Tags

Type your tag names separated by a space and hit enter

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.
Drug Metab Dispos. 2018 Aug; 46(8):1179-1189.DM

Abstract

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP), and talinolol (P-gp) were obtained in cynomolgus monkey-alone or in combination with transporter inhibitors. Single-dose rifampicin (30 mg/kg) significantly (P < 0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin [area under the plasma concentration-time curve (AUC) ratio ∼21-39]. Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (P < 0.05) impacted the renal clearance of rosuvastatin (∼8-fold). In vitro, rifampicin (10 µM) inhibited uptake of pitavastatin, rosuvastatin, and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP, whereas talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions.

Authors+Show Affiliations

Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut.Pharmacokinetics, Dynamics, and Metabolism, Medicine Design (R.E.K., S.L., Y.-a.B., B.T., C.C., A.D.R., L.M.T., M.V.V.) and Research Formulations, Pharmaceutical Sciences (D.G., S.M.), Pfizer Worldwide R&D, Groton, Connecticut manthena.v.varma@pfizer.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29880631

Citation

Kosa, Rachel E., et al. "Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 46, no. 8, 2018, pp. 1179-1189.
Kosa RE, Lazzaro S, Bi YA, et al. Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey. Drug Metab Dispos. 2018;46(8):1179-1189.
Kosa, R. E., Lazzaro, S., Bi, Y. A., Tierney, B., Gates, D., Modi, S., Costales, C., Rodrigues, A. D., Tremaine, L. M., & Varma, M. V. (2018). Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 46(8), 1179-1189. https://doi.org/10.1124/dmd.118.081794
Kosa RE, et al. Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey. Drug Metab Dispos. 2018;46(8):1179-1189. PubMed PMID: 29880631.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey. AU - Kosa,Rachel E, AU - Lazzaro,Sarah, AU - Bi,Yi-An, AU - Tierney,Brendan, AU - Gates,Dana, AU - Modi,Sweta, AU - Costales,Chester, AU - Rodrigues,A David, AU - Tremaine,Larry M, AU - Varma,Manthena V, Y1 - 2018/06/07/ PY - 2018/04/01/received PY - 2018/05/30/accepted PY - 2018/6/9/pubmed PY - 2018/11/14/medline PY - 2018/6/9/entrez SP - 1179 EP - 1189 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 46 IS - 8 N2 - We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP), and talinolol (P-gp) were obtained in cynomolgus monkey-alone or in combination with transporter inhibitors. Single-dose rifampicin (30 mg/kg) significantly (P < 0.01) increased the plasma exposure of all four drugs, with a marked effect on pitavastatin and rosuvastatin [area under the plasma concentration-time curve (AUC) ratio ∼21-39]. Elacridar, BCRP/P-gp inhibitor, increased the AUC of sulfasalazine, talinolol, as well as rosuvastatin and pitavastatin. An OAT1/3 inhibitor (probenecid) significantly (P < 0.05) impacted the renal clearance of rosuvastatin (∼8-fold). In vitro, rifampicin (10 µM) inhibited uptake of pitavastatin, rosuvastatin, and sulfasalazine by monkey and human primary hepatocytes. Transport studies using membrane vesicles suggested that all probe substrates, except talinolol, are transported by cynoBCRP, whereas talinolol is a cynoP-gp substrate. Elacridar and rifampicin inhibited both cynoBCRP and cynoP-gp in vitro, indicating potential for in vivo intestinal efflux inhibition. In conclusion, a probe substrate cocktail was validated to simultaneously evaluate perpetrator impact on multiple clinically relevant transporters using the cynomolgus monkey. The results support the use of the cynomolgus monkey as a model that could enable drug-drug interaction risk assessment, before advancing a new molecular entity into clinical development, as well as providing mechanistic insights on transporter-mediated interactions. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/29880631/Simultaneous_Assessment_of_Transporter_Mediated_Drug_Drug_Interactions_Using_a_Probe_Drug_Cocktail_in_Cynomolgus_Monkey_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=29880631 DB - PRIME DP - Unbound Medicine ER -