Docetaxel Clearance Research Articles

Contribution of hepatic organic anion-transporting polypeptides to docetaxel uptake and clearance.

The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug for the treatment of multiple solid tumors and is predominantly dependent on hepatic disposition. In this study, we evaluated drug uptake transporters capable of transporting radiolabeled docetaxel. By screening an array of drug uptake transporters in HeLa cells using a recombinant vaccinia-based method, five organic anion-transporting polypeptides (OATP) capable of docetaxel uptake were identified: OATP1A2, OATP1B1, OATP1B3, OATP1C1, and Oatp1b2. Kinetic analysis of docetaxel transport revealed similar kinetic parameters among hepatic OATP1B/1b transporters. An assessment of polymorphisms (SNPs) in SLCO1B1 and SLCO1B3 revealed that a number of OATP1B1 and OATP1B3 variants were associated with impaired docetaxel transport. A Transwell-based vectorial transport assay using MDCKII stable cells showed that docetaxel was transported significantly into the apical compartment of double-transfected (MDCKII-OATP1B1/MDR1 and MDCKII-OATP1B3/MDR1) cells compared with single-transfected (MDCKII-OATP1B1 and MDCKII-OATP1B3) cells (P < 0.05) or control (MDCKII-Co) cells (P < 0.001). In vivo docetaxel transport studies in Slco1b2(-/-) mice showed approximately >5.5-fold higher plasma concentrations (P < 0.01) and approximately 3-fold decreased liver-to-plasma ratio (P < 0.05) of docetaxel compared with wild-type (WT) mice. The plasma clearance of docetaxel in Slco1b2(-/-) mice was 83% lower than WT mice (P < 0.05). In conclusion, this study demonstrates the important roles of OATP1B transporters to the hepatic disposition and clearance of docetaxel, and supporting roles of these transporters for docetaxel pharmacokinetics.

Pharmacokinetics, dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose.

Docetaxel (Taxotere®) has been one of the most important chemotherapeutic drugs for cancer treatment since 1996. Although a large number of clinical studies have been conducted in various cancer fields, there is a discrepancy in the standard dose between Japan and Western countries. This article reviews the pharmacokinetic, pharmacodynamic and toxicological profiles of docetaxel, and explains why there exists an ethnic difference in dose, and further discusses which direction we should go forward to solve this problem. The original recommended dose was 100 mg/m2 every 3 weeks in US and European populations, while a Japanese phase I study suggested the recommended dose as 60 mg/m2 every 3 weeks. A prospective population pharmacokinetic analysis of docetaxel conducted in both the USA/Europe and Japan, indicated an absence of ethnic difference in the pharmacokinetics. Both analyses demonstrated that docetaxel clearance is related to α1-acid glycoprotein level, hepatic function, age and body surface area. The relationship was observed between increasing docetaxel dose and increased tumor response rates across the dose range of 60 to 100 mg/m2. The area under the serum concentration time curve (AUC) of docetaxel at the first cycle was significantly related to time to progression. Hematological toxicities were well correlated with the AUC of docetaxel, and severe hematological toxicities were more frequently observed in Japanese patients treated with 60 mg/m2, compared to the US/European patients treated with 75–100 mg/m2 dose. The Japanese population seems more susceptible to the toxicity of docetaxel. A docetaxel dose of 75 mg/m2 is now standard not only in global trials but also in recent Japanese trials. Although the optimal dose of docetaxel is still unclear, we need to continue to seek the appropriate dose of docetaxel depending on patient status and the goals of chemotherapy.

