-dependent manner, approaching a maximum effect at 50-100 mg dosages in Japanese healthy volunteers and patients with type 2 diabetes. The change in UGE from baseline (ΔUGE) tended to be lower in older subjects and female subjects, compared with younger subjects and male subjects, respectively. ΔUGE tended to decrease with decreasing renal function, especially in patients with type 2 diabetes with moderate or severe renal impairment.
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http://dx.doi.org/10.1007/s40262-014-0180-zDOI Listing
November 2014

QTc changes after meal intake: sex differences and correlates.

J Electrocardiol 2014 Nov-Dec;47(6):856-62. Epub 2014 Aug 2.

St. Paul's Cardiac Electrophysiology and Imperial College, London, UK. Electronic address:

Background: Detection of food-induced QTc shortening has been proposed as an assay sensitivity in thorough QT/QTc (TQT) studies. Data of a large clinical study were used to investigate the food effects on QTc intervals.

Methods: Day-time drug-free 12-lead Holter recordings starting around 8:20AM were repeated 4 times in each of 176 female and 176 male healthy subjects aged 32.7±9.1years. The recordings contained 16 episodes during which the subjects were in strict supine position. Heart rate and QTc intervals individually corrected for rate and QT/RR hysteresis were measured during these episodes and averaged over the 4 repeated recordings. In the morning hours, the subjects were fasting. Standardized lunch and dinner were served at around 2:00PM and 7:30PM, respectively. Heart rate and QTc changes induced by lunch and dinner were assessed by calculating the differences of averaged measurements from 2hours before till 2hours after the meals.

Results: In women, lunch and dinner led to statistically significant heart rate accelerations by 11.0±4.0 and 6.8±3.4 beats per minute [bpm], respectively. In men, the corresponding significant heart rate accelerations were by 9.9±3.4 and 4.5±2.6bpm, respectively. On the contrary, the QTc responses to both meals were inconsistent. After lunch, QTc intervals shortened significantly by 2.87±3.46ms and 0.79±3.64ms in women and men, respectively. However, after dinner, QTc intervals prolonged significantly by 4.69±3.66ms and 3.53±2.88ms in women and men, respectively.

Conclusions: There were systematic changes in individually corrected QTc intervals with QTc shortening after lunch and QTc lengthening after dinner, both in women and men. Because of these divergent diurnal effects, the use of meal-induced QTc changes to prove the assay sensitivity in TQT studies requires further evaluation.
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http://dx.doi.org/10.1016/j.jelectrocard.2014.07.026DOI Listing
October 2015

Cardiac Safety Research Consortium: can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward.

Am Heart J 2014 Sep 6;168(3):262-72. Epub 2014 Jun 6.

Safety Pharmacology Consultant, Sandwich, United Kingdom.

The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study.
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http://dx.doi.org/10.1016/j.ahj.2014.06.003DOI Listing
September 2014

Statistical analysis of Amenamevir (ASP2151) between pharmacokinetics and clinical efficacies with non-linear effect model for the treatment of genital herpes.

Clin Pharmacol Drug Dev 2014 09 17;3(5):365-70. Epub 2014 Feb 17.

Astellas Pharma Global Development, Inc, Northbrook, IL, USA.

Amenamevir is the international non-proprietary name for ASP2151 synthesized by Astellas Pharma, Inc. It is a structurally novel class of helicase-primase inhibitor and demonstrated more potency in vitro anti-viral activity with low cytotoxicity against varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2) than acyclovir (ACV). Phase II randomized trial assessed the safety and efficacy of ASP2151 for episodic therapy of recurrent genital herpes was conducted. Participants self-initiated with ASP2151 (100, 200, or 400 mg daily for 3 days), ASP2151 (1,200 mg as a single dose), placebo for 3 days, or Valacyclovir (500 mg twice daily for 3 days). We present a first population pharmacokinetic (PPK) modeling analysis of Amenamevir for genital herpes patients. The final model retained the effect of Weight and Albumin on CL. Statistical analysis between pharmacokinetics and clinical efficacies was done by using the time above 200 ng/mL (T200 ). T200 derived from the final PPK model to consider the correlation with Time to lesion healing and viral shedding. This finding suggested that it could be necessary to maintain the Amenamevir concentration above the threshold level to prevent the virus replication.
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http://dx.doi.org/10.1002/cpdd.108DOI Listing
September 2014

ICH E14-compatible holter bin method and its equivalence to individual heart rate correction in the assessment of drug-induced QT changes.

