Chuang Lu

Millennium Pharmaceuticals Inc, Boston, Massachusetts, United States

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Publications (26)48.96 Total impact

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    ABSTRACT: Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9, and 2C19, with IC50 values of 17.8, 27.7, 30.8, and 38.8 μM, respectively, whereas orteronel does not inhibit CYP2B6, 2D6, or 3A4/5 (IC50 > 100 μM). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Results of a static model indicated an [I]/Ki ratio > 0.1 for CYP1A2, 2C8, 2C9, and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin, and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9, and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these 4 CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios < 1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a "non-inhibitor" and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 10/2014; 35(9). DOI:10.1002/bdd.1919 · 2.18 Impact Factor
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    ABSTRACT: YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for treatment of drug addiction. However, the earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism, and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then simulate the clinical PK of YQA-14 using physiologically-based pharmacokinetics (PBPK) model to assess the likelihood of development of YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species rats and dogs for a validation purpose. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have clearance of 8.0 mL/min/kg, a volume distribution of 1.7 L/kg, and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 as an improved candidate for further research and develop as a potential DA D3R antagonism for treatment of drug addiction in clinic. This article is protected by copyright. All rights reserved.
    Biopharmaceutics & Drug Disposition 07/2014; 35(5). DOI:10.1002/bdd.1897 · 2.18 Impact Factor
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    ABSTRACT: Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 μM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose.
  • Cancer Research 08/2013; 73(8 Supplement):3532-3532. DOI:10.1158/1538-7445.AM2013-3532 · 9.28 Impact Factor
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    ABSTRACT: Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates. In this review, we discuss strategies in the applications of both in vitro and in vivo experimental models of drug metabolism and disposition.
    12/2012; 2(6):549–561. DOI:10.1016/j.apsb.2012.10.004
  • Oral Bioavailability: Basic Principles, Advanced Concepts, and Applications, 07/2011: pages 475 - 491; , ISBN: 9781118067598
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    ABSTRACT: A refined cytochrome P450 (P450) enzyme IC₅₀ shift assay for more accurately screening CYP3A time-dependent inhibitors (TDIs) is presented. In contrast to the regular IC₅₀ shift assay, in which only one pair of P450 inhibition curves is generated, this modified method generates two pairs of inhibition curves; one pair of curves is created from human liver microsomal incubations with the test article in the presence or absence of NADPH (curves 1 and 2) (same as the traditional assay), and the other pair is created from new microsomal incubations with extract (compound/metabolites) of previous incubations (curves 3 and 4). To assess the true CYP3A time-dependent inhibition, we propose a new parameter, the vertical IC₅₀ curve shift (VICS), represented by vertical shift difference between the two sets of curves divided by inhibitor concentration at which maximal vertical shift of curves 1 and 2 is observed. A shift in the curves 1 and 2 could mean a time-dependent inhibition or formation of a more active inhibitory metabolite(s). The new method provides more reliable characterization of the shift as a result of a true TDI- or metabolite-mediated reversible inhibition. Nine known TDI drugs were evaluated using this refined shift assay. The derived VICS values correlated well with the reported k(inact)/K(I) values derived via the conventional dilution assay method. Thus, the refined assay can be used to identify a true TDI and quantitatively assess the inactivation potential of TDIs in a high-throughput fashion. This assay can be invaluable to screen for true P450 TDIs in the early drug discovery.
    Drug metabolism and disposition: the biological fate of chemicals 03/2011; 39(6):1054-7. DOI:10.1124/dmd.111.038208 · 3.33 Impact Factor
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    ABSTRACT: Drug-drug interactions comprise a significant cause of morbidity and mortality worldwide as they may lead to adverse clinical events, result in decrease/inactivation of the therapeutic effect of a drug, may enhance drug toxicity and indirectly compromise treatment outcomes and adherence. Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism, and elimination (ADME). Inhibition or induction of transporter and drug metabolism enzymes can alter the ADME of a co-administered drug, which may lead to drug-induced toxicity or lack of efficacy. This review assesses our current understanding of the in vitro methods of evaluating CYPs and transporter-mediated DDI. The DDI prediction models based on in vitro assays are also discussed in this review. The applications, advantages and limitations of each method are also addressed in this review.
    Current Drug Discovery Technologies 09/2010; 7(3):199-222.
