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Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor.
Int J Clin Pharmacol Ther. 2015 May; 53(5):345-55.IJ

Abstract

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 x 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 IC(50) 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 IC(50) 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 Cmax,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.

Authors

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Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

25740267

Citation

Kulmatycki, Kenneth, et al. "Evaluation of a Potential Transporter-mediated Drug Interaction Between Rosuvastatin and Pradigastat, a Novel DGAT-1 Inhibitor." International Journal of Clinical Pharmacology and Therapeutics, vol. 53, no. 5, 2015, pp. 345-55.
Kulmatycki K, Hanna I, Meyers D, et al. Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor. Int J Clin Pharmacol Ther. 2015;53(5):345-55.
Kulmatycki, K., Hanna, I., Meyers, D., Salunke, A., Movva, A., Majumdar, T., Natrillo, A., Vapurcuyan, A., Rebello, S., Sunkara, G., & Chen, J. (2015). Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor. International Journal of Clinical Pharmacology and Therapeutics, 53(5), 345-55. https://doi.org/10.5414/CP202275
Kulmatycki K, et al. Evaluation of a Potential Transporter-mediated Drug Interaction Between Rosuvastatin and Pradigastat, a Novel DGAT-1 Inhibitor. Int J Clin Pharmacol Ther. 2015;53(5):345-55. PubMed PMID: 25740267.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor. AU - Kulmatycki,Kenneth, AU - Hanna,Imad, AU - Meyers,Dan, AU - Salunke,Atish, AU - Movva,Aishwarya, AU - Majumdar,Tapan, AU - Natrillo,Adrienne, AU - Vapurcuyan,Arpine, AU - Rebello,Sam, AU - Sunkara,Gangadhar, AU - Chen,Jin, PY - 2015/04/24/accepted PY - 2015/3/6/entrez PY - 2015/3/6/pubmed PY - 2015/8/25/medline SP - 345 EP - 55 JF - International journal of clinical pharmacology and therapeutics JO - Int J Clin Pharmacol Ther VL - 53 IS - 5 N2 - 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 x 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 IC(50) 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 IC(50) 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 Cmax,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. SN - 0946-1965 UR - https://www.unboundmedicine.com/medline/citation/25740267/Evaluation_of_a_potential_transporter_mediated_drug_interaction_between_rosuvastatin_and_pradigastat_a_novel_DGAT_1_inhibitor_ L2 - http://www.dustri.com/nc/journals-in-english?artId=13160 DB - PRIME DP - Unbound Medicine ER -