Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling

Abstract

Predicting drug pharmacokinetics in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal-fetal physiologically based pharmacokinetic models for two antiretroviral drugs, dolutegravir and raltegravir.

Conflict of interest statement

Conflict of Interest/Disclosure: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Dr. Andre Dallmann is an employee of Bayer AG, a company which is part of the Open Systems Pharmacology (OSP) member team and involved in OSP software development used in this study. The results from this study were presented in part at the American College of Clinical Pharmacology Annual Meeting, Washington DC, September 2018.

Figures

Figure 1:

Plasma concentration-time profiles of dolutegravir following oral administration once a day of 50 mg in fed state in non-pregnant subjects. Circles represent observed in vivo data from following studies: A: Ford et al [23]; B: group 1 of the study from Johnson et al [24]; C: group 2 of the study from Johnson et al [24]. D: Wang et al [25]; E: Song et al [20]; The solid line represents the simulated plasma concentration in different population and the shaded area is the predicted 5th – 95th percentile range. Semi-log scale figures are given as inset figure in the top right corners.

Figure 2:

Plasma concentration-time profiles of raltegravir following oral administration twice a day of 400mg with moderate fat meal in non-pregnant subjects. Circles represent observed in vivo data from following studies: A: Brainard et al [79]; B: group 1 of the study from Taburet et al [80]; C: group 2 of the study from Taburet et al[80]. The solid line represents the simulated plasma concentration in different population and the shaded area is the predicted 5th – 95th percentile range. Semi-log scale figures are given as inset figure in the top right corners.

Figure 3:

Plasma concentration-time profiles of dolutegravir following oral administration of 50 mg once a day in pregnant women. Semi-log scale figures are given as inset figure in the top right corners. Observed steady-state in vivo data were taken from in vivo study of IMPAACT P1026. [29] A: dolutegravir 50 mg once a day in pregnant women in 2nd trimester. Empty circles represent individual concentrations taken from in vivo study of IMPAACT P1026. [29] Black circles represent geometric mean concentrations taken from in vivo study of IMPAACT P1026. [29] The solid line represents the predicted mean concentration and the shaded area the predicted 5th – 95th percentile range; The dotted line represents the predicted mean concentration of non-pregnant population; B: dolutegravir 50 mg once a day in pregnant women in 3rd trimester. Empty circles represent individual concentrations taken from in vivo study of IMPAACT P1026. [29] The solid line represents the predicted mean concentration and the shaded area the predicted 5th – 95th percentile range; The dotted line represents the predicted mean concentration of non-pregnant population; C: dolutegravir 50 mg once a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the maternal plasma taken from in vivo study of IMPAACT P1026. [29]; the lines represent the predicted mean concentration in the maternal plasma using different partition coefficients calculated by different methods.; The solid line represents the QSAR method; The dotted line represents Poulin and Theil method; The dash-dot line represents the Rodgers and Rowland method; The dash line represents the PK-sim standard method. The shaded area represents the predicted 5th – 95th percentile range of the prediction by using QSAR method. D: dolutegravir 50 mg once a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the umbilical vein taken from in vivo study of IMPAACT P1026; [29] the lines represent the predicted mean concentration in the umbilical vein using different partition coefficients calculated by different methods: the solid line represents the QSR method; the dotted line represents Poulin and Theil method; the dash-dot line represents the Rodgers and Rowland method; and the dash line represents the PK-sim standard method. The shaded area presents the predicted 5th – 95th percentile range of the prediction by using QSAR method.

Figure 4:

Goodness-of-fit and residuals vs time plots of dolutegravir concentrations in non-pregnant subjects (A) and pregnant women (B). The solid line represents the line of identity and the dotted lines the 2-fold error range. A panel: Upper plot: GOF plot of geometric mean dolutegravir concentrations in non-pregnant populations. single dose study: blue circles indicate the study by Castellino et al. (20mg single dose) [17]; green circles indicate the study by Song et al. (50mg single dose) [19]; light blue circles indicate the high fat meal group in the study by Song et al. (50mg single dose) [21]; black circles indicate the study by Weller et al. (50mg single dose) [22]; bright green circles indicate the moderate fat meal group in the study by Song et al. (50mg single dose) [21]; grey circles indicate the low fat meal group in the study by Song et al. (50mg single dose) [21]. multiple dose study: dark blue circles indicate the study by Ford et al. (50mg once daily) [23]; orange circles indicate the group 1 in the study by Dooley et al. (50mg once daily)[18]; red circles indicate the group 2 in the study by Dooley et al. (50mg once daily)[18]; dark green circles indicate the group 1 in the study by Johnson et al. (50mg once daily) [24]; sky blue circles indicate the group 2 in the study by Johnson et al. (50mg once daily) [24]; light grey circles indicate the study by Song et al. (50mg once daily) [20]; yellow circles indicate the study by Wang et al. (50mg once daily)[25]. Lower plot: residuals vs time plot of dolutegravir in non-pregnant population. empty circles represent the geometric mean concentrations of non-pregnancy reference studies. B panel: Upper plot: GOF plot of dolutegravir in pregnant population. Blue circles indicate geometric mean concentrations in 2nd trimester and orange circles indicate geometric mean concentrations in 3rd trimester; Lower plot: residuals vs time plot of dolutegravir in pregnant population. Empty circles represent the individual concentrations in 2nd and 3rd trimesters.

