[Show abstract][Hide abstract] ABSTRACT: Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We conducted the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1 [normal]; Category 2 [mild: ALP, AST and/or ALT≤5 ХULN, and TB within normal range]; Category 3 [moderate: any ALP, and AST or ALT≤5-10ХULN, and/or TB≤1-1.5 ХULN]. Category 1, 2 and 3 patients received starting dosages of 40mg/m2, 30mg/m2 and 20mg/m2 docetaxel respectively. Pharmacokinetics was evaluated on Day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was performed weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P<0.001). Median clearance was 22.8, 16.4 and 11.3L/h/m2 in Categories 1, 2 and 3 respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (AUC) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median AUC was 1.74, 1.83 and 1.77mg·h/L in Categories 1, 2 and 3 respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and NCI-ODWG grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements.
[Show abstract][Hide abstract] ABSTRACT: Statins purportedly exert anti-tumoral effects on breast cancer. However, the biologic mechanisms for these actions are not fully elucidated. The aims of this study were 1) to explore the effects of simvastatin on apoptosis, proliferation as well as PI3K/Akt/mTOR and MAPK/ERK pathway in a window-of-opportunity breast cancer trial; 2) to further confirm findings from the clinical trial by functional studies; 3) to explore the regulatory role of mevalonate pathway on the anti-tumoral effects of simvastatin. In clinical samples, simvastatin led to increase in cleaved caspase-3 (p = 0.002) and decreased trend for Ki67 (p = 0.245). Simvastatin markedly suppressed PI3K/Akt/mTOR signalling by activating PTEN (p = 0.005) and by dephosphorylating Akt (p = 0.002) and S6RP (p = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf (p = 0.018) and ERK1/2 (p = 0.002). In ER-positive (MCF-7, T47D) and ER-negative (MDA-MB-231, BT-549) breast cancer cells, simvastatin treatment consistently induced apoptosis and inhibited proliferation by deregulating caspase cascades and cell cycle proteins in a dose dependent manner. Concordantly, simvastatin strongly suppressed PI3K/Akt/mTOR pathway by enhancing PTEN expression and by further sequentially dephosphorylating downstream cascades including Akt, mTOR, p70S6K, S6RP and 4E-BP1. Furthermore, simvastatin significantly inhibited MAPK/ERK pathway by dephosphorylating sequential cascades such as c-Raf, MEK1/2 and ERK1/2. These simvastatin anti-tumoral effects were reversed by metabolic products of the mevalonate pathway, including mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These findings shed light on the biological and potential anti-tumoral effects of simvastatin in breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Introduction: In the era of genomic medicine, it is increasingly recognized that ethnogeographic differences in drug pharmacology exist between Asian and other populations. This is particularly pertinent to oncology, where drugs forming the backbone of chemotherapy often have narrow therapeutic windows and are frequently dosed close to maximally tolerable levels.
Areas covered: At the population level, ancestry is important because historical–biogeographical confluences have shaped population genetics and pharmacoethnicity in the Asian race through allelic differentiation and interethnic differences in inheritance patterns of linkage disequilibrium. At the individual level, cis- and trans-acting germline polymorphisms and somatic mutations in genes encoding drug-metabolizing enzymes and transporters act in a multifactorial manner to determine drug disposition phenotype and clinical response in Asian cancer patients. A growing body of evidence also finds that complex genetic interactions and regulation, including a multiplicity of gene control mechanisms, are increasingly implicated in genotype–phenotype correlates than has hitherto been appreciated – potentially serving as the mechanistic links between hits in non-coding regions of genome-wide association studies and drug toxicity. Together, these genetic factors contribute to the clinical heterogeneity of drug disposition in Asian cancer patients.
Expert opinion: This topic has broad relevance for the optimization and individualization of anticancer strategies in Asians.
