Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: fromin vitrodata to clinical study design

Abstract

1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263.

Development and Application of a Mechanistic Pharmacokinetic Model for Simvastatin and its Active Metabolite Simvastatin Acid Using an Integrated Population PBPK Approach

“…For GRT and SIRT which have been assumed to follow a logit-normal generalisation, the expected value and variance of the distribution were computed by numerical integration in order to calculate the reported CV (e) Residual variability is reported as variance terms (an additive error model was applied on the log-transformed data). eps SV and eps SVA correspond to the residual error variance associated with SV and SVA plasma concentrations respectively from a completely independent study [22] with a different study design, different analytical methodology and different population characteristics compared to the studies used for model development (discussed in Supplement 5 section 2). Therefore, additional confidence was provided that the parameter estimates of the developed model are not specific only for the population used for model development and use of the model outside the studied population and experimental conditions is justifiable.…”

“…S4.12) (c) Expessed in μL/min/pmol of CYP3A for SV and mL/min/mg of microsomal protein (MP) for SVA (d) Expressed in μL/min/mg of microsomal protein routinely used in population pharmacokinetic modelling (goodness of fit plots, VPC, bootstrapping procedure) were employed to assess the robustness of parameter estimates and the ability of the model to adequately describe the observed data and their variability (see Supplement 5 section 1 for further details). Subsequently, an independent (not fitted) dataset consisting of SV/SVA plasma concentrations determined in 28 healthy volunteers [22] was used for external model validation (see Supplement 5 section 2 for further details). Finally, the model was evaluated in terms of its predictive performance in situations outside of the studied population and conditions where some of the mechanisms of the system are perturbed (e.g., genetic polymorphisms and DDIs), (see model applications below).…”

The Metabolic Drug-Drug Interaction Profile of Dabrafenib: In Vitro Investigations and Quantitative Extrapolation of the P450-Mediated DDI Risk

“…The inhibition of cytochrome P450 activity was assessed using methods previously described (Shardlow et al, 2011;Polli et al, 2013) by incubating dabrafenib or its three metabolites with human liver microsomes over a concentration range of 0.1-100 mM. Incubations were conducted in duplicate with 0.1 mg/ml of human liver microsomes in 50 mM potassium phosphate buffer (pH 7.4) at 37°C for 5 or 10 minutes with the following probe substrates at concentrations corresponding to their respective concentration at half-maximal rate (K m ) values: phenacetin (CYP1A2), coumarin (CYP2A6), bupropion (CYP2B6), rosiglitazone (CYP2C8), diclofenac (CYP2C9), S-mephenytoin (CYP2C19); and nifedipine; atorvastatin; and midazolam (CYP3A4).…”

Design of Potent and Orally Active GPR119 Agonists for the Treatment of Type II Diabetes

“…8 However, despite tremendous efforts by academia and industry, the theoretical benefits that GPR119 agonists can offer have thus far been a challenge to demonstrate clinically. 10,11 We were interested in developing a fixed-dose combination (FDC) of a GPR119 agonist and a DPP4 inhibitor in the hope that such a combination would provide greater effects than either agent alone. 12 Previously we reported the design and synthesis of a series of GPR119 agonists with a cis-cyclopropane as the core structure.…”