Volume 53, No. 2/2015(February)
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Original
Association of time-to-levodopa with initial Parkinsonian medication: a retrospective cohort study
Jens Peter Reese, Hajo Hamer, Wolfgang H. Oertel, Adam Strzelczyk,Ulrich O. Mueller, Christina Heilmaier, and Karel Kostev
Price
42.00 $
Page No. 107
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (107-114)
Association of time-to-levodopa with initial Parkinsonian medication: a retrospective cohort study
Jens Peter Reese1,2, Hajo Hamer2, Wolfgang H. Oertel2, Adam Strzelczyk2, Ulrich O. Mueller1, Christina Heilmaier3, and Karel Kostev4
1Institute of Medical Sociology and Social Medicine, 2Department of Neurology, Philipps-University Marburg, Marburg, Germany, 3City Hospital Zuerich, Switzerland, and 4IMS Health, Epidemiology, Frankfurt, Germany
Objectives: To determine the initial distribution of medication in patients with de novo Parkinson’s disease (PD), to estimate the share of patients who not receive a recommended initial therapy according to current German guidelines, and to compare the time-to-levodopa. Methods: We used the Disease Analyzer database (IMS HEALTH), containing basic medical data from ~ 20 million patients in Germany. The primary outcome was the therapy change rate from initial treatment to levodopa estimated by Kaplan-Meier analyses. A Cox proportional hazards model was used to estimate the relationship between time-to-levodopa and confounders for a maximum follow-up of 10 years (between January 2002 and December 2011). Adjusted hazard ratios (HR) and 95% confidence intervals (CI) are presented for change-to-levodopa rate. Results: A representative sample of de-novo patients diagnosed with PD was drawn (n = 108,885). 71.8% of patients received levodopa as a first line treatment. 29,708 patients started with other anti-PD substances: 13.3% with dopamine agonists (DA), 3.6% with amantadine, 5.9% with anticholinergics, and 0.8% with monoamine oxidase B (MAO-B) inhibitors. Therefore, the proportion of patients who not receive a recommended initial therapy according to current German guidelines was ~ 10%. 29.0% of patients not starting with levodopa switched to levodopa within 5 years. After 5 years, more than 80% of PD patients using anticholinergics as their initial treatment remained levodopa-free. MAOB- inhibitors and DAs showed significantly lower proportions of levodopa-free patients after 5 years (35% and 55%, respectively). Compared to MAO-B inhibitors, the HR for switching to levodopa was 0.38 (CI 0.34 – 0.43; p < 0.001) for anticholinergics and 0.85 (CI 0.75 – 0.97; p = 0.017) for nonergot DA. Conclusions: Surprisingly, initial treatment with anticholinergics is correlated with the longest delay of levodopa treatment among all monotherapies. Our results suggest re-evaluating the comparative effectiveness of all initial PD treatments in head-tohead comparisons.Correspondence to:
Dr. Karel Kostev
IMS Health, Epidemiology
Darmstädter Str. 108, 60598 Frankfurt, Germany
Email: [email protected]
Original
Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants
Damayanthi Devineni, Nicole Vaccaro, Joe Murphy, Christopher Curtin, Rao N.V.S. Mamidi, Sveta Weiner, Shean-Sheng Wang, Jay Ariyawansa, Hans Stieltjes, Ewa Wajs, Nicholas A. Di Prospero, and Paul Rothenberg
Price
42.00 $
Page No. 115
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (115-128)
Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants
Damayanthi Devineni1, Nicole Vaccaro2, Joe Murphy1, Christopher Curtin1, Rao N.V.S. Mamidi1, Sveta Weiner1, Shean-Sheng Wang1, Jay Ariyawansa1, Hans Stieltjes3, Ewa Wajs3, Nicholas A. Di Prospero1, and Paul Rothenberg1
1Janssen Research and Development, LLC, Raritan, New Jersey, 2Janssen Research and Development, LLC, San Diego, California, USA, and 3Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg, Beerse, Belgium