Abstract 3682: Contribution of hepatic uptake transporters OATP1B1/OATP1B3 to the disposition of docetaxel

Abstract The antimicrotubular agent docetaxel is a widely used chemotherapeutic drug that has been approved for the treatment of multiple malignant diseases, including cancers of the breast, lung, prostate, stomach, and head and neck. Docetaxel is predominantly dependent on hepatic disposition as ∼75% is excreted in bile. While it is known that docetaxel is a substrate of the efflux transporter P-glycoprotein (MDR1; P-gp), less is known regarding transporters that could mediate its cellular uptake and hepatic clearance. Accordingly, screening an array of drug uptake transporters and kinetic analysis for radiolabeled docetaxel transport using a recombinant vaccinia-based method demonstrated that organic anion transporting polypeptides (OATPs), including OATP1A2, OATP1B1 and OATP1B3, were capable of transporting docetaxel in vitro. In addition, an assessment of a panel of single nucleotide polymorphisms (SNPs) in SLCO1B1 revealed that a number of OATP1B1 variants were associated with impaired docetaxel transport. To further evaluate docetaxel transport by OATP1B1 and OATP1B3, we generated MDCKII cells stably expressing MDR1, OATP1B1, OATP1B3, OATP1B1-MDR1, and OATP1B3-MDR1 proteins. Using a transwell system, we then studied intracellular concentrations and transcellular transport after administration of radiolabeled docetaxel to the basal compartment. The transport assay revealed that docetaxel was transported significantly into the apical compartment of double transfected MDCKII-OATP1B1-MDR1/OATP1B3-MDR1 cells compared to the single transfected cells without MDR1 expression up to 3 hours (p &amp;lt; 0.05). Meanwhile, intracellular accumulation of docetaxel was not different between control cells and MDCKII-OATP1B1 or MDCKII-OATP1B3 cells, but was significantly lower in cell lines expressing MDR1 than in cell lines without MDR1 expression (p &amp;lt; 0.05). Consequently, in line with lower intracellular values, higher amounts of docetaxel were found in the apical compartment of cell lines expressing MDR1. Subsequently, we performed in vivo docetaxel transport studies in wild-type and Slco1b2-/- mice (ortholog to hepatic OATP1B1/OATP1B3). There was ∼&amp;gt;5-fold higher plasma concentrations of docetaxel in Slco1b2-/- versus wild-type mice (p &amp;lt; 0.01). The liver-to-plasma ratio of docetaxel was ∼3-fold decreased in Slco1b2-/- mice compared to wild-type mice (p &amp;lt; 0.05). The plasma clearance of docetaxel in Slco1b2-/- mice was 83% lower than wild-type mice (p &amp;lt; 0.05). In conclusion, we demonstrate functional interplay between transporter-mediated uptake and export in docetaxel disposition, suggesting hepatic OATP1B1 and OATP1B3 are important to docetaxel disposition. Moreover, OATP1B1 variants may contribute to the interindividual variability in docetaxel disposition and response. Accordingly, these findings reveal important new insights into the relevance of hepatic OATPs to the clinical pharmacology of docetaxel. Citation Format: Hye Jeong Lee, Brenda F. Leake, Wendy Teft, Richard B. Kim, Richard H. Ho. Contribution of hepatic uptake transporters OATP1B1/OATP1B3 to the disposition of docetaxel. [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 3682. doi:10.1158/1538-7445.AM2014-3682

Hepatic Uptake Transporters and Docetaxel Disposition in Mice—Letter

We previously reported in Clinical Cancer Research the results of a study evaluating the influence of hepatocellular OATP1B-type uptake transporters on the systemic clearance of docetaxel in mice and patients with inherited, reduced-function variants in the genes encoding these transporters ([1][1

Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel.

