maternal pbpk model  (Simcyp)

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Structure of the full maternal–fetal physiologically based pharmacokinetic (PBPK) model. Since the sublingual route of administration is not available in Simcyp, sublingual absorption is mimicked by using the first-order inhalation model. In this model, the proportion of the dose inhaled equals the proportion sublingually absorbed, where the remaining fraction is swallowed.

Article Snippet: In the current work, this model was expanded to a maternal–fetal PBPK model within the Simcyp Simulator (v21.0; Simcyp Limited, Sheffield, UK).

Techniques:

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Maternal–fetal physiologically based pharmacokinetic (PBPK) model-based predicted and observed maternal buprenorphine plasma concentrations during the ( a ) second trimester, ( b ) third trimester, and ( c ) postpartum period. Pregnant subjects received 8 mg buprenorphine twice daily as sublingual tablets. Blue solid line and shaded area represent the mean concentration–time profile and 5th to 95th percentile range of the virtual population (n = 100), respectively. Open blue circles represent concentration–time data reported by Zhang et al. [ , ].

Article Snippet: In the current work, this model was expanded to a maternal–fetal PBPK model within the Simcyp Simulator (v21.0; Simcyp Limited, Sheffield, UK).

Techniques: Clinical Proteomics, Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Individual maternal–fetal physiologically based pharmacokinetic (PBPK) model-based predicted and observed maternal and fetal buprenorphine plasma concentrations at delivery. Pregnant women received between 1 and 28 mg buprenorphine daily as sublingual tablets, and individual doses are shown in the lower left corner of each figure subsection. Closed red circles represent observed buprenorphine concentrations in maternal and umbilical cord blood reported by ( a – j ) Bartu et al. and ( k – u ) Wiegand et al. for a total of 21 mother–fetus dyads. Simulated concentration–time profiles with 5th to 95th population percentile ranges (n = 100 mother–fetus dyads) were created either under the presumption that the proportion of the administered dose sublingually absorbed by the expectant mother equals 0.754 × (38.1 − 19.7 × log (Dose)), which is the default absorption extent in the maternal–fetal PBPK model for sublingual tablets (shown in blue and green for maternal and fetal concentrations, respectively), or with the degree of maternal sublingual absorption optimized (across a range of 0.1–99.9%) post hoc to capture the reported maternal concentration–time point as accurately as possible (shown in grayscale). The final degrees of sublingual absorption are shown in the upper right corner of each figure subsection (written in blue and gray to reflect the model’s default and optimized value, respectively).

Article Snippet: In the current work, this model was expanded to a maternal–fetal PBPK model within the Simcyp Simulator (v21.0; Simcyp Limited, Sheffield, UK).

Techniques: Clinical Proteomics, Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Mean maternal–fetal physiologically based pharmacokinetic (PBPK) model-based predicted maternal (aged 18–45 years) and umbilical cord blood concentrations of buprenorphine early in the second trimester, at the end of the second trimester, and at the end of the third trimester (15, 27, and 40 weeks’ gestational age, respectively) following a standard 16 mg buprenorphine dose as sublingual tablet. The concentration–time curves are juxtaposed with the expected profile of a nonpregnant woman under the same conditions (created using the previously developed base model) .

Article Snippet: In the current work, this model was expanded to a maternal–fetal PBPK model within the Simcyp Simulator (v21.0; Simcyp Limited, Sheffield, UK).

Techniques: Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Goodness-of-fit plots for the maternal–fetal physiologically based pharmacokinetic (PBPK) model for buprenorphine, showing ( a , b ) predicted vs. observed maternal and ( c , d ) fetal concentrations following administration of buprenorphine sublingual tablets. Coefficients of determination ( R 2 ) and associated p values are shown in the lower right corner of each figure subset. Concentrations were predicted either ( a , c ) under the presumption that the proportion of the administered dose sublingually absorbed by the expectant mother equals 0.754 × (38.1 − 19.7 × log (Dose)), which is the default absorption extent in the maternal–fetal PBPK model for sublingual tablets, or ( b , d ) with the degree of maternal sublingual absorption optimized (across a range of 0.1–99.9%) post hoc to capture the reported maternal concentration–time point as accurately as possible. Blue circles (●) and green diamonds (◆) represent maternal and fetal concentration–time data reported by Bartu et al. and Wiegand et al. , respectively. Dotted lines represent the 2-fold prediction error range. Curved dashed lines represent locally estimated scatterplot smoothing (LOESS) curves.

