P‐Glycoprotein and Organic Anion Transporter Polypeptide 1B/Breast Cancer Resistance Protein Drug Transporter Activity in Pregnant Women Living With HIV

Abstract

This study evaluates the influence of pregnancy and HIV infection in conjunction with the use of raltegravir,lamivudine,and tenofovir disoproxil fumarate (combined antiretroviral therapy [cART]) on intestinal P-glycoprotein (P-gp) and hepatic organic anion transporter polypeptide (OATP) 1B1/1B3 and/or breast cancer resistance protein (BCRP) drug transporter activity using rosuvastatin (OATP1B/BCRP) and fexofenadine (P-gp) probes. Single oral doses of 5-mg rosuvastatin and 60-mg fexofenadine were administered to women living with HIV under cART in the third trimester of gestation (n = 15) and postpartum period (n = 10). A control group of 12 healthy nonpregnant women also was investigated. Pharmacokinetic parameters were estimated by using a noncompartmental method and evaluated by t test (P < .05). The rosuvastatin area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC 0-last ) value was higher in the third trimester of pregnancy (19.5 [95%CI,] ng • h/mL] when compared to postpartum (13.3 [95%CI,] ng • h/mL), while the fexofenadine AUC 0-last values did not differ between the third trimester of pregnancy (738.0 [95%CI,] ng • h/mL) and postpartum period (874.9 [95%CI, 408.2-1342.0] ng• h/mL). The rosuvastatin AUC 0-last values did not differ between healthy nonpregnant women (13.8 [95%CI,] ng • h/mL) and women living with HIV in the postpartum period (13.3 [95%CI,] ng • h/mL), and the fexofenadine AUC 0-last values did not differ between the 2 investigated groups (603.6 [95%CI,] ng • h/mL vs 874.9 [95%CI, 408.2-1342.0] ng • h/mL). It is suggested that gestation inhibits the hepatic OATP1B1/1B3 and/or BCRP activity but does not alter intestinal P-gp activity. The influence of HIV infection in conjunction with use of cART on OATP1B/BCRP and intestinal P-gp activity was not observed.

Total, Unbound, Renal, and Hepatic Clearances of Raltegravir and the Formation and Elimination Clearances of Raltegravir Glucuronide in Pregnant Women

“…Only 8 patients completed the second visit for evaluation during the postpartum period; the other patients withdrew their consent. The characteristics of the participants were previously described by Moreira et al 19 The patients were taking only the cART treatment composed of 400 mg of RAL twice daily in combination with tenofovir/lamivudine (300 mg/300 mg once daily). Patients taking any other medication were excluded from this study.…”

“…The patients also received single oral doses of 5 mg of rosuvastatin and 60 mg of fexofenadine at the same time as RAL administration. The results of the in vivo activities of organic anion transporting polypeptide 1B1/BCRP (rosuvastatin as a probe) and P‐gp (fexofenadine as a probe) in both the third trimester of gestation and the postpartum period in women living with HIV were described in a previous report from our research group 19 . The exclusion criteria were women taking any other medication that was not the cART treatment, women presenting other coinfections, and women with multiple gestations.…”

“…The results of the in vivo activities of organic anion transporting polypeptide 1B1/BCRP (rosuvastatin as a probe) and P-gp (fexofenadine as a probe) in both the third trimester of gestation and the postpartum period in women living with HIV were described in a previous report from our research group. 19 The exclusion criteria were women taking any other medication that was not the cART treatment, women presenting other coinfections, and women with multiple gestations. CD4 cell count and HIV RNA viral load results were obtained directly from their medical records.…”

Successful Prediction of Fetal Exposure to Dual BCRP/P‐gp Drug Substrates Using the Efflux Ratio‐Relative Expression Factor Approach and PBPK M&S

“…These assumptions are reasonable as the placenta has few CYP‐metabolizing enzymes and the fetal liver has small (mostly CYP3A7) metabolic capacity, likely much less than the transplacental clearance of the drugs 6 . Third, as to whether pregnancy induces changes in hepatic transporters (OATP1B1, 1B3, and 2B1) activity or abundance is unknown; one study has shown that pregnancy reduces hepatic OATP1B1 and 1B3 activity, 34 whereas another study with human hepatocytes, exposed to pregnancy‐related hormones, did not observe any significant changes in OATP transporters abundance 35 . Fourth, because the fraction of the drug unbound in fetal plasma was not available to us, we used the Simcyp‐predicted value.…”

“…Additionally, the induction of CYP2C9 by 1.4‐, 1.5‐, and 1.6‐fold during the first, second, and third trimesters was incorporated in the pregnant population 33 . Data on changes in hepatic CYP2C19 and transporter activity are not available or questionable 34,35 and thus were not incorporated in the pregnant population model. Afterwards, we optimized the passive and active placental clearances of glyburide to match the observed UV/MP data, as described previously 8,9 .…”