J Cardiovasc Electrophysiol 2014 Nov 11;25(11):1232-41. Epub 2014 Jun 11.

St. Paul's Cardiac Electrophysiology, University of London, and Imperial College, London, UK.

Introduction: The Holter bin method evaluates QT interval changes in the presence of heart rate changes without correcting the QT interval. However, the method does not allow time-matched comparisons, thus contradicting available guidance and good practice. We report a modification of the methods that allows time-matched comparisons without any heart rate correction.

Methods And Results: The modified Holter bin method (a) finds matching baseline heart rates for each QT reading on treatment and (b) calculates ΔQT values from the QT intervals on baseline and on treatment that match in heart rates. The difference between ΔQT values on active treatment and placebo provides the ΔΔQT value. The method was compared with the individual correction method in the data of the mirabegron thorough QT study in which supratherapeutic doses of this β3-adrenoceptor agonist led to substantial heart rate changes. The modified Holter bin method reproduced closely the results obtained with the individual heart rate correction. At all time points of the mirabegron study, the differences between the mean ΔΔQT values by the Holter bin method and the individual correction method were below 1 millisecond. Compared to the individual correction, the Holter bin method led to slight increases in the standard deviations of ΔΔQT values, but these were on average below 0.25 millisecond.

Conclusions: The Holter bin methodology can be modified to make it compatible with the available guidance and with good practice of clinical investigations. The results obtained with the modified Holter bin method are practically the same as with individualized heart rate corrected QT intervals. The close correspondence between the 2 methods demonstrates that the present possibilities of comparing QT interval duration in the presence of experiment-induced heart rate differences are not influenced by methodological artifacts.
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http://dx.doi.org/10.1111/jce.12450DOI Listing
November 2014

Have individual QT/RR curvatures value in QT correction?

J Electrocardiol 2014 May-Jun;47(3):386-91. Epub 2014 Jan 31.

Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, The Netherlands.

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http://dx.doi.org/10.1016/j.jelectrocard.2014.01.010DOI Listing
February 2015

Assessment of tacrolimus absorption from the human intestinal tract: open-label, randomized, 4-way crossover study.

Clin Ther 2014 May 27;36(5):748-59. Epub 2014 Mar 27.

IM/IDI Transplant, Astellas Pharma Global Development Inc, Northbrook, Illinois.

Background: Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract.

Objective: To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon.

Methods: The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters Cmax, Tmax after the capsule activation, AUC0-24, and mean residence time were determined from the concentration-time profiles.

Results: Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC0-24 values revealed some site-specific absorption tendencies, the mean AUC0-24 values obtained were similar regardless of the location of tacrolimus release from the capsule.

Conclusions: Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC0-24, possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.
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http://dx.doi.org/10.1016/j.clinthera.2014.02.021DOI Listing
May 2014

The IQ-CSRC prospective clinical Phase 1 study: "Can early QT assessment using exposure response analysis replace the thorough QT study?".

Ann Noninvasive Electrocardiol 2014 Jan 30;19(1):70-81. Epub 2013 Dec 30.

Karolinska Institutet, Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd's Hospital, Stockholm, Sweden and iCardiac Technologies, Rochester, NY.

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.
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http://dx.doi.org/10.1111/anec.12128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932720PMC
January 2014

QT/RR curvatures in healthy subjects: sex differences and covariates.

Am J Physiol Heart Circ Physiol 2013 Dec 25;305(12):H1798-806. Epub 2013 Oct 25.