Article Snippet: In the current work, this model was expanded to a maternal–fetal PBPK model within the Simcyp Simulator (v21.0; Simcyp Limited, Sheffield, UK).

Techniques: Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Goodness-of-fit plots for the maternal–fetal physiologically based pharmacokinetic (PBPK) model for buprenorphine, showing ( a , b ) dose vs. the ratio between maternal predicted and observed concentrations (concentration fold-difference) and ( c , d ) dose vs. fetal concentration fold-differences. Concentrations were predicted either ( a , c ) under the presumption that the proportion of the administered dose sublingually absorbed by the expectant mother equals 0.754 × (38.1 − 19.7 × log (Dose)), which is the default absorption extent in the maternal–fetal PBPK model for sublingual tablets, or ( b , d ) with the degree of maternal sublingual absorption optimized (across a range of 0.1–99.9%) post hoc to capture the reported maternal concentration–time point as accurately as possible. Blue circles (●) and green diamonds (◆) represent concentration fold-differences obtained from maternal and fetal concentration–time data reported by Bartu et al. and Wiegand et al. , respectively. Dotted lines represent the 2-fold prediction error range. Curved dashed lines represent locally estimated scatterplot smoothing (LOESS) curves.

Article Snippet: In the current work, this model was expanded to a maternal–fetal PBPK model within the Simcyp Simulator (v21.0; Simcyp Limited, Sheffield, UK).

Techniques: Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Maternal–fetal physiologically based pharmacokinetic (PBPK) model-based predicted and observed maternal buprenorphine plasma concentrations during the ( a ) second trimester, ( b ) third trimester, and ( c ) postpartum period. Pregnant subjects received 8 mg buprenorphine twice daily as sublingual tablets. Blue solid line and shaded area represent the mean concentration–time profile and 5th to 95th percentile range of the virtual population (n = 100), respectively. Open blue circles represent concentration–time data reported by Zhang et al. [ , ].

Article Snippet: To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0).

Techniques: Clinical Proteomics, Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Individual maternal–fetal physiologically based pharmacokinetic (PBPK) model-based predicted and observed maternal and fetal buprenorphine plasma concentrations at delivery. Pregnant women received between 1 and 28 mg buprenorphine daily as sublingual tablets, and individual doses are shown in the lower left corner of each figure subsection. Closed red circles represent observed buprenorphine concentrations in maternal and umbilical cord blood reported by ( a – j ) Bartu et al. and ( k – u ) Wiegand et al. for a total of 21 mother–fetus dyads. Simulated concentration–time profiles with 5th to 95th population percentile ranges (n = 100 mother–fetus dyads) were created either under the presumption that the proportion of the administered dose sublingually absorbed by the expectant mother equals 0.754 × (38.1 − 19.7 × log (Dose)), which is the default absorption extent in the maternal–fetal PBPK model for sublingual tablets (shown in blue and green for maternal and fetal concentrations, respectively), or with the degree of maternal sublingual absorption optimized (across a range of 0.1–99.9%) post hoc to capture the reported maternal concentration–time point as accurately as possible (shown in grayscale). The final degrees of sublingual absorption are shown in the upper right corner of each figure subsection (written in blue and gray to reflect the model’s default and optimized value, respectively).

Article Snippet: To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0).

Techniques: Clinical Proteomics, Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Mean maternal–fetal physiologically based pharmacokinetic (PBPK) model-based predicted maternal (aged 18–45 years) and umbilical cord blood concentrations of buprenorphine early in the second trimester, at the end of the second trimester, and at the end of the third trimester (15, 27, and 40 weeks’ gestational age, respectively) following a standard 16 mg buprenorphine dose as sublingual tablet. The concentration–time curves are juxtaposed with the expected profile of a nonpregnant woman under the same conditions (created using the previously developed base model) .