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    ABSTRACT: A novel in vitro model was recently developed in our laboratories for the prediction of magnitude of clinical pharmacokinetic drug-drug interactions (DDIs), based on reversible hepatic cytochrome P450 (P450) inhibition. This approach, using inhibition data from human hepatocytes incubated in human plasma, and quantitative P450 phenotyping data from hepatic microsomal incubations, successfully predicted DDIs for 15 marketed drugs with ketoconazole, a strong competitive inhibitor of CYP3A4/5, generally used to demonstrate a "worst-case scenario" for CYP3A inhibition. In addition, this approach was successfully extended to DDI predictions with the moderate competitive CYP3A inhibitor fluconazole for nine marketed drugs. In the current report, the general applicability of the model has been demonstrated by prospectively predicting the degree of inhibition and then conducting DDI studies in the clinic for an investigational CCR1 antagonist MLN3897, which is cleared predominantly by CYP3A. The clinical studies involved treatment of healthy volunteers (n = 17-20), in a crossover design, with ketoconazole (200 mg b.i.d.) or fluconazole (400 mg once a day), while receiving MLN3897. Administration of MLN3897 and ketoconazole led to an average 8.28-fold increase in area under the curve of plasma concentration-time plot (AUC) of MLN3897 at steady state, compared with the 8.33-fold increase predicted from the in vitro data. Similarly for fluconazole, an average increase of 3.93-fold in AUC was observed for MLN3897 in comparison with a predicted value of 3.26-fold. Thus, our model reliably predicted the exposure changes for MLN3897 in interaction studies with competitive CYP3A inhibitors in humans, further strengthening the utility of our in vitro model.
    Journal of Pharmacology and Experimental Therapeutics 11/2009; 332(2):562-8. DOI:10.1124/jpet.109.161893 · 3.86 Impact Factor
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    ABSTRACT: The great emphasis on ethical and humane treatment of animals in biomedical research has culminated in the promulgation of the rule of 3Rs - Replacement, Reduction, and Refinement. We have proposed an addition to the 3Rs - a fourth R for Recycling the animal. In drug discovery single-dose pharmacokinetic studies in rats, each animal is generally used only once and then euthanized. A reduction in the number of rats used in this high-throughput era can be readily implemented by reusing animals, just as larger animals are reused in multiple pharmacokinetic studies, consequently reducing the overall number of animal lives sacrificed in research. We provide evidence here for the reproducibility of pharmaco-kinetic studies of tolbutamide and fluconazole, used as test compounds, in rats receiving once-weekly oral and intravenous doses for 4 weeks, proving that recycling rats for multiple single low-dose pharmacokinetic studies is a viable option.
    09/2008; 2(3):193-7. DOI:10.2174/187231208785425827
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    ABSTRACT: Traditional cytochrome P450 (P450) based drug-drug interaction (DDI) predictions are based on the ratio of an inhibitor's physiological concentration [I] and its inhibition constant K(i). Determining [I] at the enzymatic site, although critical for predicting clinical DDIs, remains a technical challenge. In our previous study, a novel approach using cryopreserved human hepatocytes suspended in human plasma was investigated to mimic the in vivo concentration of ketoconazole at the enzymatic site (Lu et al., 2007), effectively eliminating the estimation of the elusive [I] value. P450 inhibition in this system appears to model that in vivo. Using the ketoconazole inhibition information in a human hepatocyte-plasma suspension together with quantitative P450 phenotypic information, we successfully predicted the pharmacokinetic DDIs for a small set of drugs, such as theophylline, tolbutamide, omeprazole, desipramine, midazolam, loratadine, cyclosporine, and alprazolam, as well as an investigational compound. For the applicability of this model on a wider scale the in vitro-in vivo correlation data set needed to be expanded. However, for most drugs in the literature there is not enough quantitative information on the involvement of individual P450s to predict DDIs retrospectively. To facilitate that, in this study we determined quantitative P450 phenotyping for seven marketed drugs: budesonide, buprenorphine, loratadine, sirolimus, tacrolimus, docetaxel, and methylprednisolone. Augmentation of the new data set with the one generated previously produced broader a database that provided further support for the wider applicability of this approach using ketoconazole as a potent CYP3A inhibitor. This application is predicted to be equally effective with other P450 inhibitors that are not substrates of efflux pumps.
