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
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]
Bioavailability Section
Effect of food on the oral bioavailability of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects
Surya Ayalasomayajula, Thomas Langenickel, Priya Chandra, Edward Wolfson, Diego Albrecht, Wei Zhou, Parasar Pal, Iris Rajman, Gangadhar Sunkara
Price
42.00 $
Volume 54 p. 1012 - 1018
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 54 – No. 12/2016 (1012-1018)
Effect of food on the oral bioavailability of the angiotensin receptor - neprilysin inhibitor sacubitril/valsartan (LCZ696) in healthy subjects
Surya Ayalasomayajula1, Thomas Langenickel2, Priya Chandra1, Edward Wolfson3, Diego Albrecht2, Wei Zhou1, Parasar Pal4, Iris Rajman2, Gangadhar Sunkara1
1Novartis Institutes for BioMedical Research, East Hanover, NJ, USA,
2Novartis Institutes for BioMedical Research, Basel, Switzerland,
3Novartis Institutes for BioMedical Research, Cambridge, MA, USA, and 4Biostatistical Sciences, Novartis Healthcare Pvt. Ltd., Hyderabad, India
Objective: Sacubitril/valsartan (LCZ696) provides a novel therapeutic approach of neurohormonal modulation in heart failure via simultaneous inhibition of neprilysin and blockade of the angiotensin II type-1 receptor. This study was conducted to evaluate the effect of food on the oral bioavailability of LCZ696 analytes. Materials and methods: This was an open-label, randomized, 3-period crossover study in healthy subjects. Eligible subjects (N = 36) were randomized to 6 treatment sequences, each comprising 3 treatment periods during which subjects received a single oral dose of 400 mg LCZ696 under fasting condition and following a low- and high-fat meal. Results: Following administration of LCZ696 after low- and high-fat meals, the mean Cmax of sacubitril and sacubitrilat (the active neprilysin inhibitor) decreased by 42 – 54% and 19 – 28%, respectively, while the tmax values increased. However, systemic exposure (AUCinf and AUClast) of sacubitril was slightly decreased (by 16% with low-fat meal) and that of sacubitrilat was unchanged in the presence of food. For valsartan, the Cmax decreased by ~ 40% when LCZ696 was administered after low- and high-fat meals. The systemic exposure of valsartan decreased by ~ 33% with a low-fat meal; however, it was unchanged with a high-fat meal. LCZ696 was generally safe and well tolerated in healthy subjects when administered under fasting or fed condition. Conclusion: Overall, administration of LCZ696 with meals decreased the rate and extent of absorption of sacubitril with little impact on the systemic exposure to sacubitrilat, its active metabolite. The systemic exposure to valsartan was decreased in the presence of food.
Correspondence to:
Surya Ayalasomayajula, MS, PhD
Novartis Institutes for Biomedical Research
East Hanover, NJ, USA
Email: surya.ayalasomayajula@ novartis.com
Original Research
Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
Kenneth M. Kulmatycki, Thomas Langenickel, Wai Hong Ng, Parasar Pal, Wei Zhou, Tsu-Han Lin, Iris Rajman, Priyamvada Chandra, and Gangadhar Sunkara
Price
42.00 $
Volume 55 (2017) p. 728 - 739
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 55 – No. 9/2017 (728-739)
Pharmacokinetics and safety of sacubitril/valsartan (LCZ696) in patients with mild and moderate hepatic impairment
Kenneth M. Kulmatycki1, Thomas Langenickel2, Wai Hong Ng3, Parasar Pal4, Wei Zhou3, Tsu-Han Lin3, Iris Rajman2, Priyamvada Chandra3, and Gangadhar Sunkara3
1Novartis Institutes for Biomedical Research, Cambridge, MA, USA, 2Novartis Institutes for BioMedical Research, Basel, Switzerland,
3Novartis Institutes for Biomedical Research, East Hanover, NJ, USA, and
4Novartis Healthcare Pvt. Ltd., Hyderabad, Telangana, India
Objectives: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. Methods: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. Results: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 – 109%, respectively. Conclusions: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.
