Paclitaxel Clearance Research Articles

Candesartan Has No Clinically Meaningful Effect on the Plasma Concentrations of CYP2C8 Substrate Repaglinide in Humans.

In vitro evidence show that the acyl-β-D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 µM. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl-β-D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared to placebo, with ratios of geometric means of 1.02 [P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 (P = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl-β-D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase (P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl-β-D-glucuronide were very low compared to its CYP2C8 inhibition constant (ratio << 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent. Significance Statement The findings of this study suggest that candesartan is unlikely to cause drug-drug interactions via inhibition of CYP2C8. Even though candesartan acyl-β-D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations.

Novel progressive deep learning algorithm for uncovering multiple single nucleotide polymorphism interactions to predict paclitaxel clearance in patients with nonsmall cell lung cancer.

The rate at which the anticancer drug paclitaxel is cleared from the body markedly impacts its dosage and chemotherapy effectiveness. Importantly, paclitaxel clearance varies among individuals, primarily because of genetic polymorphisms. This metabolic variability arises from a nonlinear process that is influenced by multiple single nucleotide polymorphisms (SNPs). Conventional bioinformatics methods struggle to accurately analyze this complex process and, currently, there is no established efficient algorithm for investigating SNP interactions. We developed a novel machine-learning approach called GEP-CSIs data mining algorithm. This algorithm, an advanced version of GEP, uses linear algebra computations to handle discrete variables. The GEP-CSI algorithm calculates a fitness function score based on paclitaxel clearance data and genetic polymorphisms in patients with nonsmall cell lung cancer. The data were divided into a primary set and a validation set for the analysis. We identified and validated 1184 three-SNP combinations that had the highest fitness function values. Notably, SERPINA1, ATF3 and EGF were found to indirectly influence paclitaxel clearance by coordinating the activity of genes previously reported to be significant in paclitaxel clearance. Particularly intriguing was the discovery of a combination of three SNPs in genes FLT1, EGF and MUC16. These SNPs-related proteins were confirmed to interact with each other in the protein-protein interaction network, which formed the basis for further exploration of their functional roles and mechanisms. We successfully developed an effective deep-learning algorithm tailored for the nuanced mining of SNP interactions, leveraging data on paclitaxel clearance and individual genetic polymorphisms.

Meta-analysis of the global distribution of clinically relevant CYP2C8 alleles and their inferred functional consequences.

CYP2C8 is responsible for the metabolism of 5% of clinically prescribed drugs, including antimalarials, anti-cancer and anti-inflammatory drugs. Genetic variability is an important factor that influences CYP2C8 activity and modulates the pharmacokinetics, efficacy and safety of its substrates. We profiled the genetic landscape of CYP2C8 variability using data from 96 original studies and data repositories that included a total of 33,185 unrelated participants across 44 countries and 43 ethnic groups. The reduced function allele CYP2C8*2 was most common in West and Central Africa with frequencies of 16-36.9%, whereas it was rare in Europe and Asia (< 2%). In contrast, CYP2C8*3 and CYP2C8*4 were common throughout Europe and the Americas (6.9-19.8% for *3 and 2.3-7.5% for *4), but rare in African and East Asian populations. Importantly, we observe pronounced differences (> 2.3-fold) between neighboring countries and even between geographically overlapping populations. Overall, we found that 20-60% of individuals in Africa and Europe carry at least one CYP2C8 allele associated with reduced metabolism and increased adverse event risk of the anti-malarial amodiaquine. Furthermore, up to 60% of individuals of West African ancestry harbored variants that reduced the clearance of pioglitazone, repaglinide, paclitaxel and ibuprofen. In contrast, reduced function alleles are only found in < 2% of East Asian and 8.3-12.8% of South and West Asian individuals. Combined, the presented analyses mapped the genetic and inferred functional variability of CYP2C8 with high ethnogeographic resolution. These results can serve as a valuable resource for CYP2C8 allele frequencies and distribution estimates of CYP2C8 phenotypes that could help identify populations at risk upon treatment with CYP2C8 substrates. The high variability between ethnic groups incentivizes high-resolution pharmacogenetic profiling to guide precision medicine and maximize its socioeconomic benefits, particularly for understudied populations with distinct genetic profiles.

A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies.

AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75-175 mg/m2, BEV 30-70 mg/m2). Pharmacokinetic analyses were performed. No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%-61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

Utility of Physiologically Based Pharmacokinetic Modeling to Investigate the Impact of Physiological Changes of Pregnancy and Cancer on Oncology Drug Pharmacokinetics.

The treatment of cancer during pregnancy remains challenging with knowledge gaps in drug dosage, safety, and efficacy due to the under-representation of this population in clinical trials. Our aim was to investigate physiological changes reported in both pregnancy and cancer populations into a PBPK modeling framework that allows for a more accurate estimation of PK changes in pregnant patients with cancer. Paclitaxel and docetaxel were selected to validate a population model using clinical data from pregnant patients with cancer. The validated population model was subsequently used to predict the PK of acalabrutinib in pregnant patients with cancer. The Simcyp pregnancy population model reasonably predicted the PK of docetaxel in pregnant patients with cancer, while a modified model that included a 2.5-fold increase in CYP2C8 abundance, consistent with the increased expression during pregnancy, was needed to reasonably predict the PK of paclitaxel in pregnant patients with cancer. Changes in protein binding levels of patients with cancer had a minimal impact on the predicted clearance of paclitaxel and docetaxel. PBPK modeling predicted approximately 60% lower AUC and Cmax for acalabrutinib in pregnant versus non-pregnant patients with cancer. Our results suggest that PBPK modeling is a promising approach to investigate the effects of pregnancy and cancer on the PK of oncology drugs and potentially inform dosing for pregnant patients with cancer. Further evaluation and refinement of the population model are needed for pregnant patients with cancer with additional compounds and clinical PK data.

Glabridin plays dual action to intensify anti-metastatic potential of paclitaxel via impeding CYP2C8 in liver and CYP2J2/EETs in tumor of an orthotopic mouse model of breast cancer

In spite of unprecedented advances in modern cancer therapy, there is still a dearth of targeted therapy to circumvent triple-negative breast cancer (TNBC). Paclitaxel is the front-line therapy against TNBC, but the main constraints of its treatment are dose-related adverse effects and emerging chemoresistance. In this context, glabridin (phytoconstituent from Glycyrrhiza glabra) is reported to hit multiple signalling pathways at the in-vitro level, but hardly any information is known at the in-vivo level. We aimed here to elucidate glabridin potential with an underlying mechanism in combination with a low dose of paclitaxel using a highly aggressive mouse mammary carcinoma model. Glabridin potentiated the anti-metastatic efficacy of paclitaxel by substantially curtailing tumor burden and diminishing lung nodule formation. Moreover, glabridin remarkably attenuated epithelial-mesenchymal transition (EMT) traits of hostile cancer cells via up-regulating (E-cadherin & occludin) and down-regulating (Vimentin & Zeb1) vital EMT markers. Besides, glabridin amplified apoptotic induction effect of paclitaxel in tumor tissue by declining or elevating pro-apoptotic (Procaspase-9 or Cleaved Caspase-9 & Bax) and reducing anti-apoptotic (Bcl-2) markers. Additionally, concomitant treatment of glabridin and paclitaxel predominantly lessened CYP2J2 expression with marked lowering of epoxyeicosatrienoic acid (EET)'s levels in tumor tissue to reinforce the anti-tumor impact. Simultaneous administration of glabridin with paclitaxel notably enhanced plasma exposure and delayed clearance of paclitaxel, which was mainly arbitrated by CYP2C8-mediated slowdown of paclitaxel metabolism in the liver. The fact of intense CYP2C8 inhibitory action of glabridin was also ascertained using human liver microsomes. Concisely, glabridin plays a dual role in boosting anti-metastatic activity by augmenting paclitaxel exposure via CYP2C8 inhibition-mediated delaying paclitaxel metabolism and limiting tumorigenesis via CYP2J2 inhibition-mediated restricting EETs level. Considering the safety, reported protective efficacy, and the current study results of boosted anti-metastatic effects, further investigations are warranted as a promising neoadjuvant therapy for crux paclitaxel chemoresistance and cancer recurrence.

Ritonavir-boosted antiretroviral therapy with paclitaxel: will it lead to boosted toxicity?

Ritonavir-boosted antiretroviral therapy with paclitaxel: will it lead to boosted toxicity?

Effect of Scalp Cooling on the Pharmacokinetics of Paclitaxel.

