Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK‐453,061), in healthy adult subjects
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Lersivirine (UK‐453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450 (CYP) 3A4. • Lersivirine metabolism, and thus pharmacokinetics, may be affected by concomitant administration of drugs affecting CYP3A4 and UGT2B...
Saved in:
| Published in: | British journal of clinical pharmacology Vol. 73; no. 5; pp. 768 - 775 |
|---|---|
| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
Oxford, UK
Blackwell Publishing Ltd
01.05.2012
Blackwell Blackwell Science Inc |
| Subjects: | |
| ISSN: | 0306-5251, 1365-2125, 1365-2125 |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Lersivirine (UK‐453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450 (CYP) 3A4.
• Lersivirine metabolism, and thus pharmacokinetics, may be affected by concomitant administration of drugs affecting CYP3A4 and UGT2B7.
• Ketoconazole is a potent inhibitor of CYP3A4 and an inhibitor of UGT2B7. Valproic acid is a potent inhibitor of UGT2B7.
WHAT THIS STUDY ADDS
• Combined inhibition of CYP3A4 and UGT2B7 with ketoconazole increases the exposure of lersivirine, and may warrant lersivirine dose adjustment to compensate for this interaction.
• Inhibition of UGT2B7 with valproic acid does not have a substantial effect on lersivirine pharmacokinetics.
AIMS
To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK‐453,061), a next generation non‐nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co‐administration of lersivirine with these inhibitors.
METHODS
Two open‐label, randomized, placebo‐controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1–2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3–9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1–7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo.
RESULTS
Compared with lersivirine alone, co‐administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (Cmax) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on Cmax (2.5%, 90% CI −9%, 16%). There were no serious adverse events and no treatment‐related discontinuations from either study.
CONCLUSIONS
Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7‐mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co‐administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated. |
|---|---|
| AbstractList | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Lersivirine (UK‐453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450 (CYP) 3A4.
• Lersivirine metabolism, and thus pharmacokinetics, may be affected by concomitant administration of drugs affecting CYP3A4 and UGT2B7.
• Ketoconazole is a potent inhibitor of CYP3A4 and an inhibitor of UGT2B7. Valproic acid is a potent inhibitor of UGT2B7.
WHAT THIS STUDY ADDS
• Combined inhibition of CYP3A4 and UGT2B7 with ketoconazole increases the exposure of lersivirine, and may warrant lersivirine dose adjustment to compensate for this interaction.
• Inhibition of UGT2B7 with valproic acid does not have a substantial effect on lersivirine pharmacokinetics.
AIMS
To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK‐453,061), a next generation non‐nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co‐administration of lersivirine with these inhibitors.
METHODS
Two open‐label, randomized, placebo‐controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1–2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3–9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1–7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo.