Objective: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetesmellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. Methods: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4 – 12); study 2: canagliflozin 300 mg (days 1 – 17), probenecid 500 mg twice daily (days 15 – 17); and study 3: canagliflozin 300 mg (days 1 – 8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2 – 8 (study 3). Results: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. Conclusion: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.Correspondence to:
Dr. Damayanthi
Devineni Janssen Research and Development
LLC, 920, Route 202, Raritan, NJ 08869, USA
Email: [email protected]
Original
Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants
Damayanthi Devineni, Nicole Vaccaro, David Polidori, Hans Stieltjes, and Ewa Wajs
Price
42.00 $
Page No. 129
Abstract
Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants
Damayanthi Devineni1, Nicole Vaccaro2, David Polidori2, Hans Stieltjes3, and Ewa Wajs3
1Janssen Research and Development, LLC, Raritan, NJ, 2Janssen Research and Development, LLC, San Diego, CA, USA, and 3Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium
Objective: To evaluate the pharmacokinetics of oral canagliflozin and its Oglucuronide metabolites (M7 and M5) after single and multiple doses in healthy adult participants. The pharmacodynamics, safety, and tolerability of canagliflozin were also evaluated. Methods: In this open-label, single- (day 1) and multiple-dose (days 4 – 9), parallelgroup, phase 1 study, 27 healthy participants were randomized into three groups (1 : 1 : 1) to receive 50, 100, or 300 mg canagliflozin. Pharmacokinetics and pharmacodynamics were assessed at pre-pecified timepoints on days 1, 9, and 10. Results: Mean area under the plasma concentration-time curve, and the maximum observed plasma concentration of canagliflozin, M7, and M5 increased in a dose-dependent manner, across all the 3 doses, following single- and multiple-dose administration. The mean apparent elimination halflives of canagliflozin, M7, and M5 were independent of the dose. Canagliflozin decreased the renal threshold for glucose (RTG) and increased the urinary glucose excretion (UGE) in a concentration- and dose-dependent manner. The relationship between drug concentrations and RTG was described by a sigmoidal relationship with RTGmin (minimum value of RTG) of 37.5 ng/mL (95% confidence interval (CI): 34.3, 40.8) and half-maximal effective concentration (EC50) of 21 ng/mL (95% CI: 18.3, 23.8). No deaths, serious adverse events, hypoglycemic events, or discontinuations due to adverse events were observed. Conclusion: Pharmacokinetics of canagliflozin and its metabolites (M7 and M5) were linear, and no time-dependent changes were observed after single- and multiple-dose administration. Similarly, pharmacodynamic effects of canagliflozin on RTG and UGE were found to be dose- and concentration-dependent. Overall, canagliflozin was well-tolerated in healthy participants.Correspondence to:
Dr. Damayanthi
Devineni Janssen Research and Development
LLC, 920 Route 202, Raritan, NJ 08869, USA
Email: [email protected]
Original
Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects
Anthe Zandvliet, Shirley Glasgow, Ann Horowitz, Diana Montgomery, Joanne Marjason, Anish Mehta1, Christine Xu, Marianne van Vugt, and Sauzanne Khalilieh
Price
42.00 $
Page No. 139
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (139-146)
Tildrakizumab, a novel anti-IL-23 monoclonal antibody, is unaffected by ethnic variability in Caucasian, Chinese, and Japanese subjects
Anthe Zandvliet1, Shirley Glasgow1, Ann Horowitz1, Diana Montgomery1, Joanne Marjason2, Anish Mehta1, Christine Xu1, Marianne van Vugt1, and Sauzanne Khalilieh1
1Merck & Co., Inc. Whitehouse Station, NJ, USA, and 2Q-Pharm Pty Limited, Herston, Queensland, Australia