Simple SummaryThis study investigated the correlation between scalp cooling used to prevent chemotherapy-induced alopecia and the pharmacokinetics of paclitaxel in female cancer patients with a solid tumor. In a prospective cohort study, 14 patients who were treated with weekly paclitaxel and scalp cooling were able to undergo pharmacokinetic sampling of paclitaxel during one cycle of treatment. In comparison to a control cohort of 24 patients treated with weekly paclitaxel without scalp cooling, our data showed that scalp cooling used concomitantly with one course of paclitaxel did not reduce or increase the clearance of paclitaxel. Therefore, it is unlikely that scalp cooling influences paclitaxel efficacy or toxicity. Finally, despite scalp cooling, half of the patients in our study developed a form of hair loss. Importantly, neither an association with difference in paclitaxel clearance nor change in hair loss was found.Chemotherapy-induced alopecia (CIA), a side effect with high impact, can be prevented by cooling the scalp during the administration of some cytotoxic drugs. However, the effects of this prolonged scalp cooling on the pharmacokinetics of chemotherapy have never been investigated. In this study, we compared the pharmacokinetics of the widely used chemotherapeutic agent paclitaxel (weekly dose of 80–100 mg/m2) in female patients with solid tumors using concomitant scalp cooling (n = 14) or not (n = 24). Blood samples were collected in all patients for pharmacokinetic analyses up to 6 h after one course of paclitaxel administration. The primary endpoint was the clearance (L/h) of paclitaxel. Paclitaxel clearance—expressed as relative difference in geometric means—was 6.8% (90% CI: −16.7% to 4.4%) lower when paclitaxel was administered with concomitant scalp cooling versus paclitaxel infusions without scalp cooling. Within the subgroup of patients using scalp cooling, paclitaxel clearance was not statistically significantly different between patients with CIA (alopecia grade 1 or 2) and those without CIA. Hence, scalp cooling did not negatively influence the clearance of paclitaxel treatment.

Population Pharmacokinetics and Exposure-Safety Relationship of Paclitaxel Liposome in Patients With Non-small Cell Lung Cancer.

PurposePaclitaxel liposome (Lipusu) is the first commercialized liposomal formulation of paclitaxel. There has been little data collected on the pharmacokinetics (PK) of paclitaxel liposome, especially in relation to patient use. This study aimed to build a population pharmacokinetic (PopPK) model and further explore the exposure–safety relationship for paclitaxel liposome in patients with non-small cell lung cancer (NSCLC).MethodsData from 45 patients with a total of 349 plasma concentrations were analyzed. The PopPK model was built using the non-linear mixed effect modeling technique.ResultsThe PK of paclitaxel liposome were well described by a three-compartment model with first-order elimination. For a dose of 175 mg m–2, the estimated clearance of total plasma paclitaxel was 21.55 L h–1. Age, sex, body weight, total bilirubin, albumin, serum creatinine, and creatinine clearance did not influence the paclitaxel PK. Exposure to paclitaxel had no significant change in the presence of the traditional Chinese medicine, aidi injection. The exploratory exposure–safety relationship was well described by a generalized linear regression model. Higher probabilities of grade >1 neutropenia were observed in patients with higher exposure to paclitaxel.ConclusionThis PopPK model adequately described the PK of paclitaxel liposome in patients with NSCLC. Predicted exposure of paclitaxel did not change in the presence of the traditional Chinese medicine, aidi injection. The exposure–safety analysis suggested that a higher risk of neutropenia was correlated with higher exposure to paclitaxel.

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).

Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.

A phase I study of pazopanib with weekly paclitaxel and carboplatin in advanced solid tumors.