Full-text · Article · Nov 2015 · Expert Opinion on Drug Metabolism & Toxicology
[Show abstract][Hide abstract] ABSTRACT: Clinical trials of genotype-guided dosing of warfarin have yielded mixed results, which may in part reflect ethnic differences among study participants. However, no previous study has compared genotype-guided versus clinically guided or standard-of-care dosing in a Chinese population, whereas those involving African-Americans were underpowered to detect significant differences. We present a preclinical strategy that integrates pharmacogenetics (PG) and pharmacometrics to predict the outcome or guide the design of dosing strategies for drugs that show large interindividual variability. We use the example of warfarin and focus on two underrepresented groups in warfarin research.
We identified the parameters required to simulate a patient population and the outcome of dosing strategies. PG and pharmacogenetic plus loading (PG+L) algorithms that take into account a patient's VKORC1 and CYP2C9 genotype status were considered and compared against a clinical (CA) algorithm for a simulated Chinese population using a predictive Monte Carlo and pharmacokinetic-pharmacodynamic framework. We also examined a simulated population of African-American ancestry to assess the robustness of the model in relation to real-world clinical trial data.
The simulations replicated similar trends observed with clinical data in African-Americans. They further predict that the PG+L regimen is superior to both the CA and the PG regimen in maximizing percentage time in therapeutic range in a Chinese cohort, whereas the CA regimen poses the highest risk of overanticoagulation during warfarin initiation. The findings supplement the literature with an unbiased comparison of warfarin dosing algorithms and highlights interethnic differences in anticoagulation control.
Full-text · Article · Jul 2015 · Pharmacogenetics and Genomics
[Show abstract][Hide abstract] ABSTRACT: A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the evaluation of exemestane pharmacokinetics and its metabolites, 17β-dihydroexemestane (active metabolite) and 17β-dihydroexemestane-17-O-β-D-glucuronide (inactive metabolite) in human plasma. Their respective D3 isotopes were used as internal standards. Chromatographic separation of analytes was achieved using Thermo Fisher BDS Hypersil C18 analytic HPLC column (100 × 2.1 mm, 5 μm). The mobile phase was delivered at a rate of 0.5 mL/min by gradient elution with 0.1% aqueous formic acid and acetonitrile. The column effluents were detected by API 4000 triple quadrupole mass spectrometer using electrospray ionisation (ESI) and monitored by multiple reaction monitoring (MRM) in positive mode. Mass transitions 297 > 121 m/z, 300 > 121 m/z, 299 > 135 m/z, 302 > 135 m/z, 475 > 281 m/z, and 478 > 284 m/z were monitored for exemestane, exemestane-d3, 17β-dihydroexemestane, 17β-dihydroexemestane-d3, 17β-dihydroexemestane-17-O-β-D-glucuronide, and 17β-dihydroexemestane-17-O-β-D-glucuronide-d3 respectively. The assay demonstrated linear ranges of 0.4-40.0 ng/mL, for exemestane; and 0.2-15.0 ng/mL, for 17β-dihydroexemestane and 17β-dihydroexemestane-17-O-β-D-glucuronide, with coefficient of determination (r2) of > 0.998. The precision (coefficient of variation) were ≤10.7%, 7.7% and 9.5% and the accuracies ranged from 88.8 to 103.1% for exemestane, 98.5 to 106.1% for 17β-dihydroexemestane and 92.0 to 103.2% for 17β-dihydroexemestane-17-O-β-D-glucuronide. The method was successfully applied to a pharmacokinetics/dynamics study in breast cancer patients receiving exemestane 25 mg daily orally. For a representative patient, 20.7% of exemestane in plasma was converted into 17β-dihydroexemestane and 29.0% of 17β-dihydroexemestane was inactivated as 17β-dihydroexemestane-17-O-β-D-glucuronide 24 hours after ingestion of exemestane, suggesting that altered 17-dihydroexemestane glucuronidation may play an important role in determining effect of exemestane against breast cancer cells.