Article Snippet: To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0).

Techniques: Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Goodness-of-fit plots for the maternal–fetal physiologically based pharmacokinetic (PBPK) model for buprenorphine, showing ( a , b ) predicted vs. observed maternal and ( c , d ) fetal concentrations following administration of buprenorphine sublingual tablets. Coefficients of determination ( R 2 ) and associated p values are shown in the lower right corner of each figure subset. Concentrations were predicted either ( a , c ) under the presumption that the proportion of the administered dose sublingually absorbed by the expectant mother equals 0.754 × (38.1 − 19.7 × log (Dose)), which is the default absorption extent in the maternal–fetal PBPK model for sublingual tablets, or ( b , d ) with the degree of maternal sublingual absorption optimized (across a range of 0.1–99.9%) post hoc to capture the reported maternal concentration–time point as accurately as possible. Blue circles (●) and green diamonds (◆) represent maternal and fetal concentration–time data reported by Bartu et al. and Wiegand et al. , respectively. Dotted lines represent the 2-fold prediction error range. Curved dashed lines represent locally estimated scatterplot smoothing (LOESS) curves.

Article Snippet: To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0).

Techniques: Concentration Assay

Journal: Pharmaceutics

Article Title: Forecasting Fetal Buprenorphine Exposure through Maternal–Fetal Physiologically Based Pharmacokinetic Modeling

doi: 10.3390/pharmaceutics16030375

Figure Lengend Snippet: Goodness-of-fit plots for the maternal–fetal physiologically based pharmacokinetic (PBPK) model for buprenorphine, showing ( a , b ) dose vs. the ratio between maternal predicted and observed concentrations (concentration fold-difference) and ( c , d ) dose vs. fetal concentration fold-differences. Concentrations were predicted either ( a , c ) under the presumption that the proportion of the administered dose sublingually absorbed by the expectant mother equals 0.754 × (38.1 − 19.7 × log (Dose)), which is the default absorption extent in the maternal–fetal PBPK model for sublingual tablets, or ( b , d ) with the degree of maternal sublingual absorption optimized (across a range of 0.1–99.9%) post hoc to capture the reported maternal concentration–time point as accurately as possible. Blue circles (●) and green diamonds (◆) represent concentration fold-differences obtained from maternal and fetal concentration–time data reported by Bartu et al. and Wiegand et al. , respectively. Dotted lines represent the 2-fold prediction error range. Curved dashed lines represent locally estimated scatterplot smoothing (LOESS) curves.

Article Snippet: To allow the conceptualization of fetal buprenorphine exposure, a maternal–fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0).

Techniques: Concentration Assay

Journal: Clinical Pharmacokinetics

Article Title: Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

doi: 10.1007/s40262-022-01127-0

Figure Lengend Snippet: Schematic overview of the tested mechanistic placenta model structures to estimate intrinsic placental transfer parameters of doravirine based on ex vivo perfusion data in closed–closed configuration. A simple diffusion transfer model; ( B ) diffusion model combined with p-glycoprotein-mediated active transport over the maternal-facing barrier. CL pdf clearance between fetal part of the placenta and the placental barrier, CL pdm clearance between maternal part of the placenta and the placental barrier, CL P-GP p-glycoprotein-mediated active transport, FR fetal reservoir, FP fetal part of the placenta, PB barrier of the placenta, MP maternal part of the placenta, MR maternal reservoir

Article Snippet: To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy.

Techniques: Ex Vivo, Diffusion-based Assay

Journal: Clinical Pharmacokinetics

Article Title: Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

doi: 10.1007/s40262-022-01127-0

Figure Lengend Snippet: Placental transfer of doravirine determined with ex vivo human cotyledon perfusion experiments in closed–closed configuration ( n = 4 each). Data are shown as mean ± standard deviation

Article Snippet: To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy.