Organic anion transporting polypeptides (human: OATPs and mouse: Oatps) are uptake transporters with important roles in drug pharmacokinetics and toxicity. We aimed to study the in vivo impact of mouse and human OATP1A/1B transporters on docetaxel plasma clearance and liver and intestinal uptake. Docetaxel was administered to Oatp1a/1b knockout and liver-specific humanized OATP1B1, OATP1B3 and OATP1A2 transgenic mice. Experiments were conducted with a low polysorbate 80 (2.8%) formulation, as 8% polysorbate somewhat inhibited docetaxel plasma clearance after intravenous administration. After intravenous administration (10 mg/kg), Oatp1a/1b knockout mice had an approximately threefold higher plasma area under the curve (AUC). Impaired liver uptake was evident from the significantly reduced (approximately threefold) liver-to-plasma AUC ratios. Absence of mouse Oatp1a/1b transporters did not affect the intestinal absorption of orally administered docetaxel (10 mg/kg), while the systemic exposure of docetaxel was again substantially increased owing to impaired liver uptake. Most importantly, liver-specific expression of each of the human OATP1B1, OATP1B3 and OATP1A2 transporters provided a nearly complete rescue of the increased plasma levels of docetaxel in Oatp1a/1b-null mice after intravenous administration. Our data show that one or more of the mouse Oatp1a/1b transporters and each of the human OATP1A/1B transporters can mediate docetaxel uptake in vivo. This might be clinically relevant for OATP1A/1B-mediated tumor uptake of docetaxel and for docetaxel clearance in patients in whom the transport activity of OATP1A/1B transporters is reduced owing to genetic variation or pharmacological inhibition, leading to potentially altered toxicity and therapeutic efficacy of this drug.

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

This study was conducted to evaluate potential pharmacokinetic interactions between docetaxel and atrasentan as part of a phase I/II clinical trial. Patients with prostate cancer were treated with intravenous docetaxel (60-75 mg/m(2)) every 3 weeks and oral atrasentan (10 mg) daily starting on day 3 of cycle 1 and then given continuously. The pharmacokinetics of both drugs were evaluated individually (cycle 1, day 1 for docetaxel; day 21 for atrasentan) and in combination (cycle 2, day 1 for both drugs). Pharmacogenomics of alpha-1-acid glycoprotein (AAG) were also explored. Paired pharmacokinetic data sets for both drugs were evaluable in 21 patients. Atrasentan was rapidly absorbed and plasma concentrations varied over a fourfold range at steady state within a typical patient. The median apparent oral clearance of atrasentan was 17.4 L/h in cycle 1 and was not affected by docetaxel administration (p = 0.9). Median systemic clearance of docetaxel was 51.1 L/h on the first cycle and significantly slower (p = 0.01) compared with that obtained during co-administration of atrasentan, 61.6 L/h. Docetaxel systemic clearance in cycle 1 was 70.0 L/h in patients homozygous for a variant allele in AAG compared with 44.5 L/h in those with at least one wild-type allele (p = 0.03). Genetic polymorphism in AAG may explain some inter-patient variability in docetaxel pharmacokinetics. The systemic clearance of docetaxel is increased by approximately 21 % when given concomitantly with atrasentan; however, atrasentan pharmacokinetics does not appear to be influenced by docetaxel administration.

Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro–in vivo correlations

Background:Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.Methods:The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.Results:All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.Conclusion:These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI–chemotherapy interactions involving transporters.

Effect of triacontanol on the pharmacokinetics of docetaxel in rats associated with induction of cytochrome P450 3A1/2

1. Triacontanol was confirmed to have a potential anti-cancer effect, the aim was to assess whether the co-administration of triacontanol alters the exposure of docetaxel via inducing hepatic CYP3A1/2 activity. The concentration of docetaxel in rats pretreated with triacontanol for seven successive days was determined, and the expression levels of CYP3A protein and mRNA were analyzed by the western blot and real time polymerase chain reaction (RT-PCR) technique, respectively.2. The concentrations of docetaxel in rats pretreated with triacontanol were decreased, with 61.5%, 61.9% decrease in AUC0–24h and 65.7%, 54.9% reduction in Cmax (120 and 180 mg kg−1, respectively) compared with the control. Hepatic clearance of docetaxel was enhanced in vitro and in vivo at dosage of 120 and 180 mg kg−1, and CYP3A activity was up-regulated by measuring the formation rate of 1-hydroxymidazolam. Triacontanol preferentially induced protein expression level of CYP3A2 in a dose-dependent manner and of CYP 3A1 at dosage of 120 and 180 mg kg−1. The mRNA expression of CYP3A1 was moderately different with the western blot results, but the trends appeared similar. CYP3A2 mRNA level was not markedly affected by triacontanol.3. The significant triacontanol–docetaxel interaction was largely due to the induction of CYP3A1/2, which brought useful information in the clinical therapy when the combination is administered in human.