[Show abstract][Hide abstract] ABSTRACT: Regorafenib, a multi-kinase inhibitor, is used in the treatment of patients with metastatic colorectal cancer refractory to standard therapy. However, this benefit was limited to 1.4 months improvement in overall survival, with more than half of patients experiencing grade 3 to 4 adverse events. We aim to elucidate the pharmacodynamic effects of regorafenib in metastatic colorectal cancer and discover potential biomarkers that may predict clinical benefit.
Patients with metastatic colorectal adenocarcinoma refractory to standard therapy with tumours amenable to biopsy were eligible for the study. Regorafenib was administered orally at 160 mg daily for 3 out of 4 weeks with tumour assessment every 2 cycles. Metabolic response was assessed by FDG PET-CT scans (pre-treatment and day 15); paired tumour biopsies (pre-treatment and day 21 post-treatment) were sampled for immunohistochemistry and proteomic profiling analyses. Plasma circulating cell free DNA was quantified serially before and after treatment.
There were 2(6%) partial responses out of 35 patients, and 8(23%) patients had stable disease for more than 7 months. Adverse event profile was similar to reported data. Recurrent somatic mutations in K-RAS, PIK3CA and BRAF were detected in plasma circulating cell free DNA in 14 patients; some mutations were not found in archival tumour. Total plasma circulating cell free DNA inversely correlated with progression free survival (PFS), and presence of KRAS mutations associated with shorter PFS. Immunohistochemistry of pre- and post- treatment biopsies showed majority of patients had downregulation of phosphorylated-VEGFR2, podoplanin, phosphorylated-AKT, Ki-67 and upregulation of the MEK-ERK axis, phosphorylated-C-MET, phosphorylated-SRC, phosphorylated-STAT3 and phosphorylated-JUN. Proteomic analysis of fine needle tumour aspirates showed down-regulation of PI3K was associated with longer PFS.
Plasma circulating cell free DNA may yield potential predictive biomarkers of regorafenib treatment. Downregulation of the PI3K-AKT axis may be an important predictor of clinical benefit.
Full-text · Article · Feb 2015 · Journal of Translational Medicine
[Show abstract][Hide abstract] ABSTRACT: We aim to evaluate the influence of covariates, including cytochrome P450 3A (CYP3A) genetic polymorphisms, on the pharmacokinetics of midazolam (MDZ) in Asian cancer patients, using a population pharmacokinetic approach. Pharmacokinetic data were obtained from twenty-four adult cancer patients who received an intravenous bolus dose of 1mg MDZ as a CYP3A phenotyping probe, one day before starting FOLFIRI chemotherapy. Concentrations of MDZ and its major metabolites, 1'-hydroxymidazolam (1OHM) and 1'-hydroxymidazolam glucuronide (HMG) were measured using liquid chromatography/mass spectrometry. The population pharmacokinetic study was conducted using NONMEM. Demographics, clinical characteristics and genetic polymorphisms were screened as covariates. A two-compartment model for MDZ and two sequential compartments representing 1OHM and HMG best described the data. The CYP3A5*3 and total bilirubin level significantly influenced MDZ clearance. The population typical MDZ clearance for CYP3A5*3 expressers was 22% lower than non-expressers. Baseline bodyweight was a statistically significant covariate for clearance and distribution volume of 1OHM. Creatinine clearance was positively correlated with HMG clearance. Our data indicate that CYP3A5*3, total bilirubin, bodyweight and creatinine clearance are important predictors of MDZ and metabolite pharmacokinetics. Further studies in more patients are needed to explore the links between the identified covariates and the disposition of MDZ and its metabolites.
No preview · Article · Feb 2014 · The Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: This study evaluated the pharmacokinetics of gabapentin in Chinese subjects who received a diet rich in shiitake mushrooms. Shiitake mushrooms have been shown to contain high amount of ergothioneine. In vitro studies have shown that OCTN1-mediated secretion of gabapentin is trans-stimulated by ergothioneine. This study also investigated the levels of ergothioneine in plasma at baseline and following mushroom consumption.
