title: Pharmacokinetic profiling of efavirenz-emtricitabine-tenofovir fixed dose combination in pregnant and non-pregnant rats.
abstract: During pregnancy, the disposition of various drugs is altered due to changes in physiological condition, maternal gastrointestinal absorption, gastric secretion and motility. A fixed dose combination of antiretrovirals is commonly prescribed for the treatment of HIV infection. There is a need to understand the pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir in fixed dose combination during pregnancy. The pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir fixed dose combination was evaluated in timed pregnant and non-pregnant Sprague-Dawley rats at 30, 10, 15 mg/kg p.o., respectively. The plasma, placental tissue, amniotic fluid and fetal tissue concentrations were measured using high performance liquid chromatography combined with tandem mass spectrometric detector (LC-MS/MS). To summarize, the pharmacokinetic profile of efavirenz remained similar in the pregnant and non-pregnant rats. However, a considerable difference in the pharmacokinetics of emtricitabine and tenofovir was observed in pregnant and non-pregnant rats. Efavirenz and emtricitabine showed appreciable placental, amniotic fluid and fetal exposure compared with tenofovir. The present study suggests that a profound impact on antiretroviral pharmacokinetics was observed during pregnancy and there is a need to monitor the exposure levels of each drug when administered as a fixed dose combination during pregnancy. Further studies to explore the pharmacokinetic parameters of fixed dose antiretrovirals during the preclinical stage in a timed-pregnancy rat model are required. Such studies can help in the development of safe and effective medications with a reduced risk of perinatal transmission of HIV-1 infection.
authors.affiliation: Pharmacokinetics and Drug Metabolism, Discovery Research, Suven Life Sciences Ltd, Banjara Hills, Hyderabad, 500034, India. ramakrishna_nirogi@yahoo.co.in
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Nirogi
authors.forename: Gopinadh
authors.initials: G
authors.lastname: Bhyrapuneni
authors.forename: Vishwottam
authors.initials: V
authors.lastname: Kandikere
authors.forename: Nageswararao
authors.initials: N
authors.lastname: Muddana
authors.forename: Ramanatha
authors.initials: R
authors.lastname: Saralaya
authors.forename: Prashanth
authors.initials: P
authors.lastname: Komarneni
authors.forename: Koteshwara
authors.initials: K
authors.lastname: Mudigonda
authors.forename: K
authors.initials: K
authors.lastname: Mukkanti
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000653:Amniotic Fluid / Q000737:chemistry*; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D000068257:Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D005260:Female; D005333:Fetus / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000635:transmission; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D063065:Organophosphonates / Q000097:blood / Q000493:pharmacokinetics*; D010078:Oxazines / Q000097:blood / Q000493:pharmacokinetics*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D000068257:Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; D063065:Organophosphonates; D010078:Oxazines; D003841:Deoxycytidine; D000225:Adenine