Original
Effects of meal timing relative to dosing on the pharmacokinetics and pharmacodynamics of vildagliptin in Japanese patients with Type 2 diabetes
Yan-Ling He, Harunobu Ito, Masayuki Yamaguchi, Shinji Terao, Sayaka Shimada, Shin Irie and Kaneo Sekiguchi
Price
42.00 $
Volume 50 p. 237 - 247
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 4/2012 (237-247)
Effects of meal timing relative to dosing on the pharmacokinetics and pharmacodynamics of vildagliptin in Japanese patients with Type 2 diabetes
Yan-Ling He1, Harunobu Ito2, Masayuki Yamaguchi2, Shinji Terao2, Sayaka Shimada2, Shin Irie3 and Kaneo Sekiguchi2
1Novartis Institutes for BioMedical Research Inc., Cambridge, MA, USA, and 2Novartis Pharma KK, Tokyo and 3Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan
Objective: To assess the effects of meal timing on the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin in Japanese patients with Type 2 diabetes. Methods: In this open-label, single-center crossover study, 12 Japanese patients with Type 2 diabetes were randomized to twice-daily vildagliptin 50 mg, administered 30 min before or immediately before breakfast and dinner for 7 days. After a 7-day washout period, patients received the other regimen. Blood samples were collected for the determination of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1) and glucose. Results: Vildagliptin absorption appeared slower when administered 30 min before rather than immediately before meals (tmax absolute range: 1.00 – 2.00 h vs. 0.33 – 1.58 h). Vildagliptin Cmax and AUC0–8 h were essentially the same irrespective of meal timing (geometric mean ratio: Cmax 1.08 (90% CI; 0.92 – 1.26); AUC0–8 h 0.97 (90% CI; 0.91 – 1.05)). Meal timing did not affect pharmacodynamics; complete DPP-4 inhibition (> 90%) was sustained for 8 h post-dose, and plasma active glucagon-like peptide-1 levels increased 2 – 3-fold from baseline. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPPG) reductions from baseline did not differ significantly with meal timing (30 min before vs. immediately before: FPG, –8.9 vs. –5.8 mg/dl; adjusted AUE0–4 h, –67.0 vs. –51.0 mg×h/dl). Vildagliptin was well tolerated. Conclusions: Dosing 30 min or immediately before meals did not affect vildagliptin pharmacokinetics or pharmacodynamics in Japanese patients with Type 2 diabetes.Correspondence to:
Yan-Ling He, PhD DMSc
Translational Sciences-Translational Medicine
Novartis Institutes for BioMedical Research Inc.
220 Massachusetts Avenue, Building 605
Cambridge, MA 02139-3584, USA
Email: [email protected]
Original Research
Antipsychotic treatment in older schizophrenia patients with extrapyramidal side effects in Asia (2001 – 2009)
Yu-Tao Xiang, Julie Kreyenbuhl, Faith B. Dickerson, Gabor S. Ungvari, Chuan‑Yue Wang, Tian-Mei Si, Edwin H.M. Lee, Helen F.K. Chiu, Kelly Y. C. Lai, Yan-Ling He, Shu-Yu Yang, Mian-Yoon Chong, Chay-Hoon Tan, Ee‑Heok Kua, Senta Fujii, Kang Sim, Michael K.H. Yong, Jitendra K. Trivedi, Eun‑Kee Chung, Pichet Udomratn, Kok- Yoon Chee, Norman Sartorius and Naotaka Shinfuku
Price
42.00 $
Volume 50 p. 500 - 504
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 7/2012 (500-504)
Antipsychotic treatment in older schizophrenia patients with extrapyramidal side effects in Asia (2001 – 2009)
Yu-Tao Xiang1,2, Julie Kreyenbuhl3,4, Faith B. Dickerson5, Gabor S. Ungvari6, Chuan‑Yue Wang2, Tian-Mei Si7, Edwin H.M. Lee1, Helen F.K. Chiu1, Kelly Y. C. Lai1, Yan-Ling He8, Shu-Yu Yang9, Mian-Yoon Chong10, Chay-Hoon Tan11, Ee‑Heok Kua11, Senta Fujii12, Kang Sim13, Michael K.H. Yong13, Jitendra K. Trivedi14, Eun‑Kee Chung15, Pichet Udomratn16, Kok-Yoon Chee17, Norman Sartorius18 and Naotaka Shinfuku19
1Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, 2Beijing Anding Hospital, Capital Medical University, Beijing, China, 3Division of Services Research, Department of Psychiatry, University of Maryland School of Medicine, 4Veterans Administration Capitol Healthcare Network (VISN 5) Mental Illness Research, Education, and Clinical Center (MIRECC), 5The Stanley Research Program at Sheppard Pratt, Baltimore, MD, USA, 6School of Psychiatry & Clinical Neurosciences, University of Western Australia, Perth, Australia, 7Key Laboratory of Mental Health, Ministry of Mental Health & Peking University Institute of Mental Health, Beijing, 8Shanghai Mental Health Center, Shanghai, China, 9Taipei City Hospital, Taipei, 10Kaohsiung Chang Gung Memorial Hospital and School of Medicine, Chang Gung University, Taiwan, 11National University of Singapore, Singapore, 12Hyogo Institute for Traumatic Stress (HITS), Kobe, Japan, 13Institute of Mental Health, Buangkok View, Singapore, 14Department of Psychiatry, C.S.M.Medical University UP, Lucknow, Uttar Pradesh, India, 15National Seoul Hospital, Seoul, Korea, 16Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand, 17Department of Psychiatry and Mental Health, Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Malaysia, 18Association for the Improvement of Mental Health Programs, Geneva, Switzerland and 19School of Human Sciences, Seinan Gakuin University Fukuoka, Japan