Ten healthy male subjects were recruited and received a diet containing no mushrooms (Treatment A) or a high mushroom diet (Treatment B; after at least a 7-day washout period) 1 day prior to administration of a single oral dose of gabapentin 600 mg.
Ingestion of shiitake mushrooms produced significant increases in plasma ergothioneine levels that were sustained for more than 48 hours. A statistically significant but modest increase in the renal clearance (CLR ) of gabapentin occurred after intake of the mushroom diet (91.1±25.1 versus 76.9±20.6 mL/min; P=0.031); no significant changes in AUClast of gabapentin were observed (P=0.726). Creatinine clearance did not correlate with CLR of gabapentin at baseline (Treatment A). After ingestion of the mushroom diet, creatinine clearance accounted for 65.3% of the variance in CLR of gabapentin.
These data suggest that diet-drug pharmacokinetic interactions may occur during co-exposure to gabapentin and mushroom constituents. However, as it does not affect the AUClast of gabapentin, it may not have clinically important consequences. Shiitake mushrooms can also be used as a source of ergothioneine for future clinical studies.
No preview · Article · Oct 2013 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups - Epi-A, Epi-B, Mes, Stem-A and Stem-B - exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype-specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor-prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule-related processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients.
Full-text · Article · Jul 2013 · EMBO Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.
[Show abstract][Hide abstract] ABSTRACT: Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme.
[Show abstract][Hide abstract] ABSTRACT: Aldo-ketoreductases have been implicated in the metabolism of doxorubicin. We sought to assess the influence of AKR1C3 genetic variants on doxorubicin metabolism.
We sequenced AKR1C3 exon 5 and genotyped seven functional single nucleotide polymorphisms in CBR3, ABCB1 and SLC22A16 involved in doxorubicin pharmacology in 151 Asian breast cancer patients treated with doxorubicin-containing chemotherapy, and correlated these genotypes with doxorubicin pharmacokinetics and pharmacodynamics.
Two previously reported AKR1C3 intronic variants, IVS4–212 C>G and IVS4+218 G>A, were detected. The AKR1C3 IVS4–212 GG genotype was associated with significantly lower cycle 1 day 15 leucocyte (mean leucocytes 2.49 ± 1.57 × 109vs. 3.85 ± 3.42 × 109 l−1, P = 0.007) and neutrophil counts (mean neutrophils 0.70 ± 1.01 × 109vs. 1.56 ± 2.80 × 109 l−1, P = 0.008) and significant improvement of progression-free survival [PFS, mean PFS 49.0 (95% confidence interval 42.2–55.8) vs. 31.0 (95% confidence interval 20.7–41.2) months, P = 0.017] and overall survival [OS; mean OS 64.4 (95% confidence interval 58.3–70.5) vs. 46.3 (95% confidence interval 35.1–57.5) months, P = 0.006] compared with those carrying at least one C allele. There was no significant association between AKR1C3 IVS4–212 C>G and doxorubicin pharmacokinetics. Of the other seven single nucleotide polymorphisms genotyped, CBR3 G11A correlated with doxorubicinol area under the concentration–time curve and OS, ABCB1 G2677T/A correlated with doxorubicin clearance and platelet toxicity, while ABCB1 IVS26+59 T>G correlated with OS. The AKR1C3 IVS4–212 C<G genotype remained significantly correlated with both PFS and OS on multivariate analysis with clinical prognosticators.
The AKR1C3 IVS4–212 GG genotype was associated with greater haematological toxicity and longer progression-free survival and overall survival after doxorubicin-based therapy, suggesting potential interaction of this variant with doxorubicin metabolism.