RESULTS
Compared with lersivirine alone, co‐administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (Cmax) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on Cmax (2.5%, 90% CI −9%, 16%). There were no serious adverse events and no treatment‐related discontinuations from either study.
CONCLUSIONS
Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7‐mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co‐administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated. To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors.AIMSTo investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors.Two open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo.METHODSTwo open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo.Compared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (C(max) ) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on C(max) (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study.RESULTSCompared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (C(max) ) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on C(max) (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study.Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.CONCLUSIONSInhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated. To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors. Two open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo. Compared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (C(max) ) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on C(max) (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study. Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated. |
| Author | Davis, John Chong, Chew‐Lan Weissgerber, Georges Layton, Gary Langdon, Grant Vourvahis, Manoli |
| Author_xml | – sequence: 1 givenname: Grant surname: Langdon fullname: Langdon, Grant – sequence: 2 givenname: John surname: Davis fullname: Davis, John – sequence: 3 givenname: Gary surname: Layton fullname: Layton, Gary – sequence: 4 givenname: Chew‐Lan surname: Chong fullname: Chong, Chew‐Lan – sequence: 5 givenname: Georges surname: Weissgerber fullname: Weissgerber, Georges – sequence: 6 givenname: Manoli surname: Vourvahis fullname: Vourvahis, Manoli |
| BackLink | http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25772414$$DView record in Pascal Francis https://www.ncbi.nlm.nih.gov/pubmed/22040521$$D View this record in MEDLINE/PubMed |
| BookMark | eNqNUstuEzEUtVARfcAvIG8QICXBj_FMZgESRAUqqoJQu7Y8nuvGqWMH2wkJKz6BDT_IlzCTpuWxqje27j2Pq-tziPZ88IAQpmREu_NiNqK8FENGmRgxQumIFF1htL6HDm4be-iAcFIOBRN0Hx2mNCOEclqKB2ifMVIQwegB-nlsDOiccDD4CnLQwatvwQFWvsUr5RYxWI2Vti0OHucp4MVUxbnS4cp6yFZvmX3dwzrjS_AQVbYd9uzs8_nJADuIya5s7ND42cWHX99_FIIPSEmfD7D1eArK5ekGq3bpMk7LZtZP8xDdN8oleLS7j9DF2-Pzyfvh6cd3J5PXp0MtyrocckNq1RYGhCJjpqiuTFuNNdG0gFZVBQDTvG6YGkMFjWiqpoSy5KaFyhRtWfMj9Opad7Fs5tBq8DkqJxfRzlXcyKCs_Lfj7VRehpXkBeHdDjuBpzuBGL4sIWU5t0mDc8pDWCZZ17xbOaM98vHfVrceN1_RAZ7sACpp5UxUXtv0ByeqihVbod3MOoaUIhipbd6uvJvQOkmJ7DMiZ7KPguyjIPuMyG1G5LoTGP8ncONxB-rLa-pX62BzZ558M_nUv_hvlhDWEA |
| CODEN | BCPHBM |
| CitedBy_id | crossref_primary_10_1016_j_rpsm_2014_10_005 crossref_primary_10_1016_j_rpsmen_2014_10_006 crossref_primary_10_1517_13543784_2013_846325 crossref_primary_10_1007_s40262_013_0070_9 crossref_primary_10_1016_j_pharmthera_2023_108459 crossref_primary_10_1002_ange_201903683 crossref_primary_10_1002_anie_201903683 |