The Effect of St John’s Wort on the Pharmacokinetics of Docetaxel

St John's wort (SJW), a herbal antidepressant, is commonly used by cancer patients, and its component hyperforin is a known inducer of the cytochrome P450 (CYP) isoenzyme 3A4. Here, the potential pharmacokinetic interaction between SJW and the sensitive CYP3A4 substrate docetaxel was investigated. In ten evaluable cancer patients, the pharmacokinetics of docetaxel (135 mg administered intravenously over 60 min) were compared before and after 14 days of supplementation with SJW (300 mg extract [Hyperiplant(®)] three times daily). SJW supplementation resulted in a statistically significant decrease in the mean area under the docetaxel plasma concentration-time curve extrapolated to infinity (AUC∞) from 3,035 ± 756 to 2,682 ± 717 ng · h/mL (P = 0.045). Furthermore, docetaxel clearance significantly increased from 47.2 to 53.7 L/h (P = 0.045) after SJW intake. The maximum plasma concentration and elimination half-life of docetaxel were (non-significantly) decreased after SJW supplementation. In addition, the incidence of docetaxel-related toxicities was lower after SJW supplementation. These results suggest that concomitant use of docetaxel and the applied SJW product should be avoided to prevent potential undertreatment of cancer patients.

Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer.

5066 Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC&lt;1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

Enzalutamide in combination with docetaxel in men with prostate cancer (PC): Preliminary results from a phase I study.

63 Background: Enzalutamide (ENZA), a novel oral androgen receptor (AR) inhibitor, inhibits AR signaling via inhibition of androgen binding to the AR, AR nuclear translocation, and nuclear AR-DNA binding. ENZA demonstrated a survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (Scher et al, NEJM 2012; 367:1187). A Phase III study in men with progressive chemotherapy-naïve disease (PREVAIL), is ongoing. Docetaxel (DOC) is the current standard first-line chemotherapy for mCRPC. CYP3A4, which plays a role in DOC clearance, is induced by ENZA. Patients (pts) eligible to receive DOC may benefit from continued AR inhibition with ENZA, provided the combination is well tolerated with no unacceptable drug-drug interactions. Methods: This study evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks, with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ± ENZA. A sample size of 18 pts able to receive ≥ 2 full doses of DOC was specified for PK analyses. Results: As of 21 Sept. 2012, 22 pts have been enrolled, 3 did not complete both C1 and C2; PK and C1 and C2 safety data are currently available from 15 pts reported here. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n=2), radiation (n=4) or both (n=5); median PSA was 44.7ng/mL (1.9-585). ANC&lt;1000mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ≥4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n=15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone. Conclusions: This is the first evaluation of ENZA given in combination with DOC.In mCRPC pts ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia

Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.

420 Increased Clearance of Docetaxel in Androgen Deprived Prostate Cancer Patients

420 Increased Clearance of Docetaxel in Androgen Deprived Prostate Cancer Patients

422 Antitumor Activity of BAL27862 (active Moiety of the Prodrug BAL101553) is Associated with the Generation of Short Non-centrosomal Microtubules