St. Paul's Cardiac Electrophysiology, University of London, and Imperial College, London, United Kingdom;

Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 ± 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT = χ + (δ/γ)(1 - RR(γ)) + ε, where QT and RR are QT and RR measurements (in s), χ is regression intercept, δ is the QT/RR slope, γ is the QT/RR curvature and provides the lowest regression residual, and ε represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 ± 0.661 and 0.797 ± 0.706, respectively (P = 0.0006). The corresponding QT/RR slopes were 0.158 ± 0.030 and 0.139 ± 0.023, respectively (P < 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved.
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http://dx.doi.org/10.1152/ajpheart.00577.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882544PMC
December 2013

Relationship of QT interval variability to heart rate and RR interval variability.

J Electrocardiol 2013 Nov-Dec;46(6):591-6. Epub 2013 Aug 9.

St. Paul's Cardiac Electrophysiology, London, United Kingdom. Electronic address:

The study investigated whether the beat-to-beat QT interval variability relationship to the mean heart rate and the RR interval variability depended on the cardiovascular autonomic status changed by postural positioning. Repeated long-term 12-lead Holter recordings were obtained from 352 healthy subjects (mean age 32.7 ± 9.1 years, 176 females) while they underwent postural provocative tests involving supine, unsupported sitting and unsupported standing positions. Each recording was processed as a sequence of overlapping 10-second segments. In each segment, the mean RR interval, the coefficients of variance of the RR intervals (RRCV) and the QT intervals (QTCV) were obtained. In each subject, these characteristics, corresponding to different postural positions, were firstly averaged and secondly used to obtain within-subject correlation coefficients between the different characteristics at different postural positions. While the within-subject means of RRCV generally decreased when changing the position from supine to sitting and to standing (4.53 ± 1.95%, 4.12 ± 1.51% and 3.26 ± 1.56% in females and 3.99 ± 1.44%, 4.00 ± 1.24% and 3.53 ± 1.32% in males respectively), the means of QTCV systematically increased during these position changes (0.96 ± 0.40%, 1.30 ± 0.56% and 1.88 ± 1.46% in females and 0.85 ± 0.30%, 1.13 ± 0.41% and 1.41 ± 0.59% in males, respectively). The intra-subject relationship between QTCV, RRCV and mean RR intervals was highly dependent on postural positions. The study concludes that no universally applicable normalization of the QT interval variability for the heart rate and/or the RR interval variability should be assumed. In future studies of the QT variability, it seems preferable to report on the absolute values of QT variability, RR variability and mean heart rate separately.
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http://dx.doi.org/10.1016/j.jelectrocard.2013.07.007DOI Listing
July 2014

Ipragliflozin does not prolong QTc interval in healthy male and female subjects: a phase I study.

Clin Ther 2013 Aug 2;35(8):1150-1161.e3. Epub 2013 Aug 2.

Astellas Pharma Global Development, Inc, Northbrook, IL, USA.

Background: Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval.

Objective: The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects.

Methods: This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms.

Results: A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms).

Conclusions: No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.
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http://dx.doi.org/10.1016/j.clinthera.2013.06.009DOI Listing
August 2013

The effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin, a novel sodium glucose co-transporter 2 (SGLT2) inhibitor.

Clin Drug Investig 2013 Jul;33(7):489-96

Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL 60062, USA.

Background: Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites.

Methods: In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment [Child-Pugh score 7-9] and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored.

Results: All subjects completed the study. Least-squares geometric mean ratios (GMRs) (90 % confidence interval [CI]) for maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) of ipragliflozin were 127 % (93-173 %) and 125 % (94-166 %), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least-squares GMRs for C max and AUC∞ of M2, the major metabolite, were respectively 95 % (68-133 %) and 100 % (77-130 %) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred.

Conclusions: Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100 mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment.
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http://dx.doi.org/10.1007/s40261-013-0089-6DOI Listing
July 2013

Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a β3-adrenoceptor agonist.

Clin Drug Investig 2013 Jun;33(6):429-40

Astellas Pharma Global Development, Inc, 1 Astellas Way, N2-296, Northbrook, IL 60062, USA.

Background: Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6.

Objective: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism.

Methods: Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype.

Results: Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated.