Objective: To evaluate the effect of ethnicity on the pharmacokinetics (PK) of tildrakizumab, a novel anti-IL-23 monoclonal antibody for the treatment of psoriasis. Materials and methods: This was an open-label, 2-part study in healthy adult subjects. In part 1, Japanese subjects and matched Caucasian and Chinese subjects (to Japanese) were assigned to 1 of 3 cohorts and administered tildrakizumab 50, 200, or 400 mg subcutaneously (SC). In part 2, Japanese subjects received tildrakizumab 10 mg/kg IV. Pre- and post-treatment antidrug antibodies were assessed. Safety and tolerability were assessed throughout the study. Results: 59 subjects were enrolled; 53 in part 1 and 6 in part 2. Overall geometric mean AUC∞ was 6.15, 6.05, and 6.32 day×μg/mL/mg in Japanese, Caucasian, and Chinese subjects, respectively, after administration of a single SC dose. Bioavailability was ~ 92%. Six out of 58 evaluable subjects were positive for post-treatment ADA; 2 of these positive subjects had reduced tildrakizumab exposure. Most AEs were mild in intensity and the most frequent treatment-related AEs were injection site hematoma (15%), injection site pain (10%), and injection site erythema (8%). Conclusions: The pharmacokinetics of tildrakizumab were similar in Japanese, Caucasian, and Chinese subjects. Tildrakizumab exposure increased proportionally with dose in the range of 50 – 400 mg. A single SC dose of 50, 200, and 400 mg or a single IV dose of 10 mg/kg was generally well tolerated.Correspondence to:
Anthe Zandvliet, PhD, MSD
Oss Molenstraat 110, 5342 CC, Oss, The Netherlands
Email: [email protected]
Original
Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin
Hyang-Ki Choi, Minkyung Oh, Eun Ji Kim, Geun Seog Song, Jong-lyul Ghim, Ji-Hong Shon, Ho-Sook Kim, and Jae-Gook Shin
Page No. 147
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (147-153)
Pharmacokinetic study of metformin to compare voglibose/metformin fixed-dose combination with coadministered voglibose and metformin
Hyang-Ki Choi1, Minkyung Oh1, Eun Ji Kim2, Geun Seog Song2, Jong-lyul Ghim1,3, Ji-Hong Shon1,3, Ho-Sook Kim1,3, and Jae-Gook Shin1,3
1Department of Pharmacology, Inje University College of Medicine, Busan, 2Clinical Development Division, CJ HealthCare Corp., Seoul, and 3Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
The aim of this study was to compare the pharmacokinetic characteristics of metformin between a fixed-dose combination (FDC) of voglibose/metformin and coadministered individual voglibose and metformin tablets in healthy Korean volunteers under fasting conditions. A randomized, open-label, single-dose, two-treatment, two-way crossover study with a 7-day wash-out period was conducted. Plasma samples were collected for up to 24 hours and were analyzed for metformin using a validated liquid chromatography tandem mass-spectrometry (LC/MS). A noncompartmental method was used to calculate the pharmacokinetic parameters. Vital signs and adverse events were monitored, and physical examinations and laboratory tests were conducted to evaluate safety. In total, 28 subjects completed the study. The geometric mean ratio (GMR) and the 90% confidence interval (CIs) of Cmax and AUC0–t of metformin were 102.4 (94.5 – 111.0) and 107.1 (100.1 – 114.7), respectively. In total, 7 adverse drug reactions occurred in 4 subjects during the study; of these, 3 cases were from 3 subjects in the test treatment group, and 4 cases were from 3 subjects in the reference treatment group. All adverse drug reactions had been reported previously, and all subjects recovered fully without any sequelae. In conclusion, the pharmacokinetic profiles of metformin in two different study treatments, a voglibose/metformin FDC vs. the coadministration of the individual formulations, met the regulatory criteria for bioequivalence in healthy Korean subjects under fasting conditions. There was no significant difference in safety profiles between the two treatments.Correspondence to:
Jae-Gook Shin, MD, PhD
Department of Pharmacology and Clinical Pharmacology