3021 Background: Pazopanib (pazo) is an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit. It is a weak inhibitor of CYP3A4 and CYP2C8 and may decrease paclitaxel (P) clearance. Daily pazo with P and carboplatin (C) every 21 days was not feasible on a previous study. We hypothesized that pazo dosed intermittently and on a different day from P and C may be tolerable. We sought to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of pazo with weekly P and C. Methods: Using a 3+3 standard design, a schedule of P 60-80 mg/m2 and C AUC2 on days 1, 8, and 15 with pazo 400-800 mg on days 2-5, 9-12, and 16-26 on a 28-day cycle was evaluated. Pazo alone could be continued if P and C were omitted due to maximal benefit or toxicity. PK was collected during cycles 1 and 2. Results: 34 patients (pts) were treated over 6 dose levels (Table). Mean age 57 (37-79). Tumor types: breast (22), lung (3) and other (9); 27 had prior platinum. Delay in starting cycle 2 due to grade 3 neutropenia was a DLT at dose level 2 and 5. Pts on 5A missed dosing during C1 and C2 due to neutropenia and required subsequent growth factor, and this was deemed unlikely to be sustainable long-term. All grade toxicities included anemia (62%), neutropenia (59%), and thrombocytopenia (56%). Protocol-defined MTD was not determined. PK analysis showed a dose proportional increase in pazo concentration, consistent with previous reports. Pazo did not alter the PK of C. Cmax of P was higher C2D1 vs C1D1; mean Cmax ratio between C2D1:C1D1 was 1.63 (95% CI:1.29-1.96). There were 11 objective responses (3 CRs, 8 PRs). Five breast pts were on pazo alone for a median of 9 cycles (2-52) with CR (2), PR (2) and SD (1); a squamous cell of unknown primary in CR received 22 cycles. Clinical trial information: NCT01407562. Conclusions: PK confirm that pazo is a weak inhibitor of CYP3A4 and CYP2C8. Myelosuppression was a major adverse event at all dose levels. MTD was not determined. Antitumor activity was achieved with this alternate combination schedule and sustained responses from sequential pazo monotherapy was observed.[Table: see text]

Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer.

Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included. The treatment was given as neoadjuvant chemoradiotherapy (nCRT), induction chemotherapy (iCT), or palliative chemotherapy (pCT). The treatment response was assessed by the tumor regression grade (TRG) or by the RECIST1.1 criteria, respectively. The unbound paclitaxel clearance (CL) was estimated with NONMEM. The log-transformed clearance was related to response with ANOVA and independent sample t-tests. A total of 166 patients were included, of whom 113 received nCRT, 23 iCT and 30 pCT. In patients receiving nCRT, paclitaxel clearance was not associated with tumor regression grade (p-value = 0.25), nor with pathologically complete response (geometric mean 561.6 L/h) and residual disease (geometric mean 566.1 L/h, p-value = 0.90). In patients who underwent iCT or pCT, also no association between paclitaxel clearance and RECIST outcome was identified (iCT: p-value = 0.08 and pCT: p-value = 0.81, respectively). In conclusion, systemic paclitaxel exposure was not associated with response to common paclitaxel-based treatment regimens for esophageal cancer. Future studies should focus on tumor exposure in relation to systemic exposure and treatment outcome.

Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics.

Paclitaxel (PTX) is an anticancer agent that is used to treat many cancers but it has a very low oral bioavailability due, at least in part, to the drug efflux transporter, P-glycoprotein (P-gp). Therefore, this study was performed to enhance oral bioavailability of PTX. In this study, we investigated the effects of several piperazine derivatives on P-gp function in vitro. Compound 4 was selected as the most potent P-gp inhibitor from the in vitro results for examining the pharmacokinetic (PK) changes of PTX in rats. Compound 4 increased the AUCinf of PTX without alterations in the Cmax value. The elimination half-life was extended and the oral clearance decreased. Additionally, the Tmax was delayed or widened in the treatment groups. Therefore, the bioavailability (BA) of PTX was improved 2.1-fold following the co-administration of 5 mg/kg of the derivative. A piperazine derivative, compound 4, which was confirmed as a substantial P-gp inhibitor in vitro increased the BA of PTX up to 2-fold by a lingering absorption, in part due to inhibition of intestinal P-gp and a low oral clearance of PTX. These results suggest that co-administering compound 4 may change the PK profile of PTX by inhibiting P-gp activity in the body.

Significant effect of age on docetaxel pharmacokinetics in Japanese female breast cancer patients by using the population modeling approach.

Docetaxel is frequently used in the treatment of a wide variety of solid tumors, including breast cancer. The aim of this study is to obtain the population pharmacokinetic parameters of docetaxel in Japanese female patients with breast cancer. Blood samples from 24 patients were collected sequentially before and after docetaxel infusion. Genomic DNA was isolated from the peripheral blood and genotyped for the selected polymorphisms in the candidate genes of drug transporters and metabolizing enzymes. The influence of patient characteristics on the pharmacokinetics of docetaxel was evaluated using the nonlinear-mixed-effect modeling program, NONMEM. As a basis for comparison, the pharmacokinetics of another taxane paclitaxel in 41 separate female patients with breast cancer was calculated. A two-compartment model adequately described the pharmacokinetic profiles of docetaxel. The population mean estimates of the total body clearance for patients aged 58years or less and the central volume of distribution for docetaxel were 32.6L/h and 5.77L, respectively. In patients over 58years, the clearance was 24% higher than that in the younger patients. No influences of the genotypes examined were noted on the clearance of docetaxel. The clearance of paclitaxel was not affected by patient age. Patients over the age of 58years showed significantly higher clearance of docetaxel than that in patients aged 58years or less. Since the clearance of paclitaxel was not affected by the age, it is possible that the pharmacokinetic mechanisms of docetaxel might be specifically affected by age in females.

