estrogen biosynthesis in all tissues; it is highly specific, and does not impair adrenal steroidogenesis. No clinically relevant changes have been found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH, or plasma renin activity; ACTH stimulation tests after 6 and 12 weeks of treatment do not indicate attenuation of aldosterone or cortisol production, therefore glucocorticoid supplementation is not necessary. Blockade of estrogen biosynthesis did not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by letrozole, nor is thyroid function as eva luated by TSH, T3 uptake, and T4 levels. Using patient-derived estrogen receptor positive breast cancer xenograft models, the combination of ribociclib and letrozole increased tumor growth inhibition compared to each drug alone
PHARMACOKINETICS
Ribociclib: Ribociclib is administered orally. In vitro, ribociclib is approximately 70% protein bound in human plasma, independent of concentration (10 ng/mL to 10,000 ng/mL). The mean in vivo blood-to-plasma ratio was 1.04, indicating equal distribution between red blood cells and plasma. Based on a population pharmacokinetic analysis, the apparent volume of distribution at steady-state (Vss/F) of 1,090 L. The clinical activity and safety profile of ribociclib are primarily due to the parent drug, with little contribution from the circulating metabolites M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide) which are conjugated via N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. In patients with advanced cancer, the geometric mean plasma effective half-life was 32 hours (coefficient of variation (CV%), 63%) while the terminal half-life ranged from 29.7 to 54.7 hours in healthy subjects. The geometric mean apparent oral clearance at steady-state (CL/F) was 25.5 L/hr (CV%, 66%) in patients with advanced cancer and 39.9 to 77.5 L/hr in health subjects. Steady-state was generally achieved after 8 days of daily administration of the recommended dose; the geometric mean accumulation ratio was 2.51 (range, 0.972 to 6.40). Ribociclib is extensively metabolized, with unchanged drug accounting for 17% and 12% in feces and urine, respectively. After a single radio-labeled oral dose of ribociclib, 69% of the total dose was recovered in the feces and 23% in the urine.
Letrozole: Letrozole is administered orally. It is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). It is slowly metabolized to an inactive carbinol metabolite (4,4'methanol-bisbenzonitrile); renal excretion of the glucuronide conjugate of this metabolite is the major clearance pathway. Approximately 90% of a radiolabeled letrozole dose is recovered in the urine, at least 75% as the glucuronide of the carbinol metabolite, 9% as two unidentified metabolites, and 6% as unchanged letrozole. The terminal elimination half-life of letrozole is approximately 2 days, with steady-state plasma concentrations reached in 2 to 6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from concentrations after a single dose, indicating slightly non-linear pharmacokinetics; continuous accumulation does not occur.
Affected cytochrome P450 isoenzymes (CYP450) or drug transporters: CYP3A4, CYP1A2, CYP2E1, BCRP, OCT2, MATE1, and human BSEP
In vitro and in vivo studies indi |