Inje University College of Medicine and Busan Paik Hospital
75 Bokji-ro, Busan Jin-gu, Busan,
Republic of Korea
and
Ho-Sook Kim, PhD
Department of Pharmacology and Clinical Pharmacology
Inje University College of Medicine and Busan Paik Hospital
75 Bokji-ro, Busan Jin-gu, Busan
Republic of Korea
Email: [email protected] and [email protected]
Original
Methylene tetrahydrofolate reductase genotypes frequencies: association with the toxicity of and response to methotrexate in rheumatoid arthritis patients
Mais M. Saleh, Yacoub M. Irshaid, and Khader N. Mustafa
Price
42.00 $
Page No. 154
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (154-162)
Methylene tetrahydrofolate reductase genotypes frequencies: association with the toxicity of and response to methotrexate in rheumatoid arthritis patients
Mais M. Saleh1, Yacoub M. Irshaid1, and Khader N. Mustafa2
1Department of Pharmacology, and 2Department of Internal Medicine, Faculty of Medicine, The University of Jordan, Amman, Jordan
Objectives: The purpose of this study was to determine the genotype/allele frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate (MTHFR) gene in Jordanian rheumatoid arthritis (RA) patients. In addition, the association between MTHFR gene C677T and A1298C polymorphisms and response to and toxicity of methotrexate (MTX) was evaluated. Methods: 159 adult rheumatoid arthritis ent Rheumatology Clinic at The Jordan University Hospital, between December, 2011 and April, 2012 were recruited into the study. Genomic DNA was extracted from leukocytes using Wizard Genomic DNA extraction Kit. The DNA extracts were amplified by polymerase chain reaction (PCR), and the PCR products were subjected to restriction enzymes to identify the C677T and A1298C genotypes. Genotype frequencies were identified and their relationship to some measures of MTX response and toxicity were evaluated. Results: The 677 TT genotype frequency was higher in RA patients (15.1%) compared to the healthy control group (5.9%) (odds ratio 3.09, 95% confidence interval (CI) 1.39 – 6.87, p-value = 0.0056). No such differences were seen with the A1298C genotypes. The frequencies of 677T and 1298C variant alleles were 0.346 and 0.296, respectively. None of the change-in-disease-activity measurements in MTX-treated patients has a significant association with the various genotypes. There was no significant association between A1298C genotypes and “any MTX toxicity”, but there was an association between C677T polymorphism and “any MTX toxicity” (p = 0.037). In addition, there was no association between both SNPs and specific MTX adverse effects. However, some haplotypes or combinations of the C677T and A1298C genotypes were associated with certain MTX side effects. Conclusions: More data from a larger number of RA patients are needed to evaluate the role of pharmacogenetic studies of MTHFR gene in predicting MTX response and toxicity.Correspondence to:
Yacoub M. Irshaid, MD, PhD
Department of Pharmacology, Faculty of Medicine
The University of Jordan, Amman 11942, Jordan
Email: [email protected]; [email protected]
Original
Association of fracture risk with benzodiazepine among adults in South Korea
Jin Seub Hwang, Sung-Hee Oh, Kang Seob Oh2, Kyoung-Uk Lee, Jong-Min Woo, Boung-Chul Lee, EunJeong Park, Su Jin Kwak, and Jin-Won Kwon
Price
42.00 $
Page No. 163
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (163-171)
Association of fracture risk with benzodiazepine among adults in South Korea
Jin Seub Hwang1*, Sung-Hee Oh1*, Kang Seob Oh2, Kyoung-Uk Lee3, Jong-Min Woo4, Boung-Chul Lee5, EunJeong Park1, Su Jin Kwak1, and Jin-Won Kwon1,6
1National Evidence-based Healthcare Collaborating Agency, Seoul, 2Department of Psychiatry, School of Medicine, Sungkyunkwan University, Seoul, 3Department of Psychiatry, Uijeongbu St. Mary’s Hospital, The Catholic University of Korea, College of Medicine, Seoul, 4Department of Psychiatry, Inje University Seoul Paik Hospital, Seoul, 5Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University, Seoul, and 6College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea
This study examined the association between fracture and benzodiazepine (BZD) prescription in Korean adults using case-crossover (CCO) and self-controlled case-series (SCCS) designs, which have the advantage to control confounding bias, such as individual characteristics. Patients with fracture were defined as patients who visited the emergency room and orthopedics department with the ICD-10 diagnosis code for fracture. Fractures due to motor vehicle accidents and stroke were excluded. Whereas the CCO design presented odds ratio (OR) using a conditional logistic regression model, SCCS design showed incidence rate ratio (IRR) using a conditional Poisson regression model. The concomitant drugs that can affect the fracture were adjusted. Sensitivity analysis and subgroup analysis by age (elderly vs. nonelderly), action mechanism (short-acting vs. long-acting), and prescription duration (short-term user vs. long-term user) were conducted. The adjusted OR (AOR) for control period I (prior to 90 days from case) was 1.39 (95% CI = 1.25 – 1.54) for all BZD prescriptions. The adjusted ORs for other control periods showed similar trends. The adjusted IRRs (AIRR) during the first 4 weeks, 4 – 8 weeks, 8 – 12 weeks, and 12 – 16 weeks from new BZD use were 1.46 (95% CI = 1.28 – 1.66), 1.23 (95% CI = 1.01 – 1.49), 1.09 (95% CI = 0.86 – 1.37), and 1.38 (95% CI = 1.07 – 1.77), respectively. Regardless of age group, action mechanism, or prescription duration, fracture risk was higher during case period than control. The risk for fracture was higher in both elderly and non-elderly people with BZD prescription than in those without BZD prescription. Careful monitoring for people who start BZD treatment and further research in the non-elderly is required.
*Jin Seub Hwang and Sung-Hee Oh contributed equally as co-first authors.Correspondence to:
Jin- Won Kwon, MPH, PhD
College of Pharmacy and Research
Institute of Pharmaceutical Sciences
Kyungpook National University
80 Daehak-ro, Buk-gu, Daegu 702-701, South Korea
Email: [email protected]
Bioavailability Section
Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation
Dongzhou J. Liu, Agron Collaku, and Stephen P. Youngberg
Price
42.00 $
Page No. 172
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (172-181)
Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation
Dongzhou J. Liu1, Agron Collaku1, and Stephen P. Youngberg2
1Clinical Development and Medical Affairs, GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, and 2Celerion, Lincoln, NE, USA
Objective: A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SR paracetamol formulation (2 × 1,000 mg) with those of immediaterelease (IR) paracetamol (2 × 500 mg) and existing extended-release (ER) paracetamol (2 × 665 mg). Methods: Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. Results: The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0–inf were 91% (0.86 – 0.96) for the fasted state and 99% (0.95 – 1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96 – 1.03) in the fasted state and 98% (0.95 – 1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p < 0.0001) and 0.77 (p < 0.0001) in study I and II, respectively. Conclusions: The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice-daily paracetamol treatment.Correspondence to:
Dongzhou J. Liu
Clinical Development and Medical Affairs
GlaxoSmithKline Consumer Healthcare
1500 Littleton Road, NJ 07054, USA
Email: [email protected]
Bioavailability Section
An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers
Renli Teng, Glenn Carlson, and Judith Hsia
Page No. 182
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (182-189)
An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers
Renli Teng, Glenn Carlson, and Judith Hsia
AstraZeneca LP, Wilmington, DE, USA