Influence of drug formulation on OATP1B-mediated transport of paclitaxel.

Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B-type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P<0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer.

Genome-wide association study for identification of candidate SNPs associated with carboplatin and paclitaxel clearance in ovarian cancer patients.

5563 Background: Epithelial ovarian cancer (EOC) is generally treated by cytoreductive surgery and carboplatin/paclitaxel chemotherapy. Five-year survival is ~20% for patients with advanced disease...

Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer.

ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may underlie the association. Using cell-based models, we evaluated the correlations between ABCB1 expression, polymorphisms, transporter activity and paclitaxel sensitivity in ovarian cancer (n = 10) and lymphoblastoid (n = 19) cell lines. Close associations between ABCB1 expression, transporter function and paclitaxel sensitivity were found in lymphoblastoid cell lines, although we could not demonstrate an association with common SNPs. In ovarian cancer cell lines, ABCB1 expression was low and the association between expression and function was lost. These results suggest that ABCB1 related survival difference in ovarian cancer patients is more likely to be due to differential whole body paclitaxel clearance mediated by normal cells rather than a direct effect on cancer cells.

Abstract A55: Influence of ABCB1 polymorphisms on paclitaxel pharmacokinetics in ovarian cancer patients

Abstract Introduction: Epithelial ovarian cancer is generally treated by cytoreductive surgery followed by paclitaxel and carboplatin combination chemotherapy. Despite the high initial response rate, most patients with advanced disease will relapse and eventually succumb to illness due to intrinsic or acquired chemotherapy resistance. ABCB1 (ATP–binding cassette, sub-family B, member 1) mediates cellular elimination of many chemotherapeutic drugs, including paclitaxel. We previously reported a significant association between ABCB1 SNPs (single nucleotide polymorphisms) and PFS (progression-free survival) in ovarian cancer patients (Johnatty et al Clin Cancer Res 2008; 14: 5594-601). In patients with ≥1 cm residual disease, PFS was significantly shorter in homozygote GG carriers compared with patients who carried the minor T/A alleles at the G2677T/A locus (median PFS, 18 months compared with 32 months; p = 0.002). We hypothesized that variability in paclitaxel clearance (CL) resulting from genotypic differences in ABCB1 may underlie the impact of ABCB1 SNPs on clinical outcome. Methods: Pharmacokinetic sampling was performed during the first cycle of paclitaxel (175 mg/m2) and carboplatin (AUC5 or 6) combination chemotherapy treatment in two independent patient cohorts. These included 39 patients in a hospital based series in the Netherlands and 55 patients recruited prospectively in Australia. Paclitaxel levels were measured using liquid chromatography - tandem mass spectrometry (LC-MS/MS). The individual posterior Bayesian estimates of paclitaxel CL and model-based estimate of AUC (area-under-curve) were determined by using population pharmacokinetics with the NONMEM software. Common ABCB1 SNPs in exon 12 (C1236T), 21 (G2677T/A) and 26 (C3435T) were examined by iPLEX genotyping on Sequenom's MassARRAY platform. Nonparametric Jonckheere-Terpstra tests were used to compare the distribution of paclitaxel CL and AUC between patients of different genotypes. Results: In the Netherlands cohort, there were statistically significant associations observed between ABCB1 SNPs at exon 12 (C1236T), 21 (G2677T/A) and 26 (C3435T) and paclitaxel CL and AUC. Homozygote GG carriers at the G2677T/A locus had higher paclitaxel CL and lower AUC compared with minor T/A allele carriers. Similar findings were found for C1236T and C3435T. These findings were consistent with our previous clinical observations that patients with homozygote GG at exon 21 (G2677T/A), or homozygote CC at exon 12 (C1236T) or 26 (C3435T), had shorter PFS. The paclitaxel pharmacokinetic modeling results in the Australian cohort will be available for analysis shortly. Conclusion: The results to date suggest that common ABCB1 SNPs may contribute to chemotherapy resistance in women with ovarian cancer through their effects on paclitaxel drug disposition. Citation Format: Bo Gao, Annemieke J.M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Inge M. Ghobadi Moghaddam-Helmantel, Anne-Joy M. de Graan, Peter de Bruijn, Howard Gurney, Sharon E. Johnatty, Philip Beale, Georgia Chenevix-Trench, Rosemary L. Balleine, Ron H.J. Ron H.J. Mathijssen, Paul R. Harnett. Influence of ABCB1 polymorphisms on paclitaxel pharmacokinetics in ovarian cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A55.