    Drug metabolism and disposition: the biological fate of chemicals 08/2008; 36(7):1255-60. DOI:10.1124/dmd.107.018796 · 3.33 Impact Factor
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    ABSTRACT: Whereas ketoconazole is often used to study the worst-case scenario for clinical pharmacokinetic drug-drug interactions (DDIs) for drugs that are primarily metabolized by CYP3A4, fluconazole is considered to be a moderate inhibitor of CYP3A4, providing assessment of the moderate-case scenario of CYP3A-based DDIs. Fluconazole is also a moderate inhibitor of CYP2C9 and CYP2C19. For predicting clinical DDIs using conventional approaches, determining the in vivo inhibitor concentration at the enzymatic site [I], a critical parameter, is still not practical. In our previous study, a novel method involving hepatocyte suspension in plasma was used to circumvent the need to determine the elusive [I] value. In this study, the CYP1A2, 2C9, 2C19, 2D6, and 3A4 activities remaining in the presence of fluconazole were determined in human hepatocytes suspended in human plasma, covering a range of fluconazole clinical plasma concentrations (C(avg) and C(max)). Because the protein-binding effect of fluconazole is expected to be close to that in vivo, the inhibition observed in vitro will be similar to that in vivo. This inhibition information was then applied to the cytochrome P450 (P450) phenotypic data to predict DDIs. Using the available P450 phenotypic information on theophylline, tolbutamide, omeprazole, S-warfarin, phenytoin, cyclosporine, and midazolam and that determined in this study for sirolimus and tacrolimus, we found that the predictions for area under the curve increases for most of these drugs in the presence of fluconazole were remarkably similar (within 35%) to the observed clinical values. This study proves the general applicability of our approach using human hepatocyte incubation in human plasma to predict DDIs.
    Drug metabolism and disposition: the biological fate of chemicals 08/2008; 36(7):1261-6. DOI:10.1124/dmd.107.019000 · 3.33 Impact Factor
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    ABSTRACT: Ketoconazole has generally been used as a standard inhibitor for studying clinical pharmacokinetic drug-drug interactions (DDIs) of drugs that are primarily metabolized by CYP3A4/5. However, ketoconazole at therapeutic, high concentrations also inhibits cytochromes P450 (P450) other than CYP3A4/5, which has made the predictions of DDIs less accurate. Determining the in vivo inhibitor concentration at the enzymatic site is critical for predicting the clinical DDI, but it remains a technical challenge. Various approaches have been used in the literature to estimate the human hepatic free concentrations of this inhibitor, and application of those to predict DDIs has shown some success. In the present study, a novel approach using cryopreserved human hepatocytes suspended in human plasma was applied to mimic the in vivo concentration of ketoconazole at the enzymatic site. The involvement of various P450s in the metabolism of compounds of interest was quantitatively determined (reactive phenotyping). Likewise, the effect of ketoconazole on various P450s was quantitated. Using this information, P450-mediated change in the area under the curve has been predicted without the need of estimating the inhibitor concentrations at the enzyme active site or the K(i). This approach successfully estimated the magnitude of the clinical DDI of an investigational compound, MLX, which is cleared by multiple P450-mediated metabolism. It also successfully predicted the pharmacokinetic DDIs for several marketed drugs (theophylline, tolbutamide, omeprazole, desipramine, midazolam, alprazolam, cyclosporine, and loratadine) with a correlation coefficient (r(2)) of 0.992. Thus, this approach provides a simple method to more precisely predict the DDIs for P450 substrates when coadministered with ketoconazole or any other competitive P450 inhibitors in humans.
    Drug Metabolism and Disposition 02/2007; 35(1):79-85. DOI:10.1124/dmd.106.011346 · 3.33 Impact Factor
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    ABSTRACT: Apparent intrinsic clearance (CL(int,app)) of 7-ethoxycoumarin, phenacetin, propranolol, and midazolam was measured using rat and human liver microsomes and freshly isolated and cryopreserved hepatocytes to determine factors responsible for differences in rates of metabolism in these systems. The cryopreserved and freshly isolated hepatocytes generally provided similar results, although there was greater variability using the latter system. The CL(int,app) values in hepatocytes are observed to be lower than that in microsomes, and this difference becomes greater for compounds with high CL(int,app). This could partly be attributed to the differences in the free fraction (fu). The fu in hepatocyte incubations (fu,hep-inc) was influenced not only by the free fraction of compounds in the incubation buffer (fu,buffer) but also by the rate constants of uptake (k(up)) and metabolism (k(met)). This report provides a new derivation for fu,hep-inc, which can be expressed as fu,hep-inc = [k(up)/(k(met) + k(up))]/[1 + (C(hep)/C(buffer)) x (V(hep)/V(buffer))], where the C(hep), C(buffer), V(hep), and V(buffer) represent the concentrations of a compound in hepatocytes and buffer and volumes of hepatocytes and buffer, respectively. For midazolam, the fu,hep-inc was calculated, and the maximum metabolism rate in hepatocytes was shown to be limited by the uptake rate.