Figure 5:

Plasma concentration-time profiles of raltegravir following oral administration of 400 mg twice a day in pregnant women in steady state. Semi-log scale figures are given as inset figure in the top right corners. Observed steady-state in vivo data were taken from in vivo study of IMPAACT P1026.[30] A: raltegravir 400 mg twice a day in pregnant women in 2nd trimester. Empty circles represent individual concentrations taken from in vivo study of IMPAACT P1026. [30] Black circles represent geometric mean concentrations taken from in vivo study of IMPAACT P1026. [30] The solid line represents the predicted mean concentration and the shaded area the predicted 5th – 95th percentile range; The dotted line represents the predicted mean concentration of non-pregnant population; B: raltegravir 400 mg twice a day in pregnant women in 3rd trimester. Empty circles represent individual concentrations taken from in vivo study of IMPAACT P1026. [30] The solid line represents the predicted mean concentration and the shaded area the predicted 5th – 95th percentile range; The dotted line represents the predicted mean concentration of non-pregnant population; C: raltegravir 400 mg twice a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the maternal plasma taken from in vivo study of IMPAACT P1026; [30] the lines represent the predicted mean concentrations in the maternal plasma using different partition coefficients calculated by different methods.; The solid line represents the QSAR method; The dotted line represents Poulin and Theil method; The dash-dot line represents the Rodgers and Rowland method; The dash line represents the PK-sim standard method. The shaded area represents the predicted 5th – 95th percentile range of the prediction by using QSAR method. D: raltegravir 400 mg twice a day in pregnant women with an average gestational age of 38 weeks at delivery. Empty circles represent individual concentration data in the umbilical vein taken from in vivo study of IMPAACT P1026; [30] the lines represent the predicted mean concentrations in the umbilical vein using different partition coefficients calculated by different methods: the solid line represents the QSAR method; the dotted line represents Poulin and Theil method; the dash-dot line represents the Rodgers and Rowland method; and the dash line represents the PK-sim standard method. The shaded area represents the predicted 5th – 95th percentile range of the prediction by using QSAR method.

Figure 6:

Goodness-of-fit and residuals vs time plots of raltegravir concentrations in non-pregnant subjects (A) and pregnant women (B). The solid line represents the line of identity and the dotted lines the 2-fold error range. A panel: Upper plot: GOF plot of geometric mean dolutegravir concentrations in non-pregnant populations. single dose study: bright green circles indicate the study by Iwamoto et al. (400mg single dose) [78]; dark green circles indicate the study by Rhee et al. (400mg single dose) [76]; grey circles indicate the study by Wenning et al. (400mg single dose) [77]. multiple dose study: blue circles indicate the fasted group in the study by Brainard et al. (400mg multiple dose) [79]; orange circles indicate the high fat group in the study by Brainard et al. (400mg multiple dose)[79]; dark blue circles indicate high moderate fat group in the study by Brainard et al. (400mg multiple dose) [79]; red circles indicate the low fat group in the study by Brainard et al. (400mg multiple dose) [79]; black circles indicate the study by Markowitz et al. (400mg multiple dose) [75]. sky blue circles indicate the group 1 in the study by Taburet et al. (400mg multiple dose) [80]; light blue circles indicate the group 2 in the study by Taburet et al. (400mg multiple dose) [80]; B panel: Upper plot: GOF plot of raltegravir in pregnant population. blue circles indicate geometric mean concentrations in women in the 2nd trimester; orange circles indicate geometric mean concentrations in women in the 3rd trimester. Lower plot: residuals vs time plot of raltegravir in pregnant population. Empty circles represent the individual concentrations in 2nd and 3rd trimesters.