Effects of vercirnon on the activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe substrates

Abstract

PurposeVercirnon is a CCR9 chemokine receptor antagonist being developed for the treatment of Crohn’s disease. As a variety of concomitant medications are often required for the treatment of Crohn’s disease, it is important to characterise the drug interaction profile of vercirnon. To confirm the results of previous in vitro inhibition studies, this study assessed the in vivo effect of vercirnon on the activity of cytochrome P450 enzymes (CYP3A4, CYP2C19 and CYP2C8) and drug transport proteins (BCRP and OATP1B1) using probe substrates.MethodsThis was an open-label, single-sequence, repeat-dose study conducted in 24 healthy adult subjects. On days 1–4, subjects received probe substrates (midazolam, pioglitazone, omeprazole and rosuvastatin; in that order), followed by administration of vercirnon 500 mg twice daily (BID) on days 5–14. On days 11–14, in addition to vercirnon 500 mg BID, subjects also received probe substrates as on days 1–4. Blood samples were collected for pharmacokinetic analysis of probe substrates, vercirnon and two of its metabolites.ResultsGeometric least-squares mean ratios (90 % confidence interval) of area under the concentration-time curve from time zero to infinity for probe administered with vercirnon (test) compared with probe alone (reference) for midazolam, pioglitazone, omeprazole and rosuvastatin were 0.92 (0.85, 0.99), 1.01 (0.95, 1.07), 0.99 (0.76,1.31) and 0.98 (0.88, 1.09), respectively.ConclusionsCo-administration of probe substrates midazolam, pioglitazone, omeprazole, and rosuvastatin following repeat dosing of vercirnon 500 mg BID demonstrated vercirnon had no clinically significant effect on CYP3A4, CYP2C8, CYP2C19 enzyme activity or BCRP or OATP1B1 transporter activity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-013-1592-7) contains supplementary material, which is available to authorized users.

Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans

“…Human in vivo drug–drug interaction and/or phenotyping studies that have used rosuvastatin as a BCRP probe have been conducted in healthy adults who were administered a single oral 10‐mg dose . Exceptions existed as a single 5‐mg dose, and 20 mg once daily for 10 days has also been used .…”

“…The extent of rosuvastatin AUC and C max increases due to BCRP inhibition of precipitant drugs ranges from 1.5‐ to 7.1‐fold and 2‐ to 10.6‐fold, respectively . For a few studies, a lack of agreement between in vitro BCRP inhibition and in vivo findings has been reported, with the precipitant drug showing no statistically or clinically significant change in rosuvastatin PK …”

“…17,19 Human in vivo drug-drug interaction and/or phenotyping studies that have used rosuvastatin as a BCRP probe have been conducted in healthy adults who were administered a single oral 10-mg dose. 17,[20][21][22][23][24][25] Exceptions existed as a single 5-mg dose, and 20 mg once daily for 10 days has also been used. [26][27][28] There is a lack of complete dose proportionality, as rosuvastatin AUC and C max ratios comparing the 20-and 10-mg doses are less than 1.5.…”

“…20,21,[26][27][28] For a few studies, a lack of agreement between in vitro BCRP inhibition and in vivo findings has been reported, with the precipitant drug showing no statistically or clinically significant change in rosuvastatin PK. 23,24,30 Pitavastatin. Pitavastatin is another HMG-CoA reductase inhibitor with an absolute oral bioavailability of 0.6 and is considered a class III (low-permeability, high-solubility) drug by Biopharmaceutics Classification System (BCS).…”