Effect of Pregnancy on Unbound Raltegravir Concentrations in the ANRS 160 RalFe Trial

Abstract

OBJECTIVES: A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. METHOD: RalFe ANRS160 study was a non-randomized, open label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing raltegravir 400 mg twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. RESULT: A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one compartment model with a transit compartment with first order absorption, evolving either to bound raltegravir (by a linear binding to albumin), or metabolism to RAL-glucuronide or to a first order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound AUC0-12h significantly decreased by 37 and 27% during pregnancy. Median total Ctrough decreased significantly in the evening (28%), however median total Ctrough in the morning, unbound Ctrough in the morning and unbound Ctrough in the evening showed a non-significant decrease, respectively 16%, 1% and 15% during pregnancy compared to the postpartum period. CONCLUSION: This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound Ctrough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered as clinically relevant.

When special populations intersect with drug–drug interactions: Application of physiologically‐based pharmacokinetic modeling in pregnant populations

“…Predicted/observed pregnancy/postpartum ratios for each study fell within the 50% acceptance criteria. The predicted fraction unbound in the third trimester pregnancy (fu 0.21) was in agreement with that observed from literature (fu 0.22) (Zheng et al., 2020).…”

“… Note: The target unbound minimum effective concentration is 8.33 nM (Zheng et al., 2020) and maintaining AUC(0–24) u within 50% (3.58 µM*h) to 150% (10.7 µM*h) of the simulated AUC(0–24) u for 400‐mg twice‐daily raltegravir administration in nonpregnant females (Burger, 2010). …”

“…The second study included geometric mean PK data from women at ∼33 weeks gestation ( n = 21) and 4–6 weeks postpartum ( n = 18) (Blonk et al., 2015). The third study included median PK data from women between 30 and 37 weeks gestation ( n = 43) and 4–6 weeks postpartum ( n = 39) (Zheng et al., 2020).…”

“…Unbound drug concentrations are most relevant to understanding efficacy, particularly for anti‐infective drugs (Gonzalez et al., 2013; Metsu et al., 2017). Therefore, total drug concentrations from the simulations were converted to unbound drug concentrations using reported fraction unbound for pregnant (fu 0.22) and nonpregnant (fu 0.17) populations (Zheng et al., 2020). Simulated AUC(0–24) in the various simulation scenarios was acceptable if within 50–150% of the simulated AUC(0–24) for 400‐mg twice‐daily raltegravir administration in a representative population of nonpregnant females (Burger, 2010).…”

“…Simulated AUC(0–24) in the various simulation scenarios was acceptable if within 50–150% of the simulated AUC(0–24) for 400‐mg twice‐daily raltegravir administration in a representative population of nonpregnant females (Burger, 2010). PK parameters from each population were also compared to a target unbound minimum effective concentration (8.33 nM) (Zheng et al., 2020).…”