Cho-Ming Loi

Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor

Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species. [Mol Cancer Ther 2008;7(7):1880–9]

Physiologically Based Pharmacokinetic Modeling of Palbociclib

Palbociclib is an orally available CDK4/6 inhibitor. In humans, palbociclib undergoes metabolism mediated primarily by CYP3A and SULT2A1, and it is also a weak time‐dependent CYP3A inhibitor. The objectives of the current study are to (1) develop a physiologically based pharmacokinetic (PBPK) model of palbociclib based on the in silico, in vitro, and in vivo pharmacokinetic data of palbociclib, (2) verify the PBPK model with clinical drug‐drug interaction (DDI) results of palbociclib with strong CYP3A inhibitor (itraconazole), inducer (rifampin), and a sensitive CYP3A substrate (midazolam), and (3) predict the DDI risk of palbociclib with moderate/weak CYP3A inhibitors. The developed PBPK model adequately described the observed pharmacokinetics of palbociclib after administration of a single oral or intravenous dose of palbociclib. The model‐predicted DDIs of palbociclib with itraconazole, rifampin, and midazolam were consistent with the observed DDIs, with the discrepancies of the predicted vs observed AUCR and CmaxR within 20%, except for the AUC ratio of palbociclib with coadministration of rifampin. Using this final PBPK model, it was predicted that weak CYP3A inhibitors (fluoxetine and fluvoxamine) are anticipated to have negligible DDI risk with palbociclib, whereas moderate CYP3A inhibitors (diltiazem and verapamil) may increase plasma palbociclib AUC by ∼40%. A moderate CYP3A inducer (efavirenz) may decrease plasma palbociclib AUC by ∼40%. The established model is considered sufficiently robust for other applications in support of the continued development for palbociclib.

Abstract LB-229: A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokinetics in healthy male volunteers

Introduction: Tamoxifen and one of its primary active metabolites, 4‑hydroxy‑tamoxifen, are known to induce CYP3A4 in vitro, and in vivo coadministration of tamoxifen with letrozole and anastrozole (both CYP3A4 substrates) has resulted in decreased exposures (AUC) of each by 37% and 27%, respectively. The primary route of oxidative metabolism of palbociclib (PD‑0332991) is through CYP3A4, thus coadministration of tamoxifen and palbociclib could result in decreased exposure of palbociclib. The primary objective of this study is to estimate the relative exposure of single 125 mg palbociclib oral doses alone and in the presence of steady‑state concentrations of tamoxifen and its active metabolites (4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen (N‑desmethyl‑4-hydroxytamoxifen)) in healthy male subjects in order to inform appropriate palbociclib dosing when administered in combination with tamoxifen in the upcoming Phase 3 PENELOPEB study. Methods: This was an open label, 2‑period fixed‑sequence study of the effect of multiple oral doses of tamoxifen on palbociclib pharmacokinetics in 25 healthy male volunteers. Each subject received a single 125 mg oral dose of palbociclib alone, followed by a single 125 mg dose of palbociclib on Day 22 of a 27-day tamoxifen loading dose regimen (60mg QD for 4 days, followed by 20mg QD for 23 days). Serial blood sampling for palbociclib pharmacokinetics was performed up to 144 hours post-palbociclib dose in both periods. Tamoxifen pre-dose blood sampling was performed on specified visits to document achievement of steady-state tamoxifen and metabolite concentrations. Plasma concentrations of palbociclib, tamoxifen, 4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen were each measured using validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) methods. Palbociclib plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods. Discussion: There were no significant changes in the palbociclib plasma PK parameters AUCinf (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) in the presence of steady-state tamoxifen when compared to palbociclib alone. Tamoxifen, 4‑hydroxy‑tamoxifen, N‑desmethyl‑tamoxifen, and endoxifen all achieved steady-state prior to administration of palbociclib in period 2. In general, palbociclib and the combination of palbociclib and tamoxifen were well tolerated with no reported serious adverse events; 1 subject discontinued due to generalized itchiness which resolved with a single dose of fexofenadine. Citation Format: Justin T. Hoffman, Melissa O9Gorman, Cho-Ming Loi, Anna Plotka, Tanya Boutros, Leonid Kirkovsky, Corrado Gallo Stampino, Diane Wang. A phase 1 open-label fixed-sequence two-period crossover study of the effect of multiple doses of tamoxifen on palbociclib (PD-0332991) pharmacokinetics in healthy male volunteers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2014-LB-229

Abstract 4515: 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

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 O9Gorman, 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

Abstract CT419: A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential

Introduction: Palbociclib (PD‑0332991) is an oral cyclin‑dependent kinase (CDK) 4/6 inhibitor currently in Phase 2 and Phase 3 clinical trials in multiple oncology indications. In vitro, palbociclib and its active lactam metabolite (PF‑05089326) caused time‑dependent inhibition of CYP3A-mediated midazolam 1’‑hydroxylase and testosterone 6β‑hydroxylase activities. The primary objective of this study is to investigate the effect of multiple doses of palbociclib on the pharmacokinetics of a single oral dose of the sensitive CYP3A4/5 probe substrate midazolam in healthy women of non-childbearing potential. Methods: This was an open label, randomized, 2‑period 2‑sequence study of the effect of multiple oral doses of palbociclib on midazolam pharmacokinetics in 26 healthy female volunteers of non-childbearing potential. Simulations were performed with SimCYP, using the in vitro CYP inhibition data and human pharmacokinetic data for palbociclib from Study A5481001 as inputs, to optimize the duration of dosing and washout periods. Each subject received two treatments (Treatment A = 2 mg oral dose of midazolam alone, Treatment B = 2 mg oral dose of midazolam on Day 7 of an 8-day 125 mg QD palbociclib dose regimen) in a crossover scheme. Subjects were randomized to one of two sequences (Sequence 1 = A→B, Sequence 2 = B→A). In Sequence 2 there was a washout period of no less than 14 days after the last administered dose of palbociclib to ensure that there was no carryover effect of CYP3A inhibition into Period 2. Serial blood sampling for midazolam pharmacokinetics was performed up to 36 hours post-midazolam dose in both periods. Palbociclib pre-dose blood sampling was performed on specified visits to document achievement of steady-state concentrations. Plasma concentrations of midazolam and palbociclib were each measured using validated LC/MS/MS (liquid chromatography- tandem mass spectrometry) methods. Midazolam plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods. Discussion:In general, palbociclib reached steady-state levels prior to co-administration of midazolam, allowing for a worst case assessment of the potential palbociclib-mediated time-dependent CYP3A inhibition. Midazolam geometric mean Cmax and AUCinf values increased 37% and 61%, respectively, when midazolam was co-administered with multiple doses of palbociclib as compared to its administration alone. These results indicate that palbociclib is a weak CYP3A inhibitor following daily 125 mg dosing at steady-state according to the FDA classification. In general, the combination of palbociclib and midazolam were well tolerated with no reported serious adverse events or treatment discontinuations. Reversible neutropenia was reported in 15 out of the 26 subjects. Citation Format: Justin T. Hoffman, Anna Plotka, Melissa O9Gorman, Cho-Ming Loi, Leonid Kirkovsky, Corrado Gallo-Stampino, Diane Wang. A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT419. doi:10.1158/1538-7445.AM2014-CT419