| Cites_doi | 10.1128/AAC.42.7.1592 10.1124/dmd.109.031252 10.1038/clpt.1994.137 10.1124/dmd.106.009738 10.1016/j.clinthera.2010.10.007 10.1016/S0006-2952(03)00076-5 10.1107/S0108767307099618 10.1097/QAD.0b013e32832fef5b 10.1310/GTFR-2DRX-M6YE-ELXR |
| ContentType | Journal Article |
| Copyright | 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society 2015 INIST-CNRS 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society 2012 |
| Copyright_xml | – notice: 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society – notice: 2015 INIST-CNRS – notice: 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. – notice: 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society 2012 |
| DBID | AAYXX CITATION IQODW CGR CUY CVF ECM EIF NPM 7X8 5PM |
| DOI | 10.1111/j.1365-2125.2011.04136.x |
| DatabaseName | CrossRef Pascal-Francis Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic PubMed Central (Full Participant titles) |
| DatabaseTitle | CrossRef MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Pharmacy, Therapeutics, & Pharmacology |
| EISSN | 1365-2125 |
| EndPage | 775 |
| ExternalDocumentID | PMC3403204 22040521 25772414 10_1111_j_1365_2125_2011_04136_x BCP4136 |
| Genre | article Randomized Controlled Trial Research Support, Non-U.S. Gov't Journal Article |
| GeographicLocations | United Kingdom Europe |
| GroupedDBID | --- .3N .55 .GA .GJ .Y3 05W 0R~ 10A 1OC 23N 2WC 31~ 33P 36B 3O- 3SF 4.4 50Y 50Z 51W 51X 52M 52N 52O 52P 52R 52S 52T 52U 52V 52W 52X 53G 5GY 5HH 5LA 5VS 66C 6J9 702 7PT 8-0 8-1 8-3 8-4 8-5 8UM 930 A01 A03 AAESR AAEVG AAHQN AAIPD AAMMB AAMNL AANLZ AAONW AASGY AAXRX AAYCA AAZKR ABCQN ABCUV ABEML ABOCM ABPVW ABQWH ABXGK ACAHQ ACCZN ACFBH ACGFO ACGFS ACGOF ACMXC ACPOU ACSCC ACXBN ACXQS ADBBV ADBTR ADEOM ADIZJ ADKYN ADMGS ADOZA ADXAS ADZMN AEFGJ AEGXH AEIGN AEIMD AENEX AEUYR AEYWJ AFBPY AFEBI AFFPM AFGKR AFWVQ AFZJQ AGHNM AGXDD AGYGG AHBTC AIACR AIAGR AIDQK AIDYY AITYG AIURR ALAGY ALMA_UNASSIGNED_HOLDINGS ALUQN ALVPJ AMBMR AMYDB AOIJS ATUGU AZBYB AZVAB BAFTC BAWUL BFHJK BHBCM BMXJE BROTX BRXPI BY8 C45 CAG COF CS3 D-6 D-7 D-E D-F DCZOG DIK DPXWK DR2 DRFUL DRMAN DRSTM DU5 E3Z EBS EJD EMOBN EX3 F00 F01 F04 F5P FUBAC G-S G.N GODZA GX1 H.X HF~ HGLYW HYE HZI HZ~ IHE IX1 J0M K48 KBYEO LATKE LC2 LC3 LEEKS LH4 LITHE LOXES LP6 LP7 LSO LUTES LW6 LYRES MEWTI MK4 MRFUL MRMAN MRSTM MSFUL MSMAN MSSTM MXFUL MXMAN MXSTM N04 N05 N9A NF~ O66 O9- OIG OK1 OVD P2P P2W P2X P2Z P4B P4D Q.N Q11 QB0 R.K ROL RX1 SUPJJ TEORI TR2 UB1 V8K W8V W99 WBKPD WHWMO WIH WIJ WIK WIN WOHZO WOW WQJ WVDHM WXI WXSBR X7M XG1 YFH YOC YUY ZGI ZXP ZZTAW ~IA ~WT AAYXX CITATION O8X IQODW AAHHS ACCFJ ADZOD AEEZP AEQDE AIWBW AJBDE CGR CUY CVF ECM EIF NPM 7X8 5PM |
| ID | FETCH-LOGICAL-c5696-3f09ad4fe5a082a1c7fd78c0c14eda74ee2c39b2a8e7eb5b7b6e663fde7f4d693 |
| IEDL.DBID | WIN |
| ISICitedReferencesCount | 7 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000302464500011&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 0306-5251 1365-2125 |
| IngestDate | Thu Aug 21 18:32:09 EDT 2025 Fri Jul 11 15:50:00 EDT 2025 Thu Apr 03 06:59:49 EDT 2025 Mon Jul 21 09:15:23 EDT 2025 Sat Nov 29 03:44:51 EST 2025 Tue Nov 18 20:45:53 EST 2025 Sun Sep 21 06:11:59 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 5 |
| Keywords | Human Imidazole derivatives 4-Aminobutyrate transaminase Healthy subject Ketoconazole Enzyme Transferases Non nucleoside compound UK-453,061 Enzyme inhibitor Anticonvulsant Valproic acid Histone deacetylase inhibitor Antifungal agent Mood stabilizer Transaminases Reverse transcriptase inhibitor Lersivirine Antiviral Pharmacokinetics |
| Language | English |
