Loading…
Physiologically Based Pharmacokinetic Modelling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin
Background Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetic...
Saved in:
| Published in: | Clinical pharmacokinetics 2013-08, Vol.52 (8), p.673-683 |
|---|---|
| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53 |
| container_end_page | 683 |
| container_issue | 8 |
| container_start_page | 673 |
| container_title | Clinical pharmacokinetics |
| container_volume | 52 |
| creator | Parrott, Neil Hainzl, Dominik Alberati, Daniela Hofmann, Carsten Robson, Richard Boutouyrie, Bruno Martin-Facklam, Meret |
| description | Background
Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetics.
Methods
Simulations of pharmacokinetics were initiated early in the drug discovery stage by integrating physicochemical properties and in vitro measurements into a PBPK rat model. Comparison of pharmacokinetics predicted by PBPK modelling with those measured after intravenous and oral dosing in rats and monkeys showed a good match and thus increased confidence that a similar approach could be applied for human prediction. After comparison of predicted plasma concentrations with those measured after single oral doses in the first clinical study, the human model was refined and then applied to simulate multiple-dose pharmacokinetics.
Results
Clinical plasma concentrations measured were in good agreement with PBPK predictions. Predicted area under the plasma concentration–time curve (AUC) was within twofold of the observed mean values for all dose levels. Maximum plasma concentration (
C
max
) at higher doses was well predicted but approximately twofold below observed values at the lower doses. A slightly less than dose-proportional increase in both AUC and
C
max
was observed, and model simulations indicated that when the dose exceeded 50 mg, solubility limited the fraction of dose absorbed. Refinement of the absorption model with additional solubility and permeability measurements further improved the match of simulations to observed single-dose data. Simulated multiple-dose pharmacokinetics with the refined model were in good agreement with observed data.
Conclusions
Clinical pharmacokinetics of bitopertin can be well simulated with a mechanistic PBPK model. This model supports further clinical development and provides a valuable repository for pharmacokinetic knowledge gained about the molecule. |
| doi_str_mv | 10.1007/s40262-013-0061-x |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1465368091</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3147612911</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53</originalsourceid><addsrcrecordid>eNp1kE1PGzEQhq0KVNK0P6AXZAn1aBh7117vEegHlYKIBHfL67UTh8062LsS-fd1lBQQEidr5GfemXkQ-k7hnAJUF6kEJhgBWhAAQcnzJzShtKoJrZk4QhMoKCO8FsUJ-pLSCgAkA_iMTljBa1pJmKDtfLlNPnRh4Y3uui2-0sm2eL7Uca1NePS9HbzBt6G1Xef7BR4CnkfbejPg-1x3lmDdt_h27Aa_ydXPkCy-Gde6fx-ScHD4yg9hY-Pg-6_o2Oku2W-Hd4oefv96uL4hs7s_f68vZ8Tk6wbSOFE2WkrTMuZoowF42QoOhWONaERVCeqsaDh3tWu5Bidrahpb8lKy2vBiis72sZsYnkabBrUKY-zzREVLwQshoaaZonvKxJBStE5tol_ruFUU1M612rtW2bXauVbPuef0kDw2a9u-dPyXm4EfB0CnLNdF3RufXrmKS8nkbkW251L-6hc2vlnxw-n_ADnbmI8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1465368091</pqid></control><display><type>article</type><title>Physiologically Based Pharmacokinetic Modelling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin</title><source>Springer Link</source><creator>Parrott, Neil ; Hainzl, Dominik ; Alberati, Daniela ; Hofmann, Carsten ; Robson, Richard ; Boutouyrie, Bruno ; Martin-Facklam, Meret</creator><creatorcontrib>Parrott, Neil ; Hainzl, Dominik ; Alberati, Daniela ; Hofmann, Carsten ; Robson, Richard ; Boutouyrie, Bruno ; Martin-Facklam, Meret</creatorcontrib><description>Background
Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetics.