Techniques: Ex Vivo, Standard Deviation

Journal: Clinical Pharmacokinetics

Article Title: Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

doi: 10.1007/s40262-022-01127-0

Figure Lengend Snippet: Predicted mean doravirine total plasma concentration at steady state after treatment with A , B doravirine 100 mg QD or C , D 100 mg BID using the pregnancy physiologically based pharmacokinetic model ( n = 100 subjects). The in vivo target of 0.23 mg/L was derived from in vivo exposure–response analysis . BID twice daily, QD once daily, w weeks

Article Snippet: To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy.

Techniques: Clinical Proteomics, Concentration Assay, In Vivo, Derivative Assay

Journal: Clinical Pharmacokinetics

Article Title: Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

doi: 10.1007/s40262-022-01127-0

Figure Lengend Snippet: Sensitivity analysis of the estimated placental parameters using the pregnancy physiologically based pharmacokinetic model ( n = 100 subjects). Sensitivity of CL pdm input on the doravirine A maternal plasma concentration and B fetal venous blood concentration. Sensitivity of CL pdf input on the doravirine, C maternal plasma concentration and D fetal venous blood concentration. The 2.5th and 97.5th percentile of the typical CL pdf and CL pdm are estimated with the mechanistic placenta model. Sensitivity of the FUp impute on the doravirine, E maternal plasma concentration and F fetal venous blood concentration. Sensitivity of the experimental placenta perfusion configuration on the doravirine, G maternal plasma concentration and H fetal venous blood concentration. CL pdf clearance between fetal part of the placenta and the placental barrier, CL pdm clearance between maternal part of the placenta and the placental barrier, FU P fraction unbound in the placental barrier

Article Snippet: To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy.

Techniques: Clinical Proteomics, Concentration Assay

Journal: Clinical Pharmacokinetics

Article Title: Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments

doi: 10.1007/s40262-022-01127-0

Figure Lengend Snippet:

Article Snippet: To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy.

Techniques: Derivative Assay

Journal: CPT: Pharmacometrics & Systems Pharmacology

Article Title: Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

doi: 10.1002/psp4.12274

Figure Lengend Snippet: The best practice approach to physiologically based pharmacokinetic (PBPK) model development and application in pregnant women. ADME, absorption, distribution, metabolism, and excretion; DDI, drug‐to‐drug interaction; PK, pharmacokinetic.

Article Snippet: We believe that PBPK feto‐maternal models will be highly desirable to support fetal exposure assessment.

Techniques:

Journal: CPT: Pharmacometrics & Systems Pharmacology

Article Title: Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

doi: 10.1002/psp4.12274

Figure Lengend Snippet: A mechanistic framework for applying a physiologically based pharmacokinetic (PBPK) feto‐maternal model for predicting human fetotoxicity risk from preclinical species described in the following steps. (1) Perform fetotoxicity studies in preclinical animals and establish exposure‐toxicity relationships. (2) Construct a coupled feto‐maternal PBPK model that accounts for gestational age related changes in the physiology and placenta to describe the relationship between fetal tissue and systemic concentrations together with maternal systemic concentration. (3) Use the constructed PBPK model to find the toxic doses that can cause feto‐toxic drug levels after accounting for species differences in physiological/biochemical parameters (number of placentas, weight, blood flow, transporters, and enzyme expression). (4) The human PBPK model can also be refined if in vitro and/or in vivo human data are available. (5) The human PBPK model that predicts the systemic exposure in fetus and mother can be used to predict the local fetal tissue concentration. (6) Fetal local tissue concentration can be linked to the predicted toxicity after accounting for any potential species differences in the toxicodynamic model. This figure is adapted from the publication by Abduljalil et al . Conc, concentration; IC50, half‐maximal inhibitory concentration.

Article Snippet: We believe that PBPK feto‐maternal models will be highly desirable to support fetal exposure assessment.

Techniques: Construct, Concentration Assay, Expressing, In Vitro, In Vivo