Kaohsiung Chang Gung Memorial Hospital and School of Medicine, Chang Gung University, Taiwan, National University of Singapore, Singapore, Hyogo Institute for Traumatic Stress (HITS), Kobe, Japan, Institute of Mental Health, Buangkok View,
Singapore, Department of Psychiatry, C.S.M.Medical University UP, Lucknow, Uttar
Pradesh, India, National Seoul Hospital, Seoul, Korea, Department of Psychiatry,
Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand, Department of
Psychiatry and Mental Health, Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Malaysia, Association for the Improvement of Mental Health Programs, Geneva, Switzerland and School of Human Sciences, Seinan Gakuin University Fukuoka, Japan
Objective: This study surveyed the prescribing patterns of antipsychotic medications in Asian older schizophrenia patients with extrapyramidal side effects (EPS) during the period between 2001 and 2009. Method: Information on 848 hospitalized patients with schizophrenia aged 60 or older was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001 – 2009). Data from those patients with reported EPS from 8 Asian countries and territories including China, Hong Kong, Japan, Korea, Singapore, Taiwan, India and Malaysia were analyzed. The cross-sectional data of sociodemographic and clinical characteristics and antipsychotic prescriptions were collected using a standardized protocol and data collection procedure. Results: Of the 309/848 (36%) patients suffering from EPS, 210 patients (210/309; 68.0%) received at least one type of first generation antipsychotic (FGA), and 99 (99/309; 32.0%) received second generation antipsychotics (SGAs) only. Of SGAs prescribed in patients with EPS, risperidone was the most commonly used (100/309; 32.4%) followed by olanzapine (33/309; 10.7%) and quetiapine (25/309; 8.1%). Conclusions: FGAs were frequently used in Asian older schizophrenia patients with EPS. Considering the potential adverse effects of FGAs on existing EPS, the reasons for the frequent use of FGAs need to be urgently identified.Correspondence to:
Dr. Yu-Tao Xiang
Department of Psychiatry
Chinese University of Hong Kong
Ground Floor, Multicentre, Tai Po Hospital
Tai Po, N.T., Hong Kong, China
Email: [email protected]
Original
Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment
Yan-Ling He, Kenneth Kulmatycki, Yiming Zhang, Wei Zhou, Christine Reynolds, Monica Ligueros-Saylan and Ann Taylor
Price
42.00 $
Volume 51 p. 693 - 703
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 9/2013 (693-703)
Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment
Yan-Ling He1, Kenneth Kulmatycki1, Yiming Zhang2, Wei Zhou2, Christine Reynolds2, Monica Ligueros-Saylan2 and Ann Taylor1
1Novartis Institutes for BioMedical Research, Cambridge, MA, and 2Novartis Pharmaceuticals, East Hanover, NJ, USA
Objective: The kidney plays a key role in both the metabolism and excretion of vildagliptin. This study was designed to investigate the effects of varying degrees of renal impairment (RI) on the pharmacokinetics of vildagliptin. Methods: A total of 96 subjects were enrolled, and each subject received vildagliptin 50 mg dosed orally once daily for 14 days. Vildagliptin and metabolite concentrations in plasma and urine were measured on Days 1 and 14. Results: Compared to age-, gender-, BMI-matched subjects with normal renal function, the mean AUC of vildagliptin after 14 days in patients with mild, moderate, and severe RI increased by 40%, 71%, and 100%, respectively, and the Cmax of vildagliptin showed similar and minimal increases of 37%, 32% and 36%, respectively. Conclusions: These pharmacokinetics results suggest that 50 mg once daily is an appropriate dose and recommended for patients with moderate and severe renal impairment.Correspondence to:
Yan-Ling He, PhD, DMSci
Translational Medicine
Novartis Institutes for BioMedical Research, Inc.
