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Nikunjkumar Patel, Oliver Hatley, Alexander Berg, Klaus Romero, Barbara Wisniowska, Debra Hanna, David Hermann, Sebastian Polak
Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis...
March 14, 2018: AAPS Journal
John A Troutman, Mary C Sullivan, Gregory J Carr, Jeffrey Fisher
Physiologically based pharmacokinetic (PBPK) models are developed from compound-independent information to describe important anatomical and physiological characteristics of an individual or population of interest. Modeling pediatric populations is challenging because of the rapid changes that occur during growth, particularly in the first few weeks and months after birth. Neonates who are born premature pose several unique challenges in PBPK model development. To provide appropriate descriptions for body weight (BW) and height (Ht) for age and appropriate incremental gains in PBPK models of the developing preterm and full term neonate, anthropometric measurements collected longitudinally from 1,063 preterm and 158 full term neonates were combined with 2,872 cross-sectional measurements obtained from the NHANES 2007-2010 survey...
March 14, 2018: Birth Defects Research
Alexis Viel, Jérôme Henri, Salim Bouchène, Julian Laroche, Jean-Guy Rolland, Jacqueline Manceau, Michel Laurentie, William Couet, Nicolas Grégoire
PURPOSE: The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. METHODS: Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software...
March 12, 2018: Pharmaceutical Research
V Krishnan, N J Patel, J G Mackrell, S A Sweetana, H Bullock, Y L Ma, T H Waterhouse, B C Yaden, J Henck, Q Q Zeng, K Gavardinas, P Jadhav, A Saeed, P Garcia-Losada, D A Robins, C T Benson
We have identified a non-steroidal selective androgen receptor modulator (SARM), termed LY305, that is bioavailable through a transdermal route of administration while highly cleared via hepatic metabolism to limit parent compound exposure in the liver. Selection of this compound and its transdermal formulation was based on the optimization of skin absorption properties using both in vitro and in vivo skin models that supported PBPK modeling for human PK predictions. This molecule is an agonist in perineal muscle while being a weak partial agonist in the androgenic tissues such as prostate...
March 12, 2018: Andrology
Franck Da-Silva, Xavier Boulenc, Hélène Vermet, Pauline Compigne, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Sylvie Klieber, Patrick Poulin
The objective was to compare, with the same dataset, the predictive performance of three in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (MPCC) (also referring to HepatoPac® ) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e., direct scaling method without binding correction, conventional method based either on the unbound fraction in plasma (fup ) according to the free drug hypothesis, or based on an fup value adjusted for the albumin (ALB)-facilitated hepatic uptake phenomenon)...
March 7, 2018: Journal of Pharmaceutical Sciences
Eman A Alraddadi, Ryan Lillico, Jonathan L Vennerstrom, Ted M Lakowski, Donald W Miller
Creatine is an ergogenic compound used by athletes to enhance performance. Supplementation with creatine monohydrate (CM) has been suggested for musculoskeletal and neurological disorders. Until now, little is known about its pharmacokinetic profile. Our objective was to determine the oral bioavailability of CM and the influence of dose on oral absorption. Rats were dosed orally with low dose (10 mg/kg) or high dose (70 mg/kg)13 C-labeled CM. Blood samples were removed at various time points. Muscle and brain tissue were collected at the conclusion of the study...
March 8, 2018: Pharmaceutics
Henrik Cordes, Christoph Thiel, Vanessa Baier, Lars M Blank, Lars Kuepfer
Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism...
2018: NPJ Systems Biology and Applications
Fumiyoshi Yamashita
 Drug-drug interactions mediated by drug metabolizing enzymes are serious, clinically relevant issues. Prediction and evaluation of the probability and consequences of drug-drug interactions are essential during drug development, as well as during clinical application. A physiologically based pharmacokinetic (PBPK) model, which considers the hierarchical structure of the physiological behavior of drugs, has been demonstrated to be effective for in vitro-in vivo extrapolation of the phenomena of drug-drug interaction (DDI)...
2018: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Kristin E Follman, Marilyn E Morris
Renal Impairment (RI) is a major health concern with a growing prevalence. RI leads to various physiological changes, in addition to a decrease in GFR, that impact the pharmacokinetics (PK) and specifically the renal clearance (CLR) of compounds, including alterations of drug transporter (DT)/drug metabolizing enzyme expression and activity, as well as protein binding. The objectives of this study were to utilize the physiologically based pharmacokinetic (PBPK) modeling platform, Simcyp® to (1) assess the impact of alterations in DT expression, toxin-drug interactions (TDIs) and free fraction (fu) on PK predictions for the OCT2/MATE1 substrate metformin in RI populations, and (2) utilize available in vitro data to improve predictions of ClR for two actively secreted substrates, metformin and ranitidine...
February 28, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Masanobu Sato, Kota Toshimoto, Atsuko Tomaru, Takashi Yoshikado, Yuta Tanaka, Akihiro Hisaka, Wooin Lee, Yuichi Sugiyama
Bosentan is a substrate of hepatic uptake transporter organic anion transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (CYPs), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, CYP-mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated...