| License | http://onlinelibrary.wiley.com/termsAndConditions#vor CC BY 4.0 2011 Pfizer Inc. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c5696-3f09ad4fe5a082a1c7fd78c0c14eda74ee2c39b2a8e7eb5b7b6e663fde7f4d693 |
| Notes | Current address: ESBATech, an Alcon Biomedical Research Unit, Wagistrasse 21, 8952 Zurich‐Schlieren, Switzerland. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 Current address: ESBATech, an Alcon Biomedical Research Unit, Wagistrasse 21, 8952 Zurich-Schlieren, Switzerland. |
| OpenAccessLink | https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1365-2125.2011.04136.x |
| PMID | 22040521 |
| PQID | 993316214 |
| PQPubID | 23479 |
| PageCount | 8 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_3403204 proquest_miscellaneous_993316214 pubmed_primary_22040521 pascalfrancis_primary_25772414 crossref_citationtrail_10_1111_j_1365_2125_2011_04136_x crossref_primary_10_1111_j_1365_2125_2011_04136_x wiley_primary_10_1111_j_1365_2125_2011_04136_x_BCP4136 |
| PublicationCentury | 2000 |
| PublicationDate | May 2012 |
| PublicationDateYYYYMMDD | 2012-05-01 |
| PublicationDate_xml | – month: 05 year: 2012 text: May 2012 |
| PublicationDecade | 2010 |
| PublicationPlace | Oxford, UK |
| PublicationPlace_xml | – name: Oxford, UK – name: Oxford – name: England |
| PublicationTitle | British journal of clinical pharmacology |
| PublicationTitleAlternate | Br J Clin Pharmacol |
| PublicationYear | 2012 |
| Publisher | Blackwell Publishing Ltd Blackwell Blackwell Science Inc |
| Publisher_xml | – name: Blackwell Publishing Ltd – name: Blackwell – name: Blackwell Science Inc |
| References | 2009; 23 1994; 56 2010; 32 2010; 38 2001; 2 2006; 34 1998; 42 2003; 65 2007; A63 e_1_2_7_5_2 e_1_2_7_4_2 e_1_2_7_2_2 e_1_2_7_9_2 Phillips C (e_1_2_7_3_2) 2007; 63 e_1_2_7_8_2 e_1_2_7_7_2 e_1_2_7_6_2 e_1_2_7_17_2 e_1_2_7_16_2 e_1_2_7_15_2 Trapnell CB (e_1_2_7_12_2) 1998; 42 e_1_2_7_14_2 e_1_2_7_13_2 e_1_2_7_11_2 e_1_2_7_10_2 |
| References_xml | – volume: 38 start-page: 789 year: 2010 end-page: 800 article-title: Excretion and metabolism of lersivirine (5‐([3,5‐diethyl‐1‐(2‐hydroxyethyl)(3,5‐ C )‐1 ‐pyrazol‐4‐yl]oxy)benzene‐1,3‐dicarbonitrile), a next‐generation non‐nucleoside reverse transcriptase inhibitor, after administration of [ C]Lersivirine to healthy volunteers publication-title: Drug Metab Dispos – volume: 56 start-page: 272 year: 1994 end-page: 8 article-title: Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus publication-title: Clin Pharmacol Ther – volume: 65 start-page: 1441 year: 2003 end-page: 9 article-title: The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP‐glucuronosyltransferases publication-title: Biochem Pharmacol – volume: 34 start-page: 1277 year: 2006 end-page: 82 article-title: Inhibition of UDP‐glucuronosyltransferase 2b7‐catalyzed morphine glucuronidation by ketoconazole: dual mechanisms involving a novel noncompetitive mode publication-title: Drug Metab Dispos – volume: 23 start-page: 2115 year: 2009 end-page: 22 article-title: Activity, pharmacokinetics and safety of lersivirine (UK‐453,061), a next‐generation nonnucleoside reverse transcriptase inhibitor, during 7‐day monotherapy in HIV‐1 infected patients publication-title: AIDS – volume: A63 start-page: s18 year: 2007 article-title: HIV‐1 reverse transcriptase structure‐based drug design: crystals to clinic publication-title: Acta Cryst – volume: 42 start-page: 1592 year: 1998 end-page: 6 article-title: Glucuronidation of 3′‐azido‐3′‐deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid publication-title: Antimicrob Agents Chemother – volume: 32 start-page: 1889 year: 2010 end-page: 95 article-title: Safety and tolerability of lersivirine, a nonnucleoside reverse transcriptase inhibitor, during a 28‐day, randomized, placebo‐controlled, phase I clinical study in healthy male volunteers publication-title: Clin Ther – volume: 2 start-page: 92 year: 2001 end-page: 5 article-title: World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects (revised October 7, 2000) publication-title: HIV Clin Trials – ident: e_1_2_7_2_2 – ident: e_1_2_7_16_2 – volume: 42 start-page: 1592 year: 1998 ident: e_1_2_7_12_2 article-title: Glucuronidation of 3′‐azido‐3′‐deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid publication-title: Antimicrob Agents Chemother doi: 10.1128/AAC.42.7.1592 – ident: e_1_2_7_14_2 – ident: e_1_2_7_8_2 doi: 10.1124/dmd.109.031252 – ident: e_1_2_7_11_2 doi: 10.1038/clpt.1994.137 – ident: e_1_2_7_9_2 doi: 10.1124/dmd.106.009738 – ident: e_1_2_7_7_2 doi: 10.1016/j.clinthera.2010.10.007 – ident: e_1_2_7_10_2 doi: 10.1016/S0006-2952(03)00076-5 – volume: 63 start-page: s18 year: 2007 ident: e_1_2_7_3_2 article-title: HIV‐1 reverse transcriptase structure‐based drug design: crystals to clinic publication-title: Acta Cryst doi: 10.1107/S0108767307099618 – ident: e_1_2_7_5_2 doi: 10.1097/QAD.0b013e32832fef5b – ident: e_1_2_7_6_2 – ident: e_1_2_7_13_2 doi: 10.1310/GTFR-2DRX-M6YE-ELXR – ident: e_1_2_7_17_2 – ident: e_1_2_7_15_2 – ident: e_1_2_7_4_2 |
| SSID | ssj0013165 |
| Score | 2.0749192 |
| Snippet | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Lersivirine (UK‐453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450... To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next... |
| SourceID | pubmedcentral proquest pubmed pascalfrancis crossref wiley |
| SourceType | Open Access Repository Aggregation Database Index Database Enrichment Source Publisher |
| StartPage | 768 |
| SubjectTerms | Adult Antifungal Agents - pharmacology Area Under Curve Asian People Biological and medical sciences Cross-Over Studies Cytochrome P-450 CYP3A - metabolism Drug Interactions Enzyme Inhibitors - pharmacology Glucuronosyltransferase - metabolism Humans ketoconazole Ketoconazole - pharmacology lersivirine Male Medical sciences Middle Aged Nitriles - administration & dosage Nitriles - pharmacokinetics pharmacokinetics Pharmacology. Drug treatments Pyrazoles - administration & dosage Pyrazoles - pharmacokinetics Reverse Transcriptase Inhibitors - administration & dosage Reverse Transcriptase Inhibitors - pharmacokinetics UK‐453,061 valproic acid Valproic Acid - pharmacology Young Adult |
| Title | Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK‐453,061), in healthy adult subjects |
| URI | https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fj.1365-2125.2011.04136.x https://www.ncbi.nlm.nih.gov/pubmed/22040521 https://www.proquest.com/docview/993316214 https://pubmed.ncbi.nlm.nih.gov/PMC3403204 |
| Volume | 73 |
| WOSCitedRecordID | wos000302464500011&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| journalDatabaseRights | – providerCode: PRVWIB databaseName: Wiley Online Library customDbUrl: eissn: 1365-2125 dateEnd: 20241207 omitProxy: false ssIdentifier: ssj0013165 issn: 0306-5251 databaseCode: WIN dateStart: 19970101 isFulltext: true titleUrlDefault: https://onlinelibrary.wiley.com providerName: Wiley-Blackwell – providerCode: PRVWIB databaseName: Wiley Online Library Full Collection 2020 customDbUrl: eissn: 1365-2125 dateEnd: 