    Drug Metabolism and Disposition 10/2006; 34(9):1600-5. DOI:10.1124/dmd.106.010793 · 3.33 Impact Factor
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    ABSTRACT: Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.
    Journal of Medicinal Chemistry 06/2006; 49(9):2669-72. DOI:10.1021/jm050965z · 5.48 Impact Factor
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    ABSTRACT: Bortezomib (Velcade, PS-341), a dipeptidyl boronic acid, is a first-in-class proteasome inhibitor approved in 2003 for the treatment of multiple myeloma. In a preclinical toxicology study, bortezomib-treated rats resulted in liver enlargement (35%). Ex vivo analyses of the liver samples showed an 18% decrease in cytochrome P450 (P450) content, a 60% increase in palmitoyl coenzyme A beta-oxidation activity, and a 41 and 23% decrease in CYP3A protein expression and activity, respectively. Furthermore, liver samples of bortezomib-treated rats had little change in CYP2B and CYP4A protein levels and activities. To address the likelihood of clinical drug-drug interactions, the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC(50) approximately 18.0, 10.0, and 13.2 microM, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC(50) approximately 11.5 microM). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC(50) values > 30 microM). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. Based on these results, no major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major metabolites. To our knowledge, this is the first report on P450-mediated drug-drug interaction potential of proteasome inhibitors or boronic acid containing therapeutics.
    Drug Metabolism and Disposition 04/2006; 34(4):702-8. DOI:10.1124/dmd.105.008060 · 3.33 Impact Factor
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    ABSTRACT: VELCADE (bortezomib, PS-341), reversibly inhibits the 20S proteasome and exhibits cytotoxic and antitumor activities. Pretreatment of cancer cells with bortezomib increases the chemosensitivity of these cells, suggesting that bortezomib may be used in combination chemotherapy. The relative contributions of the five major human cytochromes P450 (P450s), 1A2, 2C9, 2C19, 2D6, and 3A4 (the focus of the present study), to the metabolism of bortezomib are an important aspect of potential drug interactions. Relative activity factor (RAF), chemical inhibition, and immunoinhibition using monoclonal antibodies were three approaches employed to determine the relative contributions of the major human P450s to the net hepatic metabolism of bortezomib. RAFs for the P450 isoform-selective substrates were determined; the ratio of the rate of metabolism of bortezomib with cDNA-expressed P450s versus rate of metabolism with human liver microsomes was normalized with respect to the RAF for each P450 isoform to determine the percentage contributions of the P450s to the net hepatic metabolism of bortezomib. CYP3A4 followed by CYP2C19 were determined to be the major contributors to the metabolism of bortezomib. Chemical inhibition and immunoinhibition confirmed that CYP3A4 and CYP2C19 were the major P450s responsible for the hepatic metabolism of bortezomib. The studies were conducted with 2 muM bortezomib, and the disappearance of bortezomib, rather than appearance of a specific metabolite, was quantified to determine the contributions of the P450s to the overall hepatic metabolism of bortezomib in humans.
    Drug Metabolism and Disposition 12/2005; 33(11):1723-8. DOI:10.1124/dmd.105.005710 · 3.33 Impact Factor
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    ABSTRACT: A high-throughput analytical system for the support of absorption, distribution, metabolism, and excretion (ADME) was constructed in collaboration with Gubbs Inc. to commercialize corresponding software. We sought to quickly build and validate this system for microsomal clearance assessment using 60 commercially available non-proprietary compounds that are non-DEA-restricted in addition to 36 proprietary Millennium compounds that had already been assessed using a low-throughput infrastructure. The system was constructed such that a approximately 45 second total cycle time was achieved injection-to-injection. Software was successfully coded to enable the analyst to submit multiple batches, and modify multiple methods very quickly for use with Applied Biosystems Analyst 1.3. After acquisition the software was used to simultaneously integrate multiple injection chromatograms, regress the data, and calculate clearance such that all of the data could be easily and immediately reviewed by both bioanalytical and enzymology personnel. Unfortunately, despite an exhaustive search of the literature, we were unable to find a large number of non-proprietary compound data for validation, so we provide such a source of data here. Results are presented for the 60 literature compounds that were assessed. A good correlation was observed between literature results for 16 compounds that we were able to find and the results obtained using the system. The Millennium proprietary compounds that we assessed using both low- and high-throughput approaches also correlated well. We present here a system for the support of high-throughput in vitro ADME analysis and also present the results of 60 non-proprietary, non-DEA-scheduled compounds to facilitate the validation efforts of others. Finally, we present commercially available software to facilitate high-throughput ADME systems in the community.