February 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Jiachang Gong, Lisa Iacono, Ramaswamy A Iyer, W Griffith Humphreys, Ming Zheng
AIMS: Previous studies demonstrated direct correlation between CYP2C19 genotype and BMS-823778 clearance in healthy volunteers. The objective of the present study was to develop a PBPK model for BMS-823778 and utilize the model to predict PK and DDI in virtual populations with multiple polymorphic genes. METHODS: The PBPK model was built and verified utilizing existing clinical data. The verified model was simulated to predict PK of BMS-823778 and significance of DDI with a strong CYP3A4 inhibitor in subjects with various CYP2C19 and UGT1A4 genotypes...
February 22, 2018: British Journal of Clinical Pharmacology
Venkatesh Pilla Reddy, Michael Walker, Pradeep Sharma, Peter Ballard, Karthick Vishwanathan
Osimertinib is a potent, highly selective, irreversible inhibitor of Epidermal Growth Factor Receptor and T790M resistance mutation receptor. In vitro metabolism data suggested osimertinib is a substrate of CYP3A4/5, a weak inducer of CYP3A and an inhibitor of BCRP. A combination of in vitro data, clinical pharmacokinetic data and drug-drug interaction (DDI) data of osimertinib in oncology patients were used to develop the physiologically based pharmacokinetic (PBPK) model and verify the DDI data of osimertinib...
February 22, 2018: CPT: Pharmacometrics & Systems Pharmacology
F Yang, F Yang, W Shi, H Si, T Kong, G Wang, J Zhang
To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (PX s) for noneliminating tissues were calculated according to the area method, while the PX s for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations...
February 18, 2018: Journal of Veterinary Pharmacology and Therapeutics
Chia-Hsiang Hsueh, Vicky Hsu, Yuzhuo Pan, Ping Zhao
BACKGROUND: Physiologically-based pharmacokinetic (PBPK) modeling in predicting metabolic drug-drug interactions (mDDIs) is routinely used in drug development. Currently, the US FDA endorses the use of PBPK to potentially support dosing recommendations for investigational drugs as enzyme substrates of mDDIs, and to inform a lack of mDDIs for investigational drugs as enzyme modulators. METHODS: We systematically evaluated the performance of PBPK modeling in predicting mDDIs published in the literature...
February 17, 2018: Clinical Pharmacokinetics
Andrea Gruber, Martin Czejka, Philipp Buchner, Marie Kitzmueller, Nairi Kirchbaumer Baroian, Christian Dittrich, Azra Sahmanovic Hrgovcic
PURPOSE: In this study, a therapeutic drug monitoring (TDM) of erlotinib in pancreatic cancer patients was performed over 50 weeks to reveal possible alterations in erlotinib plasma concentrations. Additionally, a physiologically based pharmacokinetic (PBPK) model was created to assess such variations in silico. METHODS: Patients with advanced pancreatic cancer received a chemotherapeutic combination of 100 mg erlotinib q.d., 500-900 mg capecitabine b.d. and 5 mg/kg bevacizumab q...
February 16, 2018: Cancer Chemotherapy and Pharmacology
Ruijuan Xu, Weihong Ge, Qing Jiang
PURPOSE: Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction...
February 17, 2018: European Journal of Clinical Pharmacology
Nicole A Kratochwil, Miriam Triyatni, Martina B Mueller, Florian Klammers, Brian Leonard, Dan Turley, Josephine Schmaler, Aynur Ekiciler, Birgit Molitor, Isabelle Walter, Pierre-Alexis Gonsard, Charles A Tournillac, Alexandre Durrwell, Michaela Marschmann, Russell Jones, Mohammed Ullah, Franziska Boess, Giorgio Ottaviani, Yuyan Yin, Neil J Parrott, Stephen Fowler
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross species metabolism, comparison of low clearance drugs as well as induction studies. Here, we present studies using a long-term liver model which show how metabolism and active transport, drug-drug interactions and enzyme induction in healthy and diseased states, e.g. hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for PBPK modeling...
February 16, 2018: Journal of Pharmacology and Experimental Therapeutics
Ken-Ichi Umehara, Felix Huth, Christina S Won, Tycho Heimbach, Handan He
Ritonavir is one of several ketoconazole alternatives used to evaluate strong CYP3A4 inhibition potential in clinical drug-drug interaction (DDI) studies. In this study, four physiologically-based pharmacokinetic (PBPK) models of ritonavir as an in vivo time-dependent inhibitor of CYP3A4 were created and verified for the oral doses of 20, 50, 100 and 200 mg using fraction absorbed (Fa) and oral clearance (CLoral) values reported in the literature, as transporter and CYP enzyme reaction phenotyping data were not available...
February 16, 2018: Biopharmaceutics & Drug Disposition
Chie Emoto, Trevor N Johnson, Brooks T McPhail, Alexander A Vinks, Tsuyoshi Fukuda
Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration-time profiles in healthy adults and diseased patients...
February 15, 2018: CPT: Pharmacometrics & Systems Pharmacology
Ian E Templeton, Nicholas S Jones, Luna Musib
Interest in determining safe and efficacious doses for drug administration in pediatric patients has increased dramatically in recent years. However, published pediatric clinical studies have failed to increase proportionally with adult clinical study publications. In order to assess the current state of pediatric dose determination and the supporting role of physiologically based pharmacokinetic modeling and simulation in determining pediatric dose, the pediatric clinical literature (2006-2016) and case examples of pediatric PBPK modeling efforts were reviewed...
February 13, 2018: AAPS Journal
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