No preview · Article · Nov 2012 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Uridine diphosphoglucuronosyltransferases (UGTs) 1A6 is the only UGT1A isoform expressed in lung tissue. It is responsible for the detoxification of carcinogens such as benezo[a]pyrene from cigarette smoke. The purpose of this study was to evaluate the association of UGT1A6 polymorphisms and haplotypes with lung cancer risk and to evaluate the functional significance of UGT1A6 polymorphisms. Genomic DNA was isolated from leukocytes. Eight UGT1A6 polymorphisms were sequenced in a test set of 72 Chinese lung cancer patients and 62 healthy controls. Potential risk modifying alleles were validated in a separate set of 95 Chinese lung cancer patients and 100 healthy controls. UGT1A6 19T>G, 541A>G and 552A>C showed significant association with increased lung cancer risk, while UGT1A6 105C>T and IVS1+130G>T were significantly associated with reduced lung cancer risk. Multivariate logistic regression analysis demonstrated a significant association of lung cancer with UGT1A6 541A>G (OR: 3.582, 95% CI: 1.27-10.04, p = 0.015), 552A>C (OR: 5.364, 95% CI: 1.92-14.96, p = 0.001) and IVS1+130G>T (OR: 0.191, 95% CI: 0.09-0.36, p<0.001). Functional test demonstrated that UGT1A6 105C>T increased mRNA stability, providing a plausible explanation of its association with reduced lung cancer risk. Thus UGT1A6 polymorphisms may be used to identify people with increased risk of developing lung cancer.
[Show abstract][Hide abstract] ABSTRACT: The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
[Show abstract][Hide abstract] ABSTRACT: Drug interactions may be exploited to overcome pharmacokinetic issues in order to improve the therapeutic index of a drug, with clinical goals of reducing the dose of the active drug while preserving efficacy or reducing toxicity. This strategy has been used in infectious disease and transplant medicine, and, more recently, in oncology. Pharmacologic modulation strategies range from coadministration of either a drug that inhibits a metabolizing enzyme that would inactivate the drug of interest, a drug that induces an enzyme that activates the drug of interest or a drug that inhibits transporters that affect the uptake or elimination of the drug of interest. This review will discuss pharmacologic modulation strategies that have been tested clinically in order to increase systemic drug exposure. Important examples include ketoconazole inhibition of hepatic CYP3A4 in order to increase systemic exposure to docetaxel, irinotecan and etoposide, and cyclosporine inhibition of intestinal ATP-binding cassette transporters in order to decrease the toxicity of irinotecan and increase the bioavailability of oral docetaxel, paclitaxel and topotecan.
[Show abstract][Hide abstract] ABSTRACT: A novel and specific liquid chromatography-tandem mass spectrometric method (LC-MS/MS) was developed and validated for the quantification of hydroxychloroquine in human blood using its stable labeled isotope, hydroxychloroquine-d4 as the internal standard. Chromatographic separation of analytes was achieved using an Agilent ZORBAX Eclipse XDB - C8 analytical HPLC column (50 mm × 2.1 mm, 5 μm). The mobile phase comprising water containing 0.1% formic acid-acetonitrile (94:6, v/v) was delivered isocratically at a flow rate of 0.5 mL/min. The column effluent was detected by API 4000 triple quadrupole mass spectrometer using electrospray ionization (ESI) and monitored by multiple reaction monitoring with positive mode. The precursor to product ion transitions of m/z 336 → 247 and m/z 340 → 251 were used to measure the analyte and IS, respectively. The assay demonstrated a good linear dynamic range of 5-2000 ng/mL for hydroxychloroquine in human blood, with coefficient of determination (r(2)) of =0.9999. The values for intra-day and inter-day precisions of hydroxychloroquine were ≤ 7.86% with the accuracies ranged from 93.8% to 107.6%. The chromatographic run time was 3 min, making it possible to achieve a high throughput analysis. This method was used as a bio-analytical tool in a phase I clinical trial to quantify blood hydroxychloroquine concentrations in patients with non-small cell lung cancer receiving both hydroxychloroquine and gefitinib in their treatment.
No preview · Article · Dec 2011 · Journal of pharmaceutical and biomedical analysis