title: Pregnancy influences the plasma pharmacokinetics but not the cerebrospinal fluid pharmacokinetics of raltegravir: a preclinical investigation.
abstract: Alterations in antiretroviral pharmacokinetics during pregnancy must be understood for the drugs to be used safely and effectively. Present study is an attempt to understand the potential changes in raltegravir plasma and cerebrospinal fluid pharmacokinetics during pregnancy in late pregnant and non-pregnant rats. In vitro plasma protein binding, metabolic stability, intravenous blood-brain barrier (BBB) permeability and oral pharmacokinetic studies were performed. Raltegravir concentrations in different matrices were measured using LC-MS/MS. Raltegravir plasma protein binding remained similar in both groups, whereas, metabolic stability was significantly lower in pregnant rats than the non-pregnant rats liver microsomes. In oral pharmacokinetic study, peak plasma concentrations and systemic exposures were significantly lower (∼37%) and clearance was significantly higher (∼61%) in late pregnant rats compared to non-pregnant rats. However, unlike plasma pharmacokinetics, CSF pharmacokinetic profile of raltegravir was similar in both pregnant and non-pregnant rats. Following intravenous administration, raltegravir showed higher BBB permeability in pregnant rats compared to non-pregnant rats. But the mean CSF-to-plasma ratio was significantly higher in pregnant rats compared to non-pregnant rats suggesting higher brain penetration in pregnant rats. In conclusion, pregnancy significantly affected the plasma pharmacokinetics, whereas cerebrospinal fluid pharmacokinetics remained fairly similar in pregnant and non-pregnant rats. Although current plasma pharmacokinetic data is in contradiction to the reported human data, pregnancy-specific pharmacokinetic changes observed in the current study emphasize the need for close therapeutic monitoring while treating the pregnant population and also warrants the need for additional clinical data with larger group of patients.
authors.affiliation: Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad, Telangana, India; Department of Pharmacology, Sree Siddaganga College of Pharmacy, Tumkur, Karnataka, India. Electronic address: mohammad.yunus@outlook.com.
authors.forename: Mahamad Yunnus A
authors.initials: MY
authors.lastname: Mahat
authors.affiliation: Department of Pharmacology, Sree Siddaganga College of Pharmacy, Tumkur, Karnataka, India.
authors.forename: B S
authors.initials: BS
authors.lastname: Thippeswamy
authors.affiliation: Department of Pharmacology, Jayawantrao Sawant J.S.P.M. College of Pharmacy, Hadapsar, Pune, India.
authors.forename: Farhin R
authors.initials: FR
authors.lastname: Khan
authors.affiliation: Department of Pharmacology, Jayawantrao Sawant J.S.P.M. College of Pharmacy, Hadapsar, Pune, India.
authors.forename: Ramya
authors.initials: R
authors.lastname: Edunuri
authors.affiliation: Drug Discovery Research, Biology, Orchid Chemicals and Pharmaceuticals Limited, Sozhanganallur, Chennai, India.
authors.forename: Saranya
authors.initials: S
authors.lastname: Nidhyanandan
authors.affiliation: Drug Discovery Research, Biology, Orchid Chemicals and Pharmaceuticals Limited, Sozhanganallur, Chennai, India.
authors.forename: Shilpee
authors.initials: S
authors.lastname: Chaudhary
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D005260:Female; D010949:Plasma / Q000378:metabolism*; D011247:Pregnancy; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011760:Pyrrolidinones; D000068898:Raltegravir Potassium
keywords: Antiretroviral agents; Cerebrospinal fluid; HIV integrase inhibitor; Pharmacokinetics; Pregnancy; Raltegravir