A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors

Chiorean, E. Gabriela; Malireddy, S. R.; Younger, Anne; Jones, David R.; Waddell, Michael; Sloop, Melissa I.; Yu, Menggang; Hall, Stephen D.; Schneider, Bryan P.; Sweeney, Christopher J.

doi:10.1007/s00280-009-1179-2

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…However, similar to midostaurin, both masitinib and vatalanib are also CYP3A4 inducers . While no interaction studies have been published for masitinib and trametinib, one study reports that co‐administration of vatalanib and paclitaxel, a CYP2C8 and CYP3A4 substrate, increased paclitaxel clearance by 30‐80% in patients . Until clinical interaction studies have unravelled the net effects of these inhibitors on CYP2C8 and CYP3A4, they should be used with caution in patients using CYP2C8 and CYP3A4‐dependent drugs.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

Filppula

Mustonen

Backman

2018

Basic Clin Pharma Tox

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Several protein kinase inhibitors have been reported to affect cytochrome P450 (CYP) 3A by time-dependent inhibition. Herein, we tested a set of six kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A4 in human liver microsomes. Dovitinib, midostaurin and nintedanib exhibited an increased inhibition of CYP3A4 after a 30-min. pre-incubation with NADPH, as compared to no pre-incubation (IC shift >1.5). Masitinib, trametinib and vatalanib did not affect CYP2C8 or CYP3A4 by time-dependent inhibition (IC shift <1.5). The inhibitory mechanism of CYP3A4 by midostaurin and nintedanib, but not by dovitinib, was consistent with irreversible mechanism-based inhibition. The maximal inactivation rate (k ) and inhibitor concentration that supports half-maximal rate of inactivation (K ) values of midostaurin and nintedanib were 0.052 1/min. and 2.72 μM, and 0.025 1/min. and 17.3 μM, respectively. According to static predictions, inactivation of CYP3A4 by nintedanib was unlikely to cause drug-drug interactions with clinically used doses of nintedanib, whereas midostaurin was predicted to increase the plasma exposure to CYP3A4-dependent substrates several fold. Furthermore, based on reversible inhibition, masitinib and vatalanib were predicted to increase the plasma exposure to sensitive CYP2C8 and CYP3A4 substrates by ≥2-fold. In summary, our data identify midostaurin and nintedanib as time-dependent inhibitors of CYP3A4 and detect a risk of drug-drug interactions between vatalanib and CYP2C8 substrates, and between masitinib, midostaurin and vatalanib and CYP3A4 substrates. The liability of kinase inhibitors to affect CYP enzymes by time-dependent inhibition may have long-term consequences, in terms of drug-drug interactions and toxicities.

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Section: Discussionmentioning

confidence: 99%

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

Filppula

Mustonen

Backman

2018

Basic Clin Pharma Tox

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“…Blood samples were collected for paclitaxel on C1D1 and on C1D15 pre-dose, at 15 minutes, 30 minutes, 1 hour (end of infusion), 2, 4, 6, 8, and 24 hours after the start of paclitaxel infusion. Paclitaxel was quantified in plasma using internal standardization, liquid-liquid extraction, and HPLC/MS-MS in the Clinical Pharmacology Analytical Core laboratory at Indiana University School of Medicine (Indianapolis, IN) as described previously (20). Blood samples for sorafenib PK were collected on C1D7 predose, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after dosing, and on C1D15 (sorafenib was dosed at the start of paclitaxel infusion), predose, 15 minutes, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after the start of paclitaxel infusion.…”

Section: Pharmacokinetic Analysesmentioning

confidence: 99%

Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors

Chiorean

Perkins

Strother

et al. 2020

Molecular Cancer Therapeutics

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◥VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a "3 þ 3" design, using paclitaxel 80 mg/m 2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand-foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2-17) cycles. Response rates were 48% overall ( 27) and 64% for ovarian cancers ( 14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

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“…Such drug-drug interactions have been reported. In a phase I clinical study of vatalanib in combination with paclitaxel in patients with advanced solid tumors, a significant drug-drug interaction has been reported (88). In this study, patients were treated with escalating doses of paclitaxel weekly at dose levels from 75 mg/m 2 to 85 mg/m 2 , and vatalanib daily at dose levels from 250 mg to 1000 mg. A significant increase in paclitaxel clearance and concomitant decrease in paclitaxel exposure were reported and attributed to the drug-drug between vatalanib and paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and exposure toxicity analysis of Vatalanib in patients with myelodysplastic syndromes

Wang

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This thesis would never have been completed without the help, support, and encouragement of all the great people around me. First, I would like to express my sincere gratitude to my advisor Dr. Daryl J. Murry for his patient guidance, insightful discussion, encouragement, and support throughout my Ph.D. study. I have been very fortunate to have Dr. Murry as my advisor who leaded me into the exciting field of clinical pharmacology and pharmacokinetics and trained me to be a solid scientist in this area.

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A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors

Cited by 7 publications

References 23 publications

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

Phase I, Pharmacogenomic, Drug Interaction Study of Sorafenib and Bevacizumab in Combination with Paclitaxel in Patients with Advanced Refractory Solid Tumors

Population pharmacokinetics and exposure toxicity analysis of Vatalanib in patients with myelodysplastic syndromes

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