A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers

Yong, Wei‐Peng; Wang, Lingzhi; Tham, Lai-San; Wong, Chin‐Ho; Lee, Soo‐Chin; Soo, Ross A.; Sukri, Norita; Lee, How-Sung; Goh, Boon-Cher

doi:10.1007/s00280-007-0598-1

Cited by 14 publications

(12 citation statements)

References 27 publications

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“…Midazolam is a sensitive CYP3A probe for CYP3A activity in vivo. In humans, the clearance of midazolam has been reported to be reduced by approximately 85% by ketoconazole (Tsunoda et al, 1999;Tham et al, 2006;Yong et al, 2008;Krishna et al, 2009), which is comparable with the 69% decrease in the formation rate of 1Ј-hydroxymidazolam seen in the bioreactor in this study using HepaRG cells. A comparable degree of inhibition (83-100%) of the 1Ј-hydroxymidazolam formation rate by 10 M ketoconazole has also been reported in 2D-cultured primary human hepatocytes from 18 donors (Klieber et al, 2008).…”

Section: Discussionsupporting

confidence: 72%

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Darnell¹,

Schreiter²,

Zeilinger³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Reliable and stable in vitro cellular systems maintaining specific liver functions important for drug metabolism and disposition are urgently needed in preclinical drug discovery and development research. The cell line HepaRG exhibits promising properties such as expression and function of drug-metabolizing enzymes and transporter proteins, which resemble those found in freshly isolated human hepatocytes. In this study, HepaRG cells were cultured up to 68 days in a three-dimensional multicompartment capillary membrane bioreactor, which enables high-density cell culture under dynamic conditions. The activity of drug-metabolizing cytochrome P450 (P450) enzymes was investigated by a cocktail of substrates for CYP1A1/2 (phenacetin), CYP2C9 (diclofenac), CYP2B6 (bupropion), and CYP3A4 (midazolam). The model P450 substrates, which were introduced to the bioreactor system mimicking in vivo bolus doses, showed stable metabolism over the entire experimental period of several weeks with the exception of bupropion hydroxylase, which increased over time. Ketoconazole treatment decreased the CYP3A4 activity by 69%, and rifampicin induced the CYP3A4-and CYP2B6-dependent activity 6-fold, which predicts well the magnitude of changes observed in vivo. Moreover, polarity of transporter expression and formation of tissue-like structures including bile canaliculi were demonstrated by immune histochemistry. The long-lasting bioreactor system using HepaRG cells thus provides a promising and stable liver-like in vitro model for continuous investigations of the hepatic kinetics of drugs and of drug-drug interactions, which well predict the situation in vivo in humans.

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Section: Discussionsupporting

confidence: 72%

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Darnell¹,

Schreiter²,

Zeilinger³

et al. 2011

Drug Metab Dispos

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“…The probability density The ratio of mean midazolam AUC in presence and in absence of ketoconazole. AUCs of midazolam in presence and in absence of ketoconazole are calculated from clearance of midazolam, which are digitalized from two studies, Yong et al, 2008and Goh et al, 2002, respectively (as reported in Yong et al, 2008.…”

Section: Resultsmentioning

confidence: 99%

“…A complete search of the literature using the Metabolism and Transport Drug Interaction Database (University of Washington, Seattle, WA) indentified 11 clinical DDI studies and 16 dosage scenarios from 17 published clinical results using midazolam as CYP3A probe (intravenous and oral) and ketoconazole as inhibitor (400 mg QD and 200 mg QD and BID for various durations) as of 2012 (Olkkola et al, 1994;McCrea et al, 1999;Tsunoda et al, 1999;Goh et al, 2002;Lee et al, 2002;Lam et al, 2003;Eap et al, 2004;Chung et al, 2006;Tham et al, 2006;Yong et al, 2008;Krishna et al, 2009;Stoch et al, 2009). The specific treatment regimens of ketoconazole and midazolam used in the literature reports were reproduced in the simulations.…”

Section: Model Validation and Simulationmentioning

confidence: 99%

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Han

Mao²,

Chien

et al. 2013

Drug Metab Dispos

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Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f m ) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

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“…Given the in vitro Ki (0.0037 to 0.015 μM/L) of ketoconazole for CYP3A4 inhibition (37, 38), the mean ketoconazole concentrations achieved at 600 to 1200 mg/day were several orders of magnitude higher than Ki value, enough to effectively inhibit CYP3A-mediated docetaxel metabolism. Previous studies have reported that ketoconazole AUC or C max were correlated with a fold-change in docetaxel CL (12, 39). Some studies, however, observed little or no relationship between the fractional change in docetaxel CL and ketoconazole AUC (12, 13, 40), presumably owing to the small number of patients (n = 7) with a limited range of ketoconazole AUC for comparison.…”

Section: Discussionmentioning

confidence: 97%

A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer

et al. 2010

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Purpose High-dose ketoconazole and docetaxel have shown activity as single agents against castration-resistant prostate cancer (CRPC). The goal of this phase I study was to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of coadministered docetaxel and ketoconazole. Experimental Design Patients with metastatic CRPC received weekly docetaxel for 3 of every 4 weeks, plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole). Results The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly for three weeks out of four escalating from 5 to 43 mg/m2, with starting doses of ketoconazole of 600, 800, or 1200 mg/day. Declines in prostate-specific antigen of ≥ 50% were seen in 62% of patients. Of 25 patients with soft tissue disease, 7 (28%) had partial response. Median overall survival was 22.8 months, and was significantly greater in docetaxel-naïve patients than in patients pretreated with docetaxel (36.8 vs. 10.3 months; P = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy, and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (P < 0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1200 mg/day, 1.6-fold with 800 mg/day, and 1.3- to 1.5-fold with 600 mg/day. Conclusions Results suggest that the combination of weekly docetaxel and ketoconazole has significant antitumor activity in CRPC with manageable toxicities. The extremely long survival in the docetaxel-naïve cohort (36.8 months) warrants additional larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.

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A phase I study of docetaxel with ketoconazole modulation in patients with advanced cancers

Abstract: Fixed dosing was found to be feasible, without increased variability of clearance or neutrophil toxicity compared to BSA-based dosing. With ketoconazole modulation, docetaxel clearance correlated with renal function but not CYP3A phenotype.

Cited by 14 publications

References 27 publications

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer

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