Ribociclib Bioavailability Is Not Affected by Gastric pH Changes or Food Intake: In Silico and Clinical Evaluations

Abstract

Ribociclib (KISQALI), a cyclin‐dependent kinase 4/6 inhibitor approved for the first‐line treatment of HR+/HER2– advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH‐elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using 1) biorelevant media solubility, 2) physiologically based pharmacokinetic (PBPK) modeling, 3) noncompartmental analysis (NCA) of clinical trial data, and 4) population PK (PopPK) analysis. This multipronged approach indicated no effect of gastric pH changes on ribociclib PK and served as a platform for supporting ribociclib labeling language, stating no impact of gastric pH‐altering agents on the absorption of ribociclib, without a dedicated drug–drug interaction trial. The bioequivalence of ribociclib exposure with or without a high‐fat meal was demonstrated in a clinical trial. Lack of restrictions on ribociclib dosing may facilitate better patient compliance and therefore clinical benefit.

Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application

“…The concentrations of RIBO and LETRO obtained from the last sample (indicated in Table 7 as 5 and 6) resulted quite lower than the mean C min reported in literature for both drugs: RIBO concentration was 396.0 ng/mL while the population mean is 711 ng/mL [19], LETRO was measured at the concentration of 46.8 ng/mL while the reported mean is 107.0 ng/mL [11].…”

“…The first LC-MS/MS method for the simultaneous quantification of PALBO, RIBO and LETRO in human plasma was developed and successfully validated according to FDA/EMA guidelines [23,24]. Once overcome the PALBO and RIBO carryover issue by introducing blank samples to be run with a specifically developed washing method, calibration curves properly covered the in vivo concentrations of the drugs [6,11,[19][20][21][22]. The proposed method resulted linear over the concentration ranges of 0.3-250 ng/mL for PALBO, 10-10000 ng/mL for RIBO and 0.5-500 ng/mL for LETRO, while the only previously published method for the quantification of these CDKIs narrowed the concentration range to 2-200 ng/mL due to the carryover problem [18].…”

“…Moreover, the calibration range was 2-200 ng/mL for all the analytes and, thus, it does not properly cover all the in vivo concentration range, especially for RIBO. As reported in the literature, in vivo RIBO plasma concentrations (CV) fall in between 711 (72.9) ng/mL (C min ) and 3500 (65.8) ng/mL [19,20] while PALBO plasma concentrations range from the population mean C min (CV) of 61 (42) ng/mL [6] to 185.5 (27) ng/mL (C max , day 8 of cycle 1 at standard dose) [21].…”

Food Effect Projections via Physiologically Based Pharmacokinetic Modeling: Predictive Case Studies

“…PBPK absorption models of such weakly basic drugs with pH-solubility data at fasted and fed states can mechanistically describe no food effect or lack of proton pump inhibitor interactions. 24 Ribociclib is an orally bioavailable and highly selective smallmolecule inhibitor targeting cyclin-dependent kinase 4/cyclin-D1 and cyclin-dependent kinase 6/cyclin-D3 enzyme complexes. 25 This drug was overall classified as a BCS IV compound.…”

“…Ribociclib absorption was estimated with PBPK absorption modeling to be >85% with clinical formulations. 24 Ribociclib is metabolized by CYP3A (63%) followed by FMO3 (16%) in relation to hepatic metabolic CL. Contribution of renal elimination to total CL is low accounting for 7% of the dose.…”