    Rapid Communications in Mass Spectrometry 05/2005; 19(9):1191-9. DOI:10.1002/rcm.1903 · 2.64 Impact Factor
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    ABSTRACT: Efficacy and safety are the two key elements in the drug discovery and development processes. The primary goal for pharmaceutical research companies is to identify and manufacture therapeutic agents that are safe and efficacious for patients. In principle, benefits versus risks have to be considered for target patient populations. The risks are relatively high in life threatening diseases, e.g. cancer, compared to general areas, e.g. inflammation. Pharmacology, medicinal chemistry, pharmaceutical sciences, safety assessment, drug metabolism and pharmacokinetics (DMPK), clinical research, etc. are the essential multidisciplinary R&D functions assembled within the pharmaceutical R&D engine to accomplish the aforementioned mission. Pharmacokinetics (PK) is generally viewed as the universal biomarker which reflects the processes of how a drug molecule is absorbed (e.g. ka), distributed (e.g. Vd) in the body, and cleared from the body through metabolism and excretion. The area under the drug plasma concentration versus time curve (AUC) provides an indirect assessment of the exposure level and duration of action of the therapeutic agent at the site of action (e.g. synovial fluid, tumor, brain). An ideal drug candidate should possess a plasma drug level which is above the therapeutic concentration (i.e. efficacious) and below the toxic concentration (i.e. safe). In general, the therapeutic index is calculated by dividing the plasma exposure at the NO (toxic) Effect Level (NOEL), or NO Adverse Effect Level (NOAEL), by the minimum plasma concentration required for efficacy (e.g. EC50) and the safety margin is calculated by dividing NOEL (or NOAEL) plasma concentration by the maximum plasma drug concentration (Cmax) achieved at an efficacious dose.
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    ABSTRACT: Application of Physiologically Based Pharmacokinetic Modeling and Simulation for Waiver of Orteronel Drug-drug Interaction Trials Chuang Lu1, Ajit Suri2 and Shimoga Prakash1 1DMPK, 2Clinical Pharmacology, Millennium Pharmaceutical, Inc. Cambridge, MA, USA Orteronel (TAK-700) is an oral, selective, nonsteroidal 17,20‑lyase inhibitor currently in clinical development as a treatment for men with castrate‑resistant prostate cancer (CRPC). In an in vitro human liver microsomal Cytochrome P450 (CYP) inhibition study, TAK-700 showed weak inhibition toward CYP1A2, 2C8, 2C9, and 2C19 with IC50s of 17.8, 27.7, 30.8, and 38.8 uM, respectively. In contrast, TAK-700 did not inhibit CYP2B6, 2D6, and 3A4 (IC50s > 100 uM). Following the FDA DDI guidance, Physicologically-Based Pharmacokinetic (PBPK) modeling and simulation was performed in this study to assess the DDI potential of TAK-700 with sensitive CYP substrates/drugs: theophylline for CYP1A2, repaglinide for CYP2C8, S-warfarin for CYP2C9, and omeprazole for CYP2C19. The PBPK model was established for TAK-700 using Simcyp (Version 11) with in vitro ADME data and a population of 100 healthy subjects (age 50-65 years, 50% male). The model was then refined with clinical data. Simulation was performed with 4 probe substrates suggested by the FDA for the corresponding CYPs. PK at steady-state for both TAK-700 and the probe substrates were used to reflect the usage of TAK-700 and probe substrate in clinics. These PBPK simulation results, show in the Table below, suggest that TAK-700 is unlikely to cause clinical meaningful DDI when it is co-administrated with drugs that metabolized CYP1A2, 2C8, 2C9, and 2C19 as well as CYP2B6, 2D6, and 3A4. The increase of AUC of these drugs in the presence of TAK-700 is less than 25%. Therefore, clinical DDI trials can be waived according to the new FDA guidance. TAK-700 DDI Potential as a Perpetrator Using Simcyp Simulation CYP Substrate Dose TAK-700 IC50 (uM) Geometric Mean AUC ratio (5th - 95th) 1A2 theophylline (SV) 125 mg TID 17.8 1.23 (1.13 - 1.34) 2C8 repaglinide (SV) 0.25 mg BID 27.7 1.13 (1.05 - 1.22) 2C9 S-warfarin (SIM) 10 mg QD 30.8 1.19 (1.13 - 1.28) 2C19 omeprazole (SV) enteric-coated 20 mg BID 38.8 1.24 (1.13 - 1.38)
    19th MDO and 12th European Regional International society for the study of xenobiotics Meeting;