Methods
Simulations of pharmacokinetics were initiated early in the drug discovery stage by integrating physicochemical properties and in vitro measurements into a PBPK rat model. Comparison of pharmacokinetics predicted by PBPK modelling with those measured after intravenous and oral dosing in rats and monkeys showed a good match and thus increased confidence that a similar approach could be applied for human prediction. After comparison of predicted plasma concentrations with those measured after single oral doses in the first clinical study, the human model was refined and then applied to simulate multiple-dose pharmacokinetics.
Results
Clinical plasma concentrations measured were in good agreement with PBPK predictions. Predicted area under the plasma concentration–time curve (AUC) was within twofold of the observed mean values for all dose levels. Maximum plasma concentration (
C
max
) at higher doses was well predicted but approximately twofold below observed values at the lower doses. A slightly less than dose-proportional increase in both AUC and
C
max
was observed, and model simulations indicated that when the dose exceeded 50 mg, solubility limited the fraction of dose absorbed. Refinement of the absorption model with additional solubility and permeability measurements further improved the match of simulations to observed single-dose data. Simulated multiple-dose pharmacokinetics with the refined model were in good agreement with observed data.
Conclusions
Clinical pharmacokinetics of bitopertin can be well simulated with a mechanistic PBPK model. This model supports further clinical development and provides a valuable repository for pharmacokinetic knowledge gained about the molecule.</description><identifier>ISSN: 0312-5963</identifier><identifier>EISSN: 1179-1926</identifier><identifier>DOI: 10.1007/s40262-013-0061-x</identifier><identifier>PMID: 23591780</identifier><identifier>CODEN: CPKNDH</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adolescent ; Adult ; Animals ; Antipsychotic Agents - administration & dosage ; Antipsychotic Agents - pharmacokinetics ; Biological and medical sciences ; Dose-Response Relationship, Drug ; Double-Blind Method ; General pharmacology ; Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors ; Hepatocytes - metabolism ; Humans ; Internal Medicine ; Macaca fascicularis ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Models, Biological ; Original Research Article ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pharmacotherapy ; Piperazines - administration & dosage ; Piperazines - pharmacokinetics ; Rats ; Rats, Wistar ; Sulfones - administration & dosage ; Sulfones - pharmacokinetics ; Young Adult</subject><ispartof>Clinical pharmacokinetics, 2013-08, Vol.52 (8), p.673-683</ispartof><rights>Springer International Publishing Switzerland 2013</rights><rights>2014 INIST-CNRS</rights><rights>Copyright Wolters Kluwer Health Adis International Aug 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53</citedby><cites>FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27588285$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23591780$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parrott, Neil</creatorcontrib><creatorcontrib>Hainzl, Dominik</creatorcontrib><creatorcontrib>Alberati, Daniela</creatorcontrib><creatorcontrib>Hofmann, Carsten</creatorcontrib><creatorcontrib>Robson, Richard</creatorcontrib><creatorcontrib>Boutouyrie, Bruno</creatorcontrib><creatorcontrib>Martin-Facklam, Meret</creatorcontrib><title>Physiologically Based Pharmacokinetic Modelling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin</title><title>Clinical pharmacokinetics</title><addtitle>Clin Pharmacokinet</addtitle><addtitle>Clin Pharmacokinet</addtitle><description>Background
Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetics.
Methods
Simulations of pharmacokinetics were initiated early in the drug discovery stage by integrating physicochemical properties and in vitro measurements into a PBPK rat model. Comparison of pharmacokinetics predicted by PBPK modelling with those measured after intravenous and oral dosing in rats and monkeys showed a good match and thus increased confidence that a similar approach could be applied for human prediction. After comparison of predicted plasma concentrations with those measured after single oral doses in the first clinical study, the human model was refined and then applied to simulate multiple-dose pharmacokinetics.
Results
Clinical plasma concentrations measured were in good agreement with PBPK predictions. Predicted area under the plasma concentration–time curve (AUC) was within twofold of the observed mean values for all dose levels. Maximum plasma concentration (
C
max
) at higher doses was well predicted but approximately twofold below observed values at the lower doses. A slightly less than dose-proportional increase in both AUC and
C
max
was observed, and model simulations indicated that when the dose exceeded 50 mg, solubility limited the fraction of dose absorbed. Refinement of the absorption model with additional solubility and permeability measurements further improved the match of simulations to observed single-dose data. Simulated multiple-dose pharmacokinetics with the refined model were in good agreement with observed data.