Objective: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally. Methods: In this single-center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post-ticagrelor dose for pharmacokinetic analyses. Safety and tolerability was assessed throughout the study. Results: At 0.5 hours postdose, plasma concentrations of ticagrelor and AR-C124910XX were higher with crushed tablets administered orally (148.6 ng/mL and 13.0 ng/mL, respectively) or via nasogastric tube (264.6 ng/mL and 28.6 ng/mL, respectively) compared with whole-tablet administration (33.3 ng/mL and 5.2 ng/mL, respectively). A similar trend was observed at 1 hour postdose. Ticagrelor tmax was shorter following crushed vs. whole-tablet administration (1 vs. 2 hours, respectively). Geometric mean ratios between treatments for AUC and Cmax were contained within the bioequivalence limits of 80 – 125% for ticagrelor and AR-C124910XX. All treatments were generally well tolerated. Conclusions: Ticagrelor administered as a crushed tablet is bioequivalent to whole-tablet administration, independent of mode of administration (oral or via nasogastric tube), and resulted in increased plasma concentrations of ticagrelor and ARC124910XX at early timepoints.Correspondence to:
Dr. Renli Teng
Clinical Pharmacology, AstraZeneca
One MedImmune Way, Gaithersburg, MD, 20878, USA
Email: [email protected]
Bioavailability Section
A randomized, three-treatment, three-period, six-sequence-crossover, single-center, bioequivalence study to evaluate the impact of different 10-mg crystalline forms on the pharmacokinetics of lenvatinib in healthy volunteers
Lucy Lee, Pina D’Angelo, David Verbel, Gresel Martinez, Jagadeesh Aluri, and Darin Brimhall
Price
42.00 $
Page No. 190
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 2/2015 (190-198)
A randomized, three-treatment, three-period, six-sequence-crossover, single-center, bioequivalence study to evaluate the impact of different 10-mg crystalline forms on the pharmacokinetics of lenvatinib in healthy volunteers
Lucy Lee1, Pina D’Angelo2, David Verbel3, Gresel Martinez4, Jagadeesh Aluri1, and Darin Brimhall5
1Clinical Pharmacology, Eisai Inc., Woodcliff Lake, NJ, 2Biostatistics, Novum Pharmaceutical Research Services, Pittsburgh, PA, 3Biostatistics, Eisai Inc., Woodcliff Lake, NJ, 4Clinical Operations, Eisai Inc., Woodcliff Lake, NJ, and 5Clinical Science, Novum Pharmaceutical Research Services, Las Vegas, NV, USA
Objective: This study assessed the impact of varying lenvatinib crystalline forms in 10-mg lenvatinib capsules on drug bioavailability in healthy volunteers. Materials: Lenvatinib 10-mg capsules (low C and high C forms). Methods: This randomized, three-period- crossover study compared the pharmacokinetics and safety of two crystalline forms of capsules (low C-form, < 4% crystalline; high C-form, 38% crystalline) to a standard (ref Cform, 15% crystalline). Results: 59 subjects were evaluable for pharmacokinetics. Test/reference ratios of the geometric least squares means (LSM) and 90% confidence intervals (CI) for AUC0–t (t up to 120 hours), AUC0–∞, and Cmax for low C-form vs. ref C-form were 101 (94.8, 107), 101 (95.3, 107), and 98.7 (88.6, 110), respectively; and for high C-form vs. ref C-form were 96.0 (92.1, 100), 96.5 (92.5, 101), and 90.6 (83.5, 98.4), respectively. The incidence of treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE) were comparable between all formulations (TEAE range 20 – 24%; TRAE range 15 – 19%). One serious TRAE (spontaneous abortion) occurred in the low C-form group. Conclusions: For both comparisons, the 90% CIs of the test/reference ratios were within the regulatory acceptance range (80 – 125%), suggesting that both test formulations (low Cform and high C-form) were bioequivalent to the reference formulation for Cmax, AUC0–t, and AUC0–∞.Correspondence to:
Lucy Lee, PharmD, FCP
Clinical Pharmacology, Eisai Inc.
300 Tice Boulevard, Woodcliff Lake, NJ 07677, USA
Email: [email protected]
