Determination of GDC-0449, a small-molecule inhibitor of the Hedgehog signaling pathway, in human plasma by solid phase extraction-liquid chromatographic-tandem mass spectrometry

Ding, Xiao; Chou, Bilin; Graham, Richard; Cheeti, Sravanthi; Percey, S.; Matassa, Luca; Reuschel, Scott; Mei, Meng; Liu, S.; Voelker, Troy; Lum, Bert L.; Rudewicz, Patrick J.; Hop, Cornelis E. C. A.

doi:10.1016/j.jchromb.2010.01.039

Cited by 37 publications

(41 citation statements)

References 6 publications

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“…Levels of irinotecan and metabolites (SN-38 and SN-38 glucuronide), total and ultrafilterable platinum (as an estimate of oxaliplatin), 5-FU, and vismodegib were determined in plasma samples, whereas bevacizumab was measured in serum samples. All analytes were analyzed using validated assays (18).…”

Section: Pharmacokinetic Assessmentsmentioning

confidence: 99%

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Berlin

Bendell

Hart

et al. 2013

Clinical Cancer Research

154

120

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Purpose: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).Experimental design: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.Results: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P ¼ 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.Conclusions: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

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Section: Pharmacokinetic Assessmentsmentioning

confidence: 99%

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Berlin

Bendell

Hart

et al. 2013

Clinical Cancer Research

154

120

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“…Total and unbound plasma levels of vismodegib were determined using liquid chromatography-tandem mass spectrometry (16). Unbound vismodegib was measured in ultrafiltrate from plasma samples that underwent equilibrium dialysis (18).…”

Section: Safety and Pk Assessmentsmentioning

confidence: 99%

“…Vismodegib showed an unexpected PK profile upon oral daily dosing in healthy volunteers, with high, sustained micromolar plasma levels, and an estimated terminal half-life of 10 to 14 days (16). In a phase I study with continuous once daily dosing, total and unbound steady-state plasma concentrations in patients were typically achieved within 7 to 14 days of dosing; increasing the daily dose from 150 to 270 or 540 mg did not result in higher plasma concentrations, suggestive of nonlinear PKs with regard to dose and time (13).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

LoRusso

Jimeno

et al. 2011

Clinical Cancer Research

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Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing.Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n ¼ 23), TIW (n ¼ 22), or QW (n ¼ 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS.Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results.Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.

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“…The compound showed high steady-state plasma concentrations with a median concentration of approximately 16.1 M (interquartile range, 13.7-21.6) and an apparent lack of dose dependence from 150 to 540 mg. Data from healthy volunteers show that the t 1/2 of GDC-0449 in humans is very long, approximately 12 days (Ding et al, 2010). Based on the pharmacokinetic characteristics, as well as systemic concentrations observed in humans thus far, the factors influencing oral absorption of GDC-0449 in dogs may play a role in humans.…”

Section: Downloaded Frommentioning

confidence: 99%

“…These in vivo observations were consistent with in vitro metabolic stability studies performed using hepatocytes. More recently, the oral pharmacokinetics of GDC-0449 in humans has been described (Von Hoff et al, 2009;Ding et al, 2010). The clinical pharmacokinetics was characterized by remarkably high plasma exposures suggestive of a low systemic clearance.…”

mentioning

confidence: 99%

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

Wong¹,

Theil²,

Cui³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (ϳ19% of systemic clearance). Likewise, in vitro studies using sandwichcultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior.The hedgehog (Hh) signaling pathway regulates proliferation and differentiation during embryogenesis. Hh ligands bind to Patched (PTCH1), a transmembrane protein on target cells. In the absence of Hh, the role of PTCH1 is to inhibit the activity of Smoothened (SMO), a seven-transmembrane protein that serves as the signaling component of the pathway. Binding of Hh proteins to PTCH1 relieves this inhibition and initiates activation of SMO. The increase in SMO activity causes increases in activated forms of Gli, transcriptional factors that serve to regulate the expression of Hh target genes. Activation of the Hh pathway has been implicated in a number of cancers (Scales and de Sauvage, 2009). Mutations in the Hh receptor components, PTCH1 or SMO, result in constitutive pathway activation and have been identified in basal cell carcinoma (Hahn et al., 1996;Johnson et al., 1996) and medulloblastoma (Pietsch et al., 1997;Raffel et al., 1997;Vorechovský et al., 1997). It has also been observed that aberrant Hh ligand production can contribute to the growth of other tumor types, such as colorectal and pancreatic cancer (Yauch et al., 2008), prostate cancer (Fan et al., 2004), and B cell lymphoma (Dierks et al., 2007), through paracrine activation of the Hh pathway. Paracrine signaling typically involves ligand expressed on the cancer cells ...

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Determination of GDC-0449, a small-molecule inhibitor of the Hedgehog signaling pathway, in human plasma by solid phase extraction-liquid chromatographic-tandem mass spectrometry

Cited by 37 publications

References 6 publications

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors

Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling

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