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Influence of pregnancy associated with HIV on the activity of P-gp, BCRP and OATP drug transporters in women under Raltegravir treatment

Grant number: 19/13401-0
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Pharmacology - Clinical Pharmacology
Principal Investigator:Vera Lúcia Lanchote
Grantee:Igor Pavão Apolinario da Silva
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:18/05616-3 - Clinical pharmacokinetics in infectious diseases, AP.TEM


Membrane transporters are of emerging clinical importance in the absorption,distribution and elimination of drugs, including the placental transfer. Nevertheless, theeffect of pregnancy in the expression and activity of membrane transportersremains unclear. Then, the current study aims to evaluate the effect of pregnancyassociated with HIV in the activity of the membrane transporters P-gp and BCRP inwomen under raltegravir treatment (RAL) using the in vivo P-gp and OATP(fexofenadine) and BCRP and OATP (rosuvastatin) probes. RAL, a drug recentlyintroduced in Brazil as the first-choice drug for the treatment of HIV-infected pregnantwomen, is reported to be well tolerated with demonstration of rapid decline in HIV viralload. RAL primary metabolic pathway is dependent on UGT1A1 and at minor extensionby UGT1A9 and UGT1A3. In vitro studies also demonstrated that RAL is a P-gp andBCRP substrate. Therefore, the present work will identify the role of these transportersin the elimination of RAL in pregnant women, using data from in vitro studies and invitro-in vivo extrapolation through the development of a PBPK (Physiologically BasedPharmacokinetic) model. In addition, a population pharmacokinetic model (popPK) ofRAL in HIV-positive pregnant women will be developed for the first time in order toidentify covariates in the pharmacokinetics of this drug. The patients under chronictreatment with RAL (treatment for at least for two weeks) will be evaluated in twophases, during the third trimester of pregnancy and during postpartum. In the clinicalstudy, the in vivo probes fexofenadine (single oral dose of 60 mg) and rosuvastatin(single oral dose of 5 mg) will be administrated simultaneously with RAL (400 mg bid).Serial blood samples will be collected at times zero; 0.5; 1; 2; 3; 4; 6; 8; 16 and 24 h.Urine samples will be collected during 24 h. At delivery, samples will be obtained frommaternal blood, venous blood and arterial blood in order to determine the transplacentaltransfer of RAL. The concentrations of fexofenadine, rosuvastatin, RAL and RAL-glucuronide (RAL-GLU) will be determined in the biological samples using liquidchromatography coupled to mass spectrometry (LC-MS/MS). The pregnant women willbe genotyped for UGT1A1*28 and other relevant polymorphisms. In the second part ofthe study, the data generated from in vitro studies regarding drug transporters will beincorporated into a PBPK model.

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