99991231 omitProxy: false ssIdentifier: ssj0013165 issn: 0306-5251 databaseCode: DRFUL dateStart: 19970101 isFulltext: true titleUrlDefault: https://onlinelibrary.wiley.com providerName: Wiley-Blackwell |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrV1Nj9MwELVg4YC04pulfFRzQCuQGtQkTpwcYaFixSqqVi30FjmxDdFWSbVpV5QTP4ELf5BfwoyTbTdiDyvELUoyUd15Yz_b4zeMvVBuYCIdcSfTge_wwOeOjHLl-FJmmW-M0LYky6cjkSTRbBaP2_wnOgvT6ENsFtwoMmx_TQEus7ob5DZDC0foVokT--PwNfFJl7tUzODzYbLdUHBtVUliyDj3CtxuUs-lH-qMVLsLWeOfZppqF5fR0b-zKi-yXTtcje78z4beZbdb0gpvGpTdY9d0eZ_tjxvV6_UAJttDXPUA9mG81cNeP2C_GoXkGioDJ3pZ4Qxcfq_mGmSpAIGObSxykHmhoCoBCSksWvsT_O30TbKk-yWOJPDFCmUTniBJjieHA5jTmt9ZQecY4eX04-8fPxENA6QQrwZQlNAc9VyDlRqBepXR0lP9kE1H7ycHH5y2GoSTB2EcOr4ZxlJxowOJtEW6uTBKRPkwd7lWUnCtvdyPM09GWugsyEQWaqRTRmlhuApj_xHbKatSP2agaO8xQu4pQ6SDRkU6FjISkhtfIiEUPSbOPZ_mrVQ6VeyYpxemTOiTlHySkk9S65P0W4-5G8tFIxdyBZt-B1wbQ-xNBRIs3mNwjrYUg592dGSpq1WdIrlEYHv0yl4Dvq2xh90zcjNsSweWmxdIV7z7pCy-Wn1xnw99tO6x0MLyyg1J3x6M6erJvxo-Zbfwttfkkz5jO8vTlX7ObuZny6I-7bPrYhb12Y13x6PpUd-G9x_usE2K |
| linkProvider | Wiley-Blackwell |
| linkToHtml | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrV1ba9RAFB6kCgri_bJe6nmQopDIJplkkkctli5dwyJb7VuYZGY0dEmWZre4PvkTfPEP-ks8Z5LuNtiHIr6FZE7I5Hxn5pvbdxh7qbzQxDrmbq7DwOVhwF0ZF8oNpMzzwBihbUqWT2ORpvHRUTLp0gHRWZhWH2I94UaRYdtrCnCakO5Hud2ihV10J8WJDXL0BgnlVY68g_I4fB6lmyUFz-aVJI6Mo6_Q62_rufBNvb7q5lw2-NtMm-_iIkL6977K83zXdlh7t_9rVe-wWx1vhbct0O6yK7q6x3YmrfD1yoHp5hxX48AOTDaS2Kv77FcrktxAbeBYL2ochMvv9UyDrBQg1rGSZQGyKBXUFSAnhXlnf4wfT-8kS7pfYWcCX6xWNkEK0vTjdOTAjKb9Tks6ygivDg9-__iJgHCQRbx2oKygPe25Aqs2As0yp9mn5gE73Hs_3d13u4QQbhFGSeQGZphIxY0OJTIX6RXCKBEXw8LjWknBtfaLIMl9GWuh8zAXeaSRURmlheEqSoKHbKuqK_2YgaLlxxjpp4yQERoV60TIWEhuAomcUAyYOHN9VnRq6ZS0Y5adGzWhTzLySUY-yaxPsm8D5q0t561iyCVstnvoWhtigyqQY_EBgzO4ZRj_tKgjK10vmwz5JSLbpyKPWvRtjH1soZGeYV16uFwXIGnx_pOq_GolxgM-DNB6wCKLy0tXJHu3O6GrJ_9q-IJd359-GGfjUXrwlN3AIn67vfQZ21qcLPVzdq04XZTNybaN7j9huk8g |
| linkToPdf | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwrV1ba9RAFB5kKyIU79r1Us-DFIVN2SSTTPKorYulSwhlV_oWJnPR0CVZmt3i-uRP8MU_6C_xzCTdbbAPRXwLyZyQyfnmzDe37xDyRrqBjlREnVwFvkMDnzo8EtLxOc9zX2umbEqWz2OWJNHpaZy26YDMWZhGH2I94WZaho3XpoGrudTdVm63aGEX3UpxYkAO95FQblGTU6ZHtg5PRtPxZlHBtZklDUvG8Vfgdjf2XPuuTm-1Pec1_jjdZLy4jpL-vbPyKuO1Xdbo_n-t7ANyr2Wu8L6B2kNyS5WPyF7aSF-vBjDZnOSqB7AH6UYUe_WY_GpkkmuoNJypRYXDcP69mingpQREO1ayEMBFIaEqAVkpzFv7M_x4805jae6X2J3AF6uWbUAFSXIyORrAzEz8XRTmMCO8nR7__vETITFAHvFuAEUJzXnPFVi9EaiXuZl_qp-Q6ejj5OCT06aEcEQQxqHj62HMJdUq4MhduCuYliwSQ-FSJTmjSnnCj3OPR4qpPMhZHirkVFoqpqkMY_8p6ZVVqXYISLMAGSEB5SFyQi0jFTMeMU61z5EVsj5hl67PRKuXbtJ2zLIr4yb0SWZ8khmfZNYn2bc-cdeW80Yz5AY2ux10rQ0xpDJkWbRP4BJuGUYAs6zDS1Ut6wwZJiLbM0WeNejbGHsYo5GgYV06uFwXMOLi3Sdl8dWKjPt06KN1n4QWlzeuSPbhIDVXz__V8DW5kx6OsvFRcvyC3MUSXrO_9CXpLc6X6hW5LS4WRX2-2zbvP8QpT8k |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Effects+of+ketoconazole+and+valproic+acid+on+the+pharmacokinetics+of+the+next+generation+NNRTI%2C+lersivirine+%28UK-453%2C061%29%2C+in+healthy+adult+subjects&rft.jtitle=British+journal+of+clinical+pharmacology&rft.au=LANGDON%2C+Grant&rft.au=DAVIS%2C+John&rft.au=LAYTON%2C+Gary&rft.au=CHONG%2C+Chew-Lan&rft.date=2012-05-01&rft.pub=Blackwell&rft.issn=0306-5251&rft.volume=73&rft.issue=5&rft.spage=768&rft.epage=775&rft_id=info:doi/10.1111%2Fj.1365-2125.2011.04136.x&rft.externalDBID=n%2Fa&rft.externalDocID=25772414 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0306-5251&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0306-5251&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0306-5251&client=summon |