Conclusions
Clinical pharmacokinetics of bitopertin can be well simulated with a mechanistic PBPK model. This model supports further clinical development and provides a valuable repository for pharmacokinetic knowledge gained about the molecule.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Animals</subject><subject>Antipsychotic Agents - administration & dosage</subject><subject>Antipsychotic Agents - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Dose-Response Relationship, Drug</subject><subject>Double-Blind Method</subject><subject>General pharmacology</subject><subject>Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Models, Biological</subject><subject>Original Research Article</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacotherapy</subject><subject>Piperazines - administration & dosage</subject><subject>Piperazines - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Sulfones - administration & dosage</subject><subject>Sulfones - pharmacokinetics</subject><subject>Young Adult</subject><issn>0312-5963</issn><issn>1179-1926</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp1kE1PGzEQhq0KVNK0P6AXZAn1aBh7117vEegHlYKIBHfL67UTh8062LsS-fd1lBQQEidr5GfemXkQ-k7hnAJUF6kEJhgBWhAAQcnzJzShtKoJrZk4QhMoKCO8FsUJ-pLSCgAkA_iMTljBa1pJmKDtfLlNPnRh4Y3uui2-0sm2eL7Uca1NePS9HbzBt6G1Xef7BR4CnkfbejPg-1x3lmDdt_h27Aa_ydXPkCy-Gde6fx-ScHD4yg9hY-Pg-6_o2Oku2W-Hd4oefv96uL4hs7s_f68vZ8Tk6wbSOFE2WkrTMuZoowF42QoOhWONaERVCeqsaDh3tWu5Bidrahpb8lKy2vBiis72sZsYnkabBrUKY-zzREVLwQshoaaZonvKxJBStE5tol_ruFUU1M612rtW2bXauVbPuef0kDw2a9u-dPyXm4EfB0CnLNdF3RufXrmKS8nkbkW251L-6hc2vlnxw-n_ADnbmI8</recordid><startdate>20130801</startdate><enddate>20130801</enddate><creator>Parrott, Neil</creator><creator>Hainzl, Dominik</creator><creator>Alberati, Daniela</creator><creator>Hofmann, Carsten</creator><creator>Robson, Richard</creator><creator>Boutouyrie, Bruno</creator><creator>Martin-Facklam, Meret</creator><general>Springer International Publishing</general><general>Adis International</general><general>Springer Nature B.V</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>4T-</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>20130801</creationdate><title>Physiologically Based Pharmacokinetic Modelling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin</title><author>Parrott, Neil ; Hainzl, Dominik ; Alberati, Daniela ; Hofmann, Carsten ; Robson, Richard ; Boutouyrie, Bruno ; Martin-Facklam, Meret</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Animals</topic><topic>Antipsychotic Agents - administration & dosage</topic><topic>Antipsychotic Agents - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Dose-Response Relationship, Drug</topic><topic>Double-Blind Method</topic><topic>General pharmacology</topic><topic>Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Models, Biological</topic><topic>Original Research Article</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacotherapy</topic><topic>Piperazines - administration & dosage</topic><topic>Piperazines - pharmacokinetics</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Sulfones - administration & dosage</topic><topic>Sulfones - pharmacokinetics</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parrott, Neil</creatorcontrib><creatorcontrib>Hainzl, Dominik</creatorcontrib><creatorcontrib>Alberati, Daniela</creatorcontrib><creatorcontrib>Hofmann, Carsten</creatorcontrib><creatorcontrib>Robson, Richard</creatorcontrib><creatorcontrib>Boutouyrie, Bruno</creatorcontrib><creatorcontrib>Martin-Facklam, Meret</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Clinical pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parrott, Neil</au><au>Hainzl, Dominik</au><au>Alberati, Daniela</au><au>Hofmann, Carsten</au><au>Robson, Richard</au><au>Boutouyrie, Bruno</au><au>Martin-Facklam, Meret</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Physiologically Based Pharmacokinetic Modelling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin</atitle><jtitle>Clinical pharmacokinetics</jtitle><stitle>Clin Pharmacokinet</stitle><addtitle>Clin Pharmacokinet</addtitle><date>2013-08-01</date><risdate>2013</risdate><volume>52</volume><issue>8</issue><spage>673</spage><epage>683</epage><pages>673-683</pages><issn>0312-5963</issn><eissn>1179-1926</eissn><coden>CPKNDH</coden><abstract>Background
Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetics.