Background: Docetaxel is used as first line chemotherapy for metastatic castrate resistant prostate cancer (mCRPC). It has been reported that castrated men have substantially increased docetaxel clearance (CL) compared to uncastrated men treated for mCRPC (Franke et al, J Clin Oncol 28: 4562−7, 2010). These results were obtained from 20 castrated men, with 10 non-castrated men serving as controls. In this study, we aimed to validate these findings in a larger and independent cohort of patients. Material and Methods: All male patients treated within the context of a pharmacokinetic study (Dutch Trial Registry; NTR2311) with docetaxel for solid tumors were included in this analysis (n = 74). As chemotherapy alone does not result in alterations in testosterone levels, out of these 74 patients, all men with non-prostate tumors served as controls (n = 36) of the castrated mCRPC patients (n = 38). Five of these control patients received docetaxel in combination with SU014813 in a clinical phase I study, all other patients received monotherapy. SU014813 has no clinically relevant pharmacokinetic (PK) interaction with docetaxel (de Jonge et al, Eur J Cancer 47: 1328−35, 2011). Dosage ranged from 30mg/m to 100mg/m, given in different schedules. Plasma docetaxel levels were determined by HPLC or LC-MS/MS. Individual PK parameters were estimated from previously developed population PK models by non-linear mixed effects modelling using NONMEM software. P-values were calculated using an independent samples T-test, while linear regression analysis was used to adjust for age, ethnicity, body surface area, concomitant use of other anticancer drugs, and dose when analysing haematological toxicity. Results: In the castrated patients, there was an increased docetaxel CL compared to the CL of uncastrated men (48.4 L/h versus 42.1 L/h, P = 0.051). In addition, both absolute neutrophil count nadir (n = 66) and white blood cell count nadir (n = 68) were significantly higher in castrated patients during chemotherapy with docetaxel (4.1 versus 1.7 ×109/L, P = 0.003 and 5.3 versus 3.1×109/L, P = 0.016, respectively). Conclusions: Androgen deprived prostate cancer patients in this study show an increased CL. In addition, castrated patients show less pronounced haematological toxicity compared to the control group of uncastrated men treated with docetaxel. Adding these results to the existing knowledge provides a solid foundation for further investigations regarding the increase in clearance related to castration-status and also for the individualization of docetaxel treatment in male patients.

Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P-glycoprotein (P-gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C(max) of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P-gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P-gp and Cyp3A between the two taxanes.

Influence of Polymorphic OATP1B-Type Carriers on the Disposition of Docetaxel

Docetaxel is extensively metabolized by CYP3A4 in the liver but mechanisms by which the drug is taken up into hepatocytes remain poorly understood. We hypothesized that (i) liver uptake of docetaxel is mediated by the polymorphic solute carriers OATP1B1 and OATP1B3 and (ii) inherited genetic defects in this process may impair systemic drug elimination. Transport of docetaxel was studied in vitro using various cell lines stably transfected with OATP1B1*1A (wild-type), OATP1B1*5 [c.521T>C (V174A); rs4149056], OATP1B3, or the mouse transporter Oatp1b2. Docetaxel clearance was evaluated in wild-type and Oatp1b2-knockout mice as well as in two cohorts of patients with multiple variant transporter genotypes (n = 213). Docetaxel was found to be a substrate for OATP1B1, OATP1B3, and Oatp1b2 but was not transported by OATP1B1*5. Deficiency of Oatp1b2 in mice was associated with an 18-fold decrease in docetaxel clearance (P = 0.0099), which was unrelated to changes in intrinsic metabolic capacity in mouse liver microsomes. In patients, however, none of the studied common reduced function variants in OATP1B1 or OATP1B3 were associated with docetaxel clearance (P > 0.05). The existence of at least two potentially redundant uptake transporters in the human liver with similar affinity for docetaxel supports the possibility that functional defects in both of these proteins may be required to confer substantially altered disposition phenotypes. In view of the established exposure-toxicity relationships for docetaxel, we suggest that caution is warranted if docetaxel has to be administered together with agents that potently inhibit both OATP1B1 and OATP1B3.

