Abstract
Abstract Background Rifampin is a strong inducer of multiple Phase 1 and Phase 2 metabolic enzymes including cytochrome (CYP) P450 3A4 and sulfotransferases (SULT). In vitro, the metabolism of palbociclib occurs primarily through CYP3A4 and SULT2A1; thus, coadministration of rifampin and palbociclib could result in decreased exposure of palbociclib. Methods This open-label, 2-period, fixed-sequence study assessed the effect of multiple oral doses of rifampin on single-dose palbociclib pharmacokinetics (PK) in 15 healthy volunteers (ClinicalTrials.gov; NCT01953731). Each subject received the following treatments: Period 1, oral palbociclib 125 mg on day 1; Period 2, oral rifampin 600 mg for 12 days and oral palbociclib 125 mg on day 8 (washout of ≥12 days between the 2 palbociclib doses). Serial blood sampling for palbociclib PK was performed predose and up to 120 hours post-palbociclib dose in both periods. Plasma concentrations of palbociclib were measured using validated high-performance liquid chromatography tandem mass spectrometry methods. Palbociclib plasma PK parameters were estimated using standard non-compartmental methods. Results Median time to maximum plasma concentration (Tmax) and mean half-life (t1/2) were shorter with palbociclib plus rifampin relative to palbociclib alone. Adjusted geometric mean palbociclib AUCinf (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) following treatment with rifampin (242.5 ng•h/mL and 15.52 ng/mL, respectively) were considerably lower relative to palbociclib administered alone (1568 ng•h/mL and 51.42 ng/mL). Generally, study treatments were well tolerated with no reported serious adverse events; 1 subject discontinued due to liver function test abnormalities after receiving rifampin alone for 7 days in Period 2. Conclusions Treatment with multiple doses of rifampin with palbociclib decreased total (AUCinf) and peak (Cmax) palbociclib exposure by approximately 85% and 70%, respectively, versus palbociclib alone. Palbociclib was well tolerated when administered alone or in combination with rifampin. Based on these results, concurrent administration of palbociclib with strong CYP3A inducers should be avoided. Citation Format: Justin T. Hoffman, Anna Plotka, Melissa O'Gorman, Andrew Chang, Maha Kosa, Cho-Ming Loi, Corrado Gallo-Stampino, Diane D. Wang. A phase 1 randomized, open-label, fixed-sequence, 2-period study of the effect of multiple doses of rifampin on palbociclib (PD-0332991) pharmacokinetics in healthy volunteers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4515. doi:10.1158/1538-7445.AM2015-4515
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