Methods
Simulations of pharmacokinetics were initiated early in the drug discovery stage by integrating physicochemical properties and in vitro measurements into a PBPK rat model. Comparison of pharmacokinetics predicted by PBPK modelling with those measured after intravenous and oral dosing in rats and monkeys showed a good match and thus increased confidence that a similar approach could be applied for human prediction. After comparison of predicted plasma concentrations with those measured after single oral doses in the first clinical study, the human model was refined and then applied to simulate multiple-dose pharmacokinetics.
Results
Clinical plasma concentrations measured were in good agreement with PBPK predictions. Predicted area under the plasma concentration–time curve (AUC) was within twofold of the observed mean values for all dose levels. Maximum plasma concentration (
C
max
) at higher doses was well predicted but approximately twofold below observed values at the lower doses. A slightly less than dose-proportional increase in both AUC and
C
max
was observed, and model simulations indicated that when the dose exceeded 50 mg, solubility limited the fraction of dose absorbed. Refinement of the absorption model with additional solubility and permeability measurements further improved the match of simulations to observed single-dose data. Simulated multiple-dose pharmacokinetics with the refined model were in good agreement with observed data.
Conclusions
Clinical pharmacokinetics of bitopertin can be well simulated with a mechanistic PBPK model. This model supports further clinical development and provides a valuable repository for pharmacokinetic knowledge gained about the molecule.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>23591780</pmid><doi>10.1007/s40262-013-0061-x</doi><tpages>11</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0312-5963 |
| ispartof | Clinical pharmacokinetics, 2013-08, Vol.52 (8), p.673-683 |
| issn | 0312-5963 1179-1926 |
| language | eng |
| recordid | cdi_proquest_journals_1465368091 |
| source | Springer Link |
| subjects | Adolescent Adult Animals Antipsychotic Agents - administration & dosage Antipsychotic Agents - pharmacokinetics Biological and medical sciences Dose-Response Relationship, Drug Double-Blind Method General pharmacology Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors Hepatocytes - metabolism Humans Internal Medicine Macaca fascicularis Male Medical sciences Medicine Medicine & Public Health Models, Biological Original Research Article Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions Pharmacology. Drug treatments Pharmacology/Toxicology Pharmacotherapy Piperazines - administration & dosage Piperazines - pharmacokinetics Rats Rats, Wistar Sulfones - administration & dosage Sulfones - pharmacokinetics Young Adult |
| title | Physiologically Based Pharmacokinetic Modelling to Predict Single- and Multiple-Dose Human Pharmacokinetics of Bitopertin |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-21T10%3A37%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Physiologically%20Based%20Pharmacokinetic%20Modelling%20to%20Predict%20Single-%20and%20Multiple-Dose%20Human%20Pharmacokinetics%20of%20Bitopertin&rft.jtitle=Clinical%20pharmacokinetics&rft.au=Parrott,%20Neil&rft.date=2013-08-01&rft.volume=52&rft.issue=8&rft.spage=673&rft.epage=683&rft.pages=673-683&rft.issn=0312-5963&rft.eissn=1179-1926&rft.coden=CPKNDH&rft_id=info:doi/10.1007/s40262-013-0061-x&rft_dat=%3Cproquest_cross%3E3147612911%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c402t-bf64ba88cd22f1ba0054d6503f2b6b67761fe6b55f9fd5a0f891cbe454829c53%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1465368091&rft_id=info:pmid/23591780&rfr_iscdi=true |