Saturable sinusoidal uptake is rate-determining process in hepatic elimination of docetaxel in rats

Identifying kinetic determinants of hepatic elimination of drugs would be crucial for better understanding its pharmacokinetics and predicting drug interactions. Present study investigated the kinetics of sinusoidal uptake of docetaxel and its impact on the overall hepatic elimination of docetaxel in rats.The non-renal clearance (CLNR; hepatic elimination) of docetaxel were significantly reduced by co-administration of intravenous rifampicin, a potent inhibitor of organic anion transporting peptides (OATPs; Oatps), at a dose of 20 mg/kg. Docetaxel uptake into isolated rat hepatocytes was found to be temperature/concentration/energy-dependent, saturable, and reduced by Oatps inhibitors (rifampicin and bromosulfophthalein). Moreover, docetaxel uptake into perfused rat liver was significantly reduced in the presence of 10-µM rifampicin. However, docetaxel metabolism in rat hepatic microsome was not affected by rifampicin at less than 50 µM.Based on the comparison of intrinsic clearances related to hepatic clearance, it can be suggested that sinusoidal uptake could be the rate-determining process in the overall hepatic elimination of docetaxel in rats.

Gefitinib in Combination with Weekly Docetaxel in Patients with Metastatic Breast Cancer Caused Unexpected Toxicity: Results from a Randomized Phase II Clinical Trial

In patients with metastatic breast cancer, taxane treatment demonstrates activity but is not curative. Targeted treatment modalities are therefore necessary in order to improve outcomes in this group. A randomized placebo-controlled phase II trial was initiated to evaluate effect and toxicity of gefitinib (250 mg QD) and docetaxel 35 mg/m2 (six of seven weeks) (NCT 00319618). The inclusion of 66 patients was planned. The study was closed due to treatment-related toxicity. Of the 18 included patients, seven (of which three received gefitinib) were withdrawn from the study due to toxicity. Of the nine patients receiving gefitinib and chemotherapy, one achieved a partial response and four stable disease. In the chemotherapy of nine patients, four had a partial response and four stable disease. The breast cancer patients in this study were genotyped using a panel of 14 single-nucleotide polymorphisms (SNPs), previously found associated with docetaxel clearance in a cohort of lung cancer patients. We were unable to identify genes related to toxicity in this study. Nevertheless, toxicity was aggravated by the addition of the tyrosine kinase inhibitor. In conclusion, despite adequately tolerated as monotherapy, combination regimens should be carefully considered for overlapping adverse events in order to avoid increased treatment-related toxicity.

Influence of SLCO1B3 haplotype‐tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients

SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel. The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing. The SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n= 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n= 50). Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition. This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMS To completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n= 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients. Genomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK. A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P= 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,∞)): r(2) = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,∞) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P= 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (P= 0.002). The functional SLCO1B3 haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR-890 binding site in the 3'-untranslated region which may influence the transport characteristics of SLCO1B3. This study highlights the importance of SLCO1B3 polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.

Neutropenia as a potential pharmacodynamic marker for docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).

51 Background: Data suggest docetaxel clearance is increased in castrate men. An association of docetaxel-induced grade ≥3 neutropenia with overall survival (OS) may provide a rationale for tailored dosing in mCRPC. Methods: The association of cycle 1 neutropenia with OS was examined in a randomized phase II trial of 221 men with mCRPC receiving docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor), which performed weekly blood cell counts during the first cycle. Patients from both arms were combined as no outcome or neutropenia differences were observed. OS was calculated from randomization by the Kaplan-Meier method and Cox proportional hazards regression models were used to estimate the association with OS. Results: The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for stratification factors (HR: 0.64, p= 0.048). Excluding men with delayed cycle 2 yielded a more significant association of grade 3-4 neutropenia on day 8 with survival (Table). Men with ≥grade 3 neutropenia and ≥30% PSA decline by day 90 had improved OS compared with men exhibiting neither (HR: 0.51, p=0.014). Conclusions: In mCRPC receiving docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, suggesting its potential utility as a pharmacodynamic marker in this hypothesis-generating analysis. Since the association was stronger after excluding patients that experienced dose delays, grade 3 neutropenia may confer a more favorable therapeutic index than grade 4 neutropenia. The exploration of dose modulation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted. [Table: see text]