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Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO
PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment‐experienced, HIV‐1‐infected patients (≥6 to
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| Published in: | Journal of clinical pharmacology 2016-11, Vol.56 (11), p.1395-1405 |
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| cites | cdi_FETCH-LOGICAL-c4946-226de38504b7a5c15f043bb548590e25e9d40fc6d1d080c9e0a44140119633843 |
| container_end_page | 1405 |
| container_issue | 11 |
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| container_title | Journal of clinical pharmacology |
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| creator | Kakuda, Thomas N. Brochot, Anne Green, Bruce Nijs, Steven Vis, Peter Opsomer, Magda Tomaka, Frank L. Hoetelmans, Richard M. W. |
| description | PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment‐experienced, HIV‐1‐infected patients (≥6 to |
| doi_str_mv | 10.1002/jcph.746 |
| format | article |
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W.</creator><creatorcontrib>Kakuda, Thomas N. ; Brochot, Anne ; Green, Bruce ; Nijs, Steven ; Vis, Peter ; Opsomer, Magda ; Tomaka, Frank L. ; Hoetelmans, Richard M. W.</creatorcontrib><description>PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment‐experienced, HIV‐1‐infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C0h and AUC0‐12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero‐ and first‐order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first‐order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h−1, respectively. Overall, median (range) estimated etravirine C0h and AUC0‐12h were 287 (2‐2276) ng/mL and 4560 (62‐28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC0‐12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment‐experienced, HIV‐1‐infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.746</identifier><identifier>PMID: 27060341</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adolescent ; Adult ; Child ; Drug Administration Schedule ; etravirine ; Female ; HIV Infections - blood ; HIV Infections - drug therapy ; HIV Protease Inhibitors - administration & dosage ; HIV Protease Inhibitors - blood ; HIV Protease Inhibitors - pharmacokinetics ; HIV-1 - drug effects ; HIV/AIDS ; Humans ; Male ; pediatrics ; pharmacodynamics ; pharmacokinetics ; Pyridazines - administration & dosage ; Pyridazines - blood ; Pyridazines - pharmacokinetics ; Reverse Transcriptase Inhibitors - administration & dosage ; Reverse Transcriptase Inhibitors - blood ; Reverse Transcriptase Inhibitors - pharmacokinetics ; Teenagers ; Treatment Outcome</subject><ispartof>Journal of clinical pharmacology, 2016-11, Vol.56 (11), p.1395-1405</ispartof><rights>2016, The American College of Clinical Pharmacology</rights><rights>2016 American College of Clinical Pharmacology</rights><rights>2016, The American College of Clinical Pharmacology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4946-226de38504b7a5c15f043bb548590e25e9d40fc6d1d080c9e0a44140119633843</citedby><cites>FETCH-LOGICAL-c4946-226de38504b7a5c15f043bb548590e25e9d40fc6d1d080c9e0a44140119633843</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27060341$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kakuda, Thomas N.</creatorcontrib><creatorcontrib>Brochot, Anne</creatorcontrib><creatorcontrib>Green, Bruce</creatorcontrib><creatorcontrib>Nijs, Steven</creatorcontrib><creatorcontrib>Vis, Peter</creatorcontrib><creatorcontrib>Opsomer, Magda</creatorcontrib><creatorcontrib>Tomaka, Frank L.</creatorcontrib><creatorcontrib>Hoetelmans, Richard M. W.