220 Massachusetts Avenue
Cambridge, MA 02139, USA
Email: [email protected]
Original
Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes
Masayuki Yamaguchi, Takami Saji1, Sachiko Mita, Kenneth Kulmatycki, Yan-Ling He, Kenichi Furihata and Kaneo Sekiguchi
Price
42.00 $
Volume 51 p. 641 - 651
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 8/2013 (641-651)
Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes
Masayuki Yamaguchi1, Takami Saji1, Sachiko Mita1, Kenneth Kulmatycki2, Yan-Ling He2, Kenichi Furihata3 and Kaneo Sekiguchi1
1Novartis Pharma K.K., Tokyo, Japan, 2Novartis Institute of Biomedical Research, Cambridge, MA, USA, and 3Keikokai Medical Corp. P-one Clinic, Tokyo, Japan
Objective: To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. Methods: In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. Results: Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). Conclusions: Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. Vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.Correspondence to:
Masayuki Yamaguchi, Dr., PhD
Novartis Pharma K.K. Tokyo
4-17-30, Nishi-Azabu
Minato-ku, Tokyo 106-8618, Japan
Email: [email protected]
Original
High-quality triplicate electrocardiogram monitoring in a first-in-man study: potential for early detection of drug-induced QT prolongation
Yan-Ling He, Yiming Zhang, Jing-He Yan, Wei Zhou, Steven Komjathy and Ann Taylor
Price
42.00 $
Volume 51 p. 948 - 957
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 12/2013 (948-957)
High-quality triplicate electrocardiogram monitoring in a first-in-man study: potential for early detection of drug-induced QT prolongation
Yan-Ling He1, Yiming Zhang2, Jing-He Yan2, Wei Zhou2, Steven Komjathy3 and Ann Taylor1
1Novartis Institutes for BioMedical Research, Cambridge, MA, 2Novartis, East Hanover, NJ, and 3Charles River Clinical Services Northwest Inc., Tacoma, WA, USA
Background: QT interval prolongation is associated with an increased risk of potentially fatal ventricular tachycardias, including torsade de pointes. Regulatory guidance recommends the “thorough QT/QTc” (TQT) study as the gold standard for assessing the propensity of novel nonantiarrhythmic drugs to delay cardiac repolarization. An opportunity exists, however, to use high-quality electrocardiogram (ECG) data from first-in-man trials as an exploratory and complementary approach to gain early insight into potential risk of QT prolongation. Methods: We collected high-quality, triplicate, 12-lead ECG data during a first-in-man trial of a drug developed for the treatment of Type 2 diabetes that had shown in vitro hERG inhibition and potential to prolong QT intervals in an animal model. Results: QTc prolongation was observed at the highest dose, leading to a maximum QTcF prolongation > 19 ms at 6 hours after the 14th daily dose. QTcF increases from time-matched baseline relative to placebo were positively correlated with peak plasma concentrations. Conclusions: Clinically relevant QT interval prolongations can be detected during first-in-man studies using high-quality ECG monitoring. Such data may facilitate early decision making on whether to terminate the development of a compound and invest resources in more promising molecules; and it may enable more efficient TQT study design or preclude the need for future TQT studies.Correspondence to:
Yan-Ling He, PhD, DMSc
Translational Medicine
Novartis Institutes for BioMedical Research
220 Massachusetts Avenue, Building 605
Cambridge, MA, 02139-3584, USA
Email: [email protected]
Bioavailability Section
Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects
Sachiko Mita, Shripad D. Chitnis, Kenneth Kulmatycki, Atish Salunke, Yan-Ling He, Wei Zhou, and Hikoe Suzuki
Price
42.00 $
Volume 54 p. 305 - 314
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 4/2016 (305-314)
Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects
Sachiko Mita1, Shripad D. Chitnis2, Kenneth Kulmatycki2, Atish Salunke3, Yan-Ling He2, Wei Zhou4, and Hikoe Suzuki1
1Novartis Pharma K.K., Tokyo, Japan; 2Novartis Institutes for BioMedical Research, Cambridge, MA, USA, 3Novartis Healthcare Private Limited, Hyderabad, India, and 4Novartis Institute for BioMedical Research, East Hanover, NJ, USA
Objective: To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Methods: Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 – 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, Cmax, tmax, t1/2) were calculated for vildagliptin and metformin. Results: In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged tmax (3 hours in fasted state vs. 4 hours in fed state) and decrease in Cmax by 26%, however, the extent of absorption (AUClast) was similar to that in the fasted state. Conclusions: Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the Cmax of metformin by 26%, while AUClast was unchanged, consistent with previous reports. No food effect was observed on the Cmax or AUClast of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.Correspondence to:
Sachiko Nozaki (Mita)
Novartis Pharma K.K.
23-1, Toranomon 1-chome, Minato-ku, Tokyo 105-6333, Japan
Email: [email protected]