Conclusions: Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.
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http://dx.doi.org/10.1007/s40261-013-0084-yDOI Listing
June 2013

Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults.

Clin Ther 2013 Mar;35(3):333-41

Astellas Pharma Global Development Inc, Northbrook, IL 60062, USA.

Background: Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology.

Objective: This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations.

Methods: In this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0-∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG.

Results: Thirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0-∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%-125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%-68.6%]) and AUC0-∞, by 17% (GMR, 83.2% [90% CI, 74.2%-93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0-∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%-78.7%]) and 18% (82.4% [72.6%-93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%-31.3%]) and AUC0-∞ by 51% (48.7% [43.3%-54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%-46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%-60.5%]) for AUC0-∞. The fed/fasted ratios for mirabegron Cmax and AUC0-∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5-2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states.

Conclusions: Mirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.
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http://dx.doi.org/10.1016/j.clinthera.2013.02.014DOI Listing
March 2013

Pharmacokinetics of intravenous conivaptan in subjects with hepatic or renal impairment.

Clin Pharmacokinet 2013 May;52(5):385-95

Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL 60062, USA.

Background: Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment.

Objective: The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function.

Study Design: These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US.

Patients: Men and non-pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups.

Intervention: Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered.

Main Outcome Measure: Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUC∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48).

Results: For each of C LD, C 48, and AUC∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUC∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event.

Conclusion: Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.
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http://dx.doi.org/10.1007/s40262-013-0047-8DOI Listing
May 2013

Effect of renal or hepatic impairment on the pharmacokinetics of mirabegron.

Clin Drug Investig 2013 Jan;33(1):11-23

Astellas Pharma Europe, Global Clinical Pharmacology Exploratory Development, PO Box 108, 2350 AC, Leiderdorp, The Netherlands.

Background And Objectives: Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated.

Methods: Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites.

Results: Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects.

Conclusion: Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.
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http://dx.doi.org/10.1007/s40261-012-0031-3DOI Listing
January 2013

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval.

J Electrocardiol 2012 Nov-Dec;45(6):571-81. Epub 2012 Sep 20.

St Paul's Cardiac Electrophysiology, London, England.

Objective: A statistical modelling study investigated whether incorporating the curvatures of QT/RR patterns into the individual-specific QT heart rate correction increases QTc data accuracy.

Methods: Repeated ECG readings were available from 4 different drug-free recordings made in 176+176 healthy female and male subjects (aged 32 ± 10 and 33 ± 8 years, respectively). In each subject, up to 1440 ECG readings were made of QT intervals and of the corresponding QT/RR hysteresis corrected RR intervals. The QT/RR patterns of each study participant was fitted with 12 different regression formulae that corresponded to differently curved physiologically plausible QT/RR profiles. In each subject, each of the regression fits was converted into a QT heart rate correction formula and the optimum model that fitted the data of the subject best was identified. Correction formulae were applied to modelled QT/RR data with RR intervals between 400 ms and 1600 ms. Differences in QTc intervals calculated by the correction formulae corresponding to the individually optimum QT/RR regression models and by the same type of regression in all study subjects were statistically summarised in females and males.

Results: Compared to the individually curvature optimised QTc heart rate correction formulae, formulae of the different regression models overestimated or underestimated the QTc values when applied on all study subjects. At RR of 500 ms, the model assuming linear QT/RR relationship led to errors of -5.01 ± 6.63 ms and of -4.80 ± 7.23 ms in females and males, respectively. At the same RR interval level, the model assuming the linear relationship between the logarithms of QT and RR intervals led to errors of +11.51 ± 6.36 ms and of +15.09 ± 7.61 ms in females and males, respectively.

Conclusion: The differences in the curvatures of QT/RR patterns should be considered in the optimisation of subject-specific heart rate corrections. Forcing an arbitrary simple regression model on the QT/RR patterns of different subjects may lead to appreciable errors in QTc estimates. The frequently used linear and log-linear regression models were among the least precise if used without checking their appropriateness in individual subjects.
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http://dx.doi.org/10.1016/j.jelectrocard.2012.07.017DOI Listing
May 2013
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