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Books: 0	Journals: 1	Articles: 4

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

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Volume 51 p. 693 - 703

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

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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 (AUC_τ,ss)) and maximum plasma concentration at steady state (C_max,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

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

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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, AUC_τ,ss of rosuvastatin was unchanged and its C_max,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC_τ,ss and C_max,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]

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

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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, C_max, t_max, t_1/2) 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 t_max (3 hours in fasted state vs. 4 hours in fed state) and decrease in C_max by 26%, however, the extent of absorption (AUC_last) was similar to that in the fasted state. Conclusions: Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C_max of metformin by 26%, while AUC_last was unchanged, consistent with previous reports. No food effect was observed on the C_max or AUC_last 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]

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