Original Research
Pharmacokinetics of single and multiple oral doses of valsartan/amlodipine (80/5 mg) in healthy Chinese subjects
Jingli Duan, Jin Chen, Qi Yin, Rajesh Karan, Karin Meiser, Harold Tom Smith and Gangadhar Sunkara
Price
42.00 $
Volume 50 p. 33 - 43
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 50 – No. 1/2012 (33-43)
Pharmacokinetics of single and multiple oral doses of valsartan/amlodipine (80/5 mg) in healthy Chinese subjects
Jingli Duan1*, Jin Chen2*, Qi Yin3, Rajesh Karan4, Karin Meiser5, Harold Tom Smith2 and Gangadhar Sunkara2
1Pharmacy Department, Peking University Third Hospital, Beijing, China, 2Translational Sciences, Novartis Institutes for Biomedical Research Inc., East Hanover, NJ, USA, 3Novartis Pharmaceuticals Corporation, Beijing, China, 4Novartis Healthcare Pvt. Ltd., Hyderabad, India and 5Translational Sciences Biostatistics, Novartis Pharma AG, Basel, Switzerland
*Both authors contributed equally to the manuscript.
Objective: The efficacy and safety of valsartan/amlodipine combination have been demonstrated for the treatment of hypertension. In China, where the prevalence of hypertension is increasing the pharmacokinetic study of valsartan, amlodipine assumes significance. The aim of this study was to characterize the pharmacokinetics (PK) of valsartan and amlodipine following single- and multiple-dose oral administrations of valsartan/ amlodipine 80/5 mg fixed-dose combination in healthy Chinese subjects. Materials and methods: This was an open-label, two-period (single-dose treatment followed by a multipledose (once-daily for 9 days), with a 7-day intertreatment washout period) study conducted in 18 subjects. Serial blood samples were collected at pre-defined time points, and the plasma concentrations of valsartan and amlodipine were measured using LC-MS/MS. Safety was evaluated after single- and multiple-dose drug administration. Results: Following the singledose oral administration of valsartan/amlodipine 80/5 mg, valsartan and amlodipine plasma concentrations reached peak levels at median tmax of 3 and 6 h, respectively. These concentrations declined thereafter, with mean elimination half-lives of 7.7 h (single dose) and 8.6 h (multiple dose) for valsartan, and 47 h (single dose) and 45 h (multiple dose) for amlodipine. After a 9-day multiple-dose treatment (at steady state), accumulation of valsartan and amlodipine was consistent with their half-lives. The single- and multiple-dose administration of valsartan/amlodipine 80/5 mg was associated with asymptomatic hypotension, consistent with the pharmacological activity of the combination of these two blood pressure-lowering drugs when co-administered in healthy subjects. Conclusion: The PK of valsartan and amlodipine are linear following oral administration of valsartan/amlodipine fixed-dose combination.Correspondence to:
Gangadhar Sunkara, PhD
Bldg 438/3407, One Health Plaza
Novartis Pharmaceuticals
East Hanover, NJ 07936,USA
Email: [email protected]
Original
Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor
Kenneth Kulmatycki, Imad Hanna, Dan Meyers, Atish Salunke, Aishwarya Movva, Tapan Majumda, Adrienne Natrillo, Arpine Vapurcuyan, Sam Rebello, Gangadhar Sunkara, and Jin Chen
Price
42.00 $
Volume 53 p. 345 - 355
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 5/2015 (345-355)
Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor
Kenneth Kulmatycki1, Imad Hanna2, Dan Meyers1, Atish Salunke3, Aishwarya Movva1, Tapan Majumdar2, Adrienne Natrillo2, Arpine Vapurcuyan2, Sam Rebello2, Gangadhar Sunkara2, and Jin Chen2
1Novartis Institutes for BioMedical Research, Cambridge, MA, 2Novartis Institutes for BioMedical Research, East Hanover, NJ, USA, and 3Novartis Institutes for BioMedical Research, Hyderabad, India
Objective: An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. Methods: The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily × 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Results: Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC50 value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC50 values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUCτ,ss of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUCτ,ss and Cmax,ss were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. Conclusion: These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.Correspondence to:
Kenneth Kulmatycki, PhD
Novartis Institutes for BioMedical Research, Inc.
200 Technology Square
Cambridge, MA 02139, USA
Email: [email protected]
Original
Effect of pradigastat, a diacylglycerol acyltransferase 1 inhibitor, on the pharmacokinetics of a combination oral contraceptive in healthy female subjects
Jin Chen, Suraj Bhansali, Srikanth Neelakantham, Craig Trusley, Tapan Majumdar, Sam Rebello, Gangadhar Sunkara, and Charles Meyers
Price
42.00 $
Volume 53 p. 317 - 324
Abstract
International Journal of Clinical Pharmacology and Therapeutics, Vol. 53 – No. 4/2015 (317-324)
Effect of pradigastat, a diacylglycerol acyltransferase 1 inhibitor, on the pharmacokinetics of a combination oral contraceptive in healthy female subjects
Jin Chen1, Suraj Bhansali1, Srikanth Neelakantham2, Craig Trusley3, Tapan Majumdar1, Sam Rebello1, Gangadhar Sunkara1, and Charles Meyers3
1Novartis Institutes for BioMedical Research, East Hanover, NJ, USA, 2Novartis Healthcare Private Ltd., Hyderabad, India, and 3Novartis Institutes for BioMedical Research, Cambridge, MA, USA
Objective: We evaluated the potential pharmacokinetic interaction between pradigastat, a potent and selective diacylglycerol acyltransferase 1 inhibitor, and Levora-28®, a combination oral contraceptive (COC) containing 30 μg ethinylestradiol (EE) and 150 μg levonorgestrel (LVG). Methods: An open-label, single-sequence three-period (period 1, single dose of COC; period 2, pradigastat 100 mg × 3 days followed by 40 mg × 7 days; and period 3, both pradigastat 40 mg and a single dose of COC) study involving 24 healthy female subjects of childbearing potential was conducted. Results: The pharmacokinetic parameters of EE were similar when administered alone or in combination with pradigastat, as the 90% confidence interval (CI) of geometric mean ratios for EE exposure (AUC and Cmax) were all within the range of 0.80 – 1.25. The AUC∞, AUClast, and Cmax of LVG were slightly increased in the presence of pradigastat, the geometric mean ratios (90% CI) were 1.25 (1.16, 1.35), 1.24 (1.15, 1.34), and 1.16 (1.06, 1.27), respectively. Conclusions: Pradigastat did not elicit clinically relevant changes in the magnitude of Levora-28® exposure. Therefore, dose adjustment is not required for Levora-28® when co-administered with pradigastat.Correspondence to:
Jin Chen, PhD
Clinical PK/PD, Novartis Institutes for BioMedical Research
One Health Plaza, 438-3406, East Hanover, NJ 07936-1080, USA
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]