A Pharmacogenetic Predictive Model for Paclitaxel Clearance Based on the DMET Platform

Paclitaxel is used in the treatment of solid tumors and displays high interindividual variation in exposure. Low paclitaxel clearance could lead to increased toxicity during treatment. We present a genetic prediction model identifying patients with low paclitaxel clearance, based on the drug-metabolizing enzyme and transporter (DMET)-platform, capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. In 270 paclitaxel-treated patients, unbound plasma concentrations were determined and pharmacokinetic parameters were estimated from a previously developed population pharmacokinetic model (NONMEM). Patients were divided into a training- and validation set. Genetic variants determined by the DMET platform were selected from the training set to be included in the prediction model when they were associated with low paclitaxel clearance (1 SD below mean clearance) and subsequently tested in the validation set. A genetic prediction model including 14 single-nucleotide polymorphisms (SNP) was developed on the training set. In the validation set, this model yielded a sensitivity of 95%, identifying most patients with low paclitaxel clearance correctly. The positive predictive value of the model was only 22%. The model remained associated with low clearance after multivariate analysis, correcting for age, gender, and hemoglobin levels at baseline (P = 0.02). In this first large-sized application of the DMET-platform for paclitaxel, we identified a 14 SNP model with high sensitivity to identify patients with low paclitaxel clearance. However, due to the low positive predictive value we conclude that genetic variability encoded in the DMET-chip alone does not sufficiently explain paclitaxel clearance.

Highlights of This Issue

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of cancer, with few effective treatments and a five-year survival of only ∼ 40%. To identify potentially useful therapies, a meta-analysis of multiple siRNA screens was performed, which identified HSP90 as a major hub controlling drug resistance. Ganetespib is a second generation HSP90 inhibitor that is showing considerable promise in clinical trials. In multiple mouse models, ganetespib had single-agent activity and also strongly enhanced the activity of paclitaxel, a standard cytotoxic agent used for EOC treatment, suggesting the potential value of clinical assessment of this drug combination.Integration of transcriptomics and metabolomics is a novel approach to reveal the underlying mechanisms of tumor progression and to identify potential therapeutic targets. Zhang and colleagues have used this approach to investigate the mechanism of disease aggressiveness in pancreatic cancer and showed that an impaired lipolytic network involving four lipases and their metabolites play an important role in the progression of pancreatic cancer and are candidate targets for therapeutic intervention. The article shows that the integration of “omics” data provides a system-level perspective of pancreatic cancer that could facilitate the development of novel treatment strategy.This article reports that epidermal growth factor receptor (EGFR) over-expression is frequently observed in follicular dendritic cell sarcoma (FDC-S). In a patient-derived short term culture, the engagement of surface EGFR by EGF drives the survival and proliferation of tumor cells via MAPK and STAT pathways. Remarkably, EGFR ligands, and Betacellulin (BTC) in particular, are produced in the tumor microenvironment of FDC-S. Lack of somatic mutations of KRAS, NRAS, BRAF, and PI3KCA in FDC-S tumor samples predicts sensitivity to anti-EGFR monoclonal antibody and suggests possible candidates for EGFR blockade in this neoplasm.The drug-metabolizing enzyme and transporter (DMET)-platform is capable of detecting 1,936 genetic variants in 225 metabolizing enzyme and drug transporter genes. de Graan and colleagues developed a genetic prediction model for paclitaxel pharmacokinetics based on the DMET-platform. In the validation set, the model had a 95% sensitivity to identify patients with a low paclitaxel clearance. The positive predictive value was 22%. After multivariate analysis, the model remained associated with low paclitaxel clearance.