Abstract 4008
Background
Ribociclib (KISQALI®) is a CDK4/6 inhibitor that has been approved recently in the United States for use in combination with an aromatase inhibitor as a first-line therapy for HR+, HER2− advanced or metastatic breast cancer. The recommended ribociclib dose is 600 mg/day (3-weeks-on/1-week-off) with no restrictions on food intake or concomitant proton pump inhibitor (PPI) use. Here we examine the influence of gastric pH and food intake on ribociclib bioavailability using physiology-based pharmacokinetics (PBPK) modelling, observed clinical pharmacokinetic (PK) data, and population PK (pop-PK) analysis.
Methods
In silico PBPK models based on in vitro and preclinical data were built and fitted with clinical PK data from healthy volunteers. Sensitivity analyses were performed to evaluate the effect of gastric pH (range, 0.5-8.0) on ribociclib PK and absorption. A descriptive statistical analysis of clinical PK data from patients with and without concomitant PPI use and a pop-PK analysis were used to examine the effect of PPI dose intensity on ribociclib bioavailability. The effect of a high-fat meal on ribociclib exposure was evaluated in a bioequivalence trial in healthy volunteers.
Results
Sensitivity analyses using validated PBPK models predicted no effect of varying stomach pH on ribociclib absorption. PK data (AUC0-24h and Cmax) from several clinical studies showed similar ribociclib exposure regardless of PPI use (Table). The pop-PK analysis supported the PBPK models and clinical findings by showing that PPI use is a statistically insignificant and clinically unimportant covariate on ribociclib bioavailability. Food intake did not affect the rate or extent of ribociclib absorption.Table:
294P Ribociclib PK parameters by PPI usea
| Study No. | PK Parameter | n | PPI Use | Geometric Mean (Geometric Coefficient of Variation, %) |
|---|---|---|---|---|
| X2107 | AUC0-24h (ng*hr/mL) | 8 | Yes | 24,700 (30.6) |
| 10 | No | 21,100 (57.2) | ||
| Cmax (ng/mL) | 10 | Yes | 1,780 (34.6) | |
| 13 | No | 1,620 (53.2) | ||
| X2101 | AUC0-24h (ng*hr/mL) | 12 | Yes | 25,900 (79.1) |
| 46 | No | 23,700 (61.3) | ||
| Cmax (ng/mL) | 13 | Yes | 2,050 (74.7) | |
| 48 | No | 1,870 (60.3) | ||
| X1101 | AUC0-24h (ng*hr/mL) | 2 | Yes | 42,600 (28.7) |
| 6 | No | 55,100 (68.6) | ||
| Cmax (ng/mL) | 2 | Yes | 2,700 (53.0) | |
| 6 | No | 3,500 (65.8) |
AUC0-24h, area under the concentration-time curve from time zero to 24 hours; Cmax, maximal concentration; PK, pharmacokinetics; PPI, proton pump inhibitor. aDefined by PPI use prior to and on the day of sampling on C1D15 for AUC0-24h and Cmax, and on the dosing date corresponding to the AUC0-24h or Cmax. “Yes” was defined as PPI use for at least 5 consecutive days; “No” was defined as no PPIs use for at least 13 consecutive days.
Conclusions
In silico models and clinical PK data indicate that ribociclib can be administered without regard to PPI use or food intake. This lack of dosing restriction may facilitate greater patient compliance and clinical benefit.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation
Funding
Novartis Pharmaceuticals Corporation
Disclosure
T. Samant, M. Elmeliegy, Y. Lu, S. Yang, M. Miller, C. Germa: Employee of Novartis Pharmaceuticals Corporation. S. Dhuria: Was an employee Novartis Pharmaceuticals Corporation at the time this study was conducted; currently a consultant for Novartis Pharmaceuticals Corporation. M. Laisney, A. Grandeury, M. Mueller-Zsigmondy, K-I. Umehara, F. Huth: Employee of Novartis Pharma AG.