Correspondence to:
Kenneth M. Kulmatycki, PhD
Novartis Institutes for Biomedical Research
220 Massachusetts Avenue, 342E
Cambridge, MA 02139, USA
Email: [email protected]
Original
The impact of residual renal function on quality of life in patients with peritoneal dialysis
Wei Zhou, Weifeng Hu, Guofeng Han, Huiling Wang, Jinyuan Zhang, and Changlin Mei
Volume 90 (2018) p. 106 - 111
Abstract
Clinical Nephrology, Vol. 90 – No. 2/2018 (106-111)
The impact of residual renal function on quality of life in patients with peritoneal dialysis
Wei Zhou1#2, Weifeng Hu2, Guofeng Han2, Huiling Wang2, Jinyuan Zhang2, and Changlin Mei1
1Department of Nephrology, Changzheng Hospital, Second Military Medical University, and 2Division of Nephrology, Jimin Hospital, Shanghai, China
Background: Residual renal function (RRF) is a crucial factor that plays an important role in peritoneal dialysis (PD) patients, but whether RRF influences the quality of life (QOL) of PD patients is still controversial. The aims of this study were to explore the effects of RRF on QOL in patients with continuous ambulatory peritoneal dialysis (CAPD) and analyze the related factors that might affect patients’ QOL. Materials and methods: All 120 adult patients in this study received regular CAPD treatment for at least 3 months. Patients were divided into two groups: an RRF group (residual glomerular filtration (rGFR) ≥ 1 mL×min–1×(1.73m2)–1) and a non-RRF group (rGFR < 1 mL×min–1×(1.73m2)–1). The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was used as a reference to calculate the scores of CAPD patients for assessing their QOL. Multiple- and single-linear regression analysis was performed to analyze correlation degree of several SF-36-related indexes. Results: The indexes of age, gender, cause of disease, complication, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), hemoglobin (HB), cholesterol, triglycerides, high- and low-density lipoprotein, normalized protein catabolic rate (nPCR), and cardiothoracic ratio (CTR) showed no difference between the two groups (RRF and non-RRF). Comparing with RRF group, the patients without RRF showed a significant difference on indexes of PD duration, urine volume, ultrafiltration volume, dialysis dose, serum albumin, potassium, Kt/V (urea reduction ratio), creatinine, calcium, phosphate, C-reactive protein (CRP), and parathyroid hormone (PTH). Single-linear regression analysis that achieved total score of SF-36 showed no correlation with rGFR, but there was a correlation of SF-36 score with CRP, creatinine, CTR, albumin, and ultrafiltration volume. Conclusion: These results suggested that there was no correlation between RRF and QOL in CAPD patients, but chronic inflammation, fluid overload, and malnutrition were considered as the main factors that affect patients’ QOL.
Correspondence to:
Prof. Changlin Mei, Master
Department of Nephrology
Changzheng Hospital Second Military Medical University
415 Fengyang Road, Shanghai 200003, China
Email: [email protected]
Bioavailability Section
Pharmacokinetics, safety, and bioequivalence of apixaban tablets in healthy Chinese subjects under fasting and fed conditions
Hong-Yu Luo, Zhen-Jiang Yao, Hui-Zhi Long, Zi-Wei Zhou, Shuo-Guo Xu, Feng-Jiao Li, Yan Cheng, Dan-Dan Wen, Ping Deng, Yue-Qing Guan, and Li-Chen Gao
Price
42.00 $
Volume 61 (2023) p. 129 - 138
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 61 – No. 3/2023 (129-138)
Pharmacokinetics, safety, and bioequivalence of apixaban tablets in healthy Chinese subjects under fasting and fed conditions
Hong-Yu Luo1#2, Zhen-Jiang Yao3, Hui-Zhi Long1#2, Zi-Wei Zhou1#2, Shuo-Guo Xu1#2, Feng-Jiao Li1#2, Yan Cheng1#2, Dan-Dan Wen1#2, Ping Deng1#2, Yue-Qing Guan3, and Li-Chen Gao1#2
1School of Pharmacy, Department of Pharmacy, Phase I Clinical Trial Center, Changsha Central Hospital Affiliated to University of South China, University of South China, Hengyang, 2Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Changsha, and 3Ningbo High Tech Zone Minova Pharmaceutical Innovation Research Institute Co., Ltd., Ningbo, China
Objective:/b> To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions.
Materials and methods:<7´/b> A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUC0–t and AUC0–∞) and the maximal plasma concentration (Cmax). Safety was assessed mainly from the occurrence of adverse events (AEs).
Results: A single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUC0–t were 95.4 – 100.9% and 97.8 – 103.8%, and for AUC0–∞ were 95.3 – 100.6% and 98.3 – 104.3% under fasting (36 subjects) and fed (27 subjects) conditions, respectively. Similarly, the 90% CIs for Cmax were 94.6 – 103.1% and 88.8 – 102.0% under fasting (36 subjects) and the fed (27 subjects) conditions, respectively. Therefore, the 90% CIs for the T/R AUC and Cmax ratios were within the standard range for bioequivalence (80.0 – 125.0%). There were no serious adverse events (SAEs).
Conclusion: The test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.Correspondence to:
Li-Chen Gao, MD
School of Pharmacy, Department of Pharmacy
Phase I Clinical Trial Centre
Changsha Central Hospital
Affiliated to University of South China
Changsha, 410004 China
Email: [email protected]
