Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors

Tan, Antoinette R.; Gibbon, Darlene; Stein, Mark N.; Lindquist, Diana; Edenfield, Jeffery W.; Martin, Julie P.; Gregory, Charles; Suttle, A. Benjamin; Tada, Hiroomi; Botbyl, Jeffrey; Stephenson, Joseph

doi:10.1007/s00280-013-2164-3

Cited by 89 publications

(82 citation statements)

References 17 publications

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“…To identify these mean exposure levels in the absence of pharmacokinetic data, we fitted an E max model to mean AUC values reported in previous clinical trials; this approach enabled us to account for the less‐than‐dose‐proportional increase in AUC. Data from five clinical trials that investigated pazopanib doses of 5 mg to 2,000 mg administered once daily were pooled for the analysis 28, 29, 30, 31, 32. According to the E max model, mean exposure was 771.6 μg·h/mL (range, 629.4–802.4 μg·h/mL) corresponding to a mean dose of 727 mg (range: 473–800 mg) through the population of 47 patients.…”

Section: Resultsmentioning

confidence: 99%

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Ouerdani

Struemper

Suttle

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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The objective was to leverage tumor size data from preclinical experiments to propose a model of tumor growth and angiogenesis inhibition for the analysis of pazopanib efficacy in renal cell carcinoma (RCC) patients. We analyzed tumor data in mice with RCC CAKI‐2 cell line treated with pazopanib. Clinical tumor size data obtained in a subset of patients with RCC were also analyzed. A model accounting for the processes of tumor growth, angiogenesis, and drug effect was developed. The final tumor model was composed of two variables: the tumor and its vasculature. Our results show that, both in mice and in humans, pazopanib exhibits a dual mechanism of action, and parameter estimation values highlight the inherent difference between mice and humans on the time scale of tumor size response. We developed a semimechanistic tumor growth inhibition model that takes into account tumor angiogenesis in order to describe the effects of pazopanib in mice. Analyzing rich preclinical data with a semimechanistic model may be a relevant approach to facilitate the description of sparse clinical longitudinal tumor size data and to provide insights for the understanding of the drug mechanisms of action in patients.

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Section: Resultsmentioning

confidence: 99%

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Ouerdani

Struemper

Suttle

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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“…CYP3A4 is abundant in human liver microsomes and plays an important role in the metabolism of many drugs, including anticancer drugs. Furthermore, CYP3A4 shows about five-to tenfold inter-patient variability [25][26][27] in the disposition of these drugs metabolic efficiency, and intra-patient variability is widely recognized for several major inducers [28,29] or inhibitors [30,31].…”

Section: Discussionmentioning

confidence: 99%

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug–drug interaction

Motonaga

Yamamoto²,

Makino

et al. 2015

Cancer Chemother Pharmacol

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“…An intake of pazopanib 800 mg with lapatinib 1000 mg led to an increase in the pazopanib AUC 24 from 324.6 to 853.4 lgÁh/mL and C max from 22.9 to 48.9 lg/mL [36,[45][46][47][48].…”

Section: Ddismentioning

confidence: 97%

“…Co-administration of oral pazopanib with CYP3A4 inhibitors, such as ketoconazole, clarithromycin, or lapatinib has resulted in increased plasma pazopanib concentrations when compared with pazopanib alone [38,[46][47][48]. When pazopanib was combined with ketoconazole, the AUC from time zero to 24 h (AUC 24 ) was increased by 66 % and C max by 45 % as compared with pazopanib alone.…”

Section: Ddismentioning

confidence: 99%

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Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

2015

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Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR-TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug-drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.

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Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors

Cited by 89 publications

References 17 publications

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Preclinical Modeling of Tumor Growth and Angiogenesis Inhibition to Describe Pazopanib Clinical Effects in Renal Cell Carcinoma

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug–drug interaction

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

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