PMID- 30815916 OWN - NLM STAT- MEDLINE DCOM- 20200427 LR - 20201209 IS - 1875-9114 (Electronic) IS - 0277-0008 (Linking) VI - 39 IP - 4 DP - 2019 Apr TI - Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the ANRS-163 ETRAL Study. PG - 514-520 LID - 10.1002/phar.2242 [doi] AB - STUDY OBJECTIVE: The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady-state total and unbound etravirine, raltegravir, and inactive raltegravir-glucuronide concentrations 12 hours after last intake (C(12h) ) in blood plasma (BP) and seminal plasma (SP). DESIGN: Pharmacokinetic analysis of data from the ANRS163-ETRAL study. PATIENTS: One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and raltegravir 400 mg twice daily. MEASUREMENTS AND MAIN RESULTS: Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir-glucuronide C(12h) were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC(95) ) for wild-type (WT) HIV: etravirine (116 ng/ml) and raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C(12h) (536 ng/ml [376-719]) and raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C(12h) ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and < 1%, respectively, raltegravir 1.8 (1.3-3.3) and 12%, respectively, and raltegravir-glucuronide 12.0 (6.5-17.7) and > 99%, respectively. The BP raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C(12h) < PBIC(95) simultaneously. CONCLUSION: No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy. CI - (c) 2019 Pharmacotherapy Publications, Inc. FAU - Le, Minh Patrick AU - Le MP AUID- ORCID: 0000-0002-4670-8288 AD - IAME, UMR 1137, Sorbonne Paris Cite and INSERM, Universite Paris Diderot, Paris, France. AD - Laboratoire de Pharmacologie-Toxicologie, AP-HP, Hopital Bichat-Claude Bernard, Paris, France. FAU - Valantin, Marc-Antoine AU - Valantin MA AD - Service de Maladies Infectieuses et Tropicales, AP-HP, Hopital Pitie-Salpetriere, Paris, France. AD - INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP UMRS 1136), Sorbonne Universite, UPMC Univ Paris 06, Paris, France. FAU - Assoumou, Lambert AU - Assoumou L AD - INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP UMRS 1136), Sorbonne Universite, UPMC Univ Paris 06, Paris, France. FAU - Soulie, Cathia AU - Soulie C AD - Laboratoire de Virologie, INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP), AP-HP, Hopital Pitie Salpetriere, Sorbonne Universite, Paris, France. FAU - Le Mestre, Soizic AU - Le Mestre S AD - France Recherche Nord & Sud SIDA-HIV Hepatites (ANRS), Paris, France. FAU - Weiss, Laurence AU - Weiss L AD - Service d'Immunologie Clinique, AP-HP, Hopital Europeen Georges Pompidou, Paris, France. FAU - Yazdanpanah, Yazdan AU - Yazdanpanah Y AD - IAME, UMR 1137, Sorbonne Paris Cite and INSERM, Universite Paris Diderot, Paris, France. AD - Service de Maladies Infectieuses et Tropicales, AP-HP, Hopital Bichat-Claude Bernard, Paris, France. FAU - Molina, Jean-Michel AU - Molina JM AD - Service de Maladies Infectieuses et Tropicales, INSERM U941, AP-HP, Hopital Saint Louis, Universite Denis Diderot Paris VII, Paris, France. FAU - Bouchaud, Olivier AU - Bouchaud O AD - Service de Maladies Infectieuses et Tropicales, AP-HP, Hopital Avicenne, Bobigny, France. FAU - Raffi, Francois AU - Raffi F AD - Department of Infectious Diseases, Hotel-Dieu Hospital - INSERM CIC 1413, Nantes University Hospital, Nantes, France. FAU - Reynes, Jacques AU - Reynes J AD - Service de Maladies Infectieuses et Tropicales, CHU Montpellier, Montpellier, France. AD - INSERM U1175, IRD UMI 233, University of Montpellier, Montpellier, France. FAU - Calvez, Vincent AU - Calvez V AD - Laboratoire de Virologie, INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP), AP-HP, Hopital Pitie Salpetriere, Sorbonne Universite, Paris, France. FAU - Marcelin, Anne-Genevieve AU - Marcelin AG AD - Laboratoire de Virologie, INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP), AP-HP, Hopital Pitie Salpetriere, Sorbonne Universite, Paris, France. FAU - Costagliola, Dominique AU - Costagliola D AD - INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP UMRS 1136), Sorbonne Universite, UPMC Univ Paris 06, Paris, France. FAU - Katlama, Christine AU - Katlama C AD - Service de Maladies Infectieuses et Tropicales, AP-HP, Hopital Pitie-Salpetriere, Paris, France. AD - INSERM, Institut Pierre Louis d'Epidemiologie et de Sante Publique (iPLESP UMRS 1136), Sorbonne Universite, UPMC Univ Paris 06, Paris, France. FAU - Peytavin, Gilles AU - Peytavin G AD - IAME, UMR 1137, Sorbonne Paris Cite and INSERM, Universite Paris Diderot, Paris, France. AD - Laboratoire de Pharmacologie-Toxicologie, AP-HP, Hopital Bichat-Claude Bernard, Paris, France. CN - ANRS-163 ETRAL study group LA - eng PT - Clinical Trial PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190401 PL - United States TA - Pharmacotherapy JT - Pharmacotherapy JID - 8111305 RN - 0 (Anti-HIV Agents) RN - 0 (Nitriles) RN - 0 (Pyridazines) RN - 0 (Pyrimidines) RN - 0C50HW4FO1 (etravirine) RN - 43Y000U234 (Raltegravir Potassium) SB - IM MH - Anti-HIV Agents/*administration & dosage/blood/*pharmacokinetics/therapeutic use MH - Drug Interactions MH - Drug Therapy, Combination MH - Female MH - HIV Infections/blood/*drug therapy MH - HIV-1/drug effects MH - Humans MH - Male MH - Middle Aged MH - Nitriles MH - Protein Binding MH - Pyridazines/*administration & dosage/blood/*pharmacokinetics/therapeutic use MH - Pyrimidines MH - Raltegravir Potassium/*administration & dosage/blood/*pharmacokinetics/therapeutic use MH - Semen/*drug effects/metabolism OTO - NOTNLM OT - antiretroviral OT - dual therapy OT - etravirine OT - interaction OT - pharmacokinetics OT - raltegravir OT - seminal fluid FIR - Duvivier, Claudine IR - Duvivier C FIR - Goujard, Cecile IR - Goujard C FIR - Jeantils, Vincent IR - Jeantils V FIR - Salmon, Dominique IR - Salmon D FIR - Simon, Anne IR - Simon A FIR - Colin de Verdiere, Nathalie IR - Colin de Verdiere N FIR - Morlat, Philippe IR - Morlat P FIR - Poizot-Martin, Isabelle IR - Poizot-Martin I FIR - Allavena, Clotilde IR - Allavena C FIR - Naqvi, Alissa IR - Naqvi A FIR - Bernard, Louis IR - Bernard L FIR - Chidiac, Christian IR - Chidiac C FIR - Hamdoud, Karima IR - Hamdoud K EDAT- 2019/03/01 06:00 MHDA- 2020/04/28 06:00 CRDT- 2019/03/01 06:00 PHST- 2019/03/01 06:00 [pubmed] PHST- 2020/04/28 06:00 [medline] PHST- 2019/03/01 06:00 [entrez] AID - 10.1002/phar.2242 [doi] PST - ppublish SO - Pharmacotherapy. 2019 Apr;39(4):514-520. doi: 10.1002/phar.2242. Epub 2019 Apr 1.