</creatorcontrib><title>Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO</title><title>Journal of clinical pharmacology</title><addtitle>The Journal of Clinical Pharmacology</addtitle><description>PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment‐experienced, HIV‐1‐infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C0h and AUC0‐12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero‐ and first‐order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first‐order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h−1, respectively. Overall, median (range) estimated etravirine C0h and AUC0‐12h were 287 (2‐2276) ng/mL and 4560 (62‐28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC0‐12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment‐experienced, HIV‐1‐infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Child</subject><subject>Drug Administration Schedule</subject><subject>etravirine</subject><subject>Female</subject><subject>HIV Infections - blood</subject><subject>HIV Infections - drug therapy</subject><subject>HIV Protease Inhibitors - administration & dosage</subject><subject>HIV Protease Inhibitors - blood</subject><subject>HIV Protease Inhibitors - pharmacokinetics</subject><subject>HIV-1 - drug effects</subject><subject>HIV/AIDS</subject><subject>Humans</subject><subject>Male</subject><subject>pediatrics</subject><subject>pharmacodynamics</subject><subject>pharmacokinetics</subject><subject>Pyridazines - administration & dosage</subject><subject>Pyridazines - blood</subject><subject>Pyridazines - pharmacokinetics</subject><subject>Reverse Transcriptase Inhibitors - administration & dosage</subject><subject>Reverse Transcriptase Inhibitors - blood</subject><subject>Reverse Transcriptase Inhibitors - pharmacokinetics</subject><subject>Teenagers</subject><subject>Treatment Outcome</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp10d9u0zAUBnALgVgZSDwBisQNF8tmx3-SXFZVWYumrkKFSdxYrn2iuE2cYidsfRZeFpd1Q0xwZfnop-8c6UPoLcHnBOPsYqN39XnOxDM0IpxnKROYPUcjjEuSZjnGJ-hVCBuMiWCcvEQncSYwZWSEfi5r5Vulu6110FsdEuVM8mR48fA3e6daq5PP0Kjedi7UdheSrkqmvVc_rI88sS6Zzb-mJJ27CnQP5ixZeVB9C65Pp3c78BacBpNMatsYD-73xrHpGgg6mnBIWM7Hi-vX6EWlmgBvju8p-vJxuprM0qvry_lkfJVqVjKRZpkwQAuO2TpXXBNeYUbXa84KXmLIOJSG4UoLQwwusC4BK8YIw4SUgtKC0VP04T5357vvA4Retjae0jTKQTcESQrKaZnlooj0_RO66Qbv4nVRZSLjGcvzP4HadyF4qOTO21b5vSRYHgqTh8JkLCzSd8fAYd2CeYQPDUVwdg9uu6YHH7bNcAte1qCavv5XXnrktoH9f_fKT5Pl7C9vQw93j175rRQ5zbm8WVxKurr5xvNFKWf0F9Uzvfw</recordid><startdate>201611</startdate><enddate>201611</enddate><creator>Kakuda, Thomas N.</creator><creator>Brochot, Anne</creator><creator>Green, Bruce</creator><creator>Nijs, Steven</creator><creator>Vis, Peter</creator><creator>Opsomer, Magda</creator><creator>Tomaka, Frank L.</creator><creator>Hoetelmans, Richard M. 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W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>The Journal of Clinical Pharmacology</addtitle><date>2016-11</date><risdate>2016</risdate><volume>56</volume><issue>11</issue><spage>1395</spage><epage>1405</epage><pages>1395-1405</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment‐experienced, HIV‐1‐infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C0h and AUC0‐12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero‐ and first‐order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first‐order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h−1, respectively. Overall, median (range) estimated etravirine C0h and AUC0‐12h were 287 (2‐2276) ng/mL and 4560 (62‐28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC0‐12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment‐experienced, HIV‐1‐infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>27060341</pmid><doi>10.1002/jcph.746</doi><tpages>11</tpages></addata></record> |
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| subjects | Adolescent Adult Child Drug Administration Schedule etravirine Female HIV Infections - blood HIV Infections - drug therapy HIV Protease Inhibitors - administration & dosage HIV Protease Inhibitors - blood HIV Protease Inhibitors - pharmacokinetics HIV-1 - drug effects HIV/AIDS Humans Male pediatrics pharmacodynamics pharmacokinetics Pyridazines - administration & dosage Pyridazines - blood Pyridazines - pharmacokinetics Reverse Transcriptase Inhibitors - administration & dosage Reverse Transcriptase Inhibitors - blood Reverse Transcriptase Inhibitors - pharmacokinetics Teenagers Treatment Outcome |
| title | Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO |
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