Journal: Pharmaceutics

Article Title: A Physiologically-Based Pharmacokinetic Simulation to Evaluate Approaches to Mitigate Efavirenz-Induced Decrease in Levonorgestrel Exposure with a Contraceptive Implant

doi: 10.3390/pharmaceutics16081050

Figure Lengend Snippet: Values of levonorgestrel physicochemical and PK properties used in the PBPK model.

Article Snippet: Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction.

Techniques:

Journal: Pharmaceutics

Article Title: A Physiologically-Based Pharmacokinetic Simulation to Evaluate Approaches to Mitigate Efavirenz-Induced Decrease in Levonorgestrel Exposure with a Contraceptive Implant

doi: 10.3390/pharmaceutics16081050

Figure Lengend Snippet: Population ( left plot ) and study-specific ( right plot ) predicted levonorgestrel plasma concentration, based on a MEM, versus observed mean concentration from one two-oral dose study without efavirenz (□) and with efavirenz (■) , two single-oral dose studies without efavirenz (+ and ×) [ , ], one single-IV dose study without efavirenz (∆) , and one implant study without efavirenz (○) and with efavirenz (●) . ‘Population’ predictions ( left plot ) use point estimates of parameters for the model, whereas ‘Study-specific’ predictions ( right plot ) consider inter-study variability (i.e., use post hoc parameters). The inset plots enlarge the lower left quadrant for ease of viewing.

Article Snippet: Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction.

Techniques: Clinical Proteomics, Concentration Assay

Journal: Pharmaceutics

Article Title: A Physiologically-Based Pharmacokinetic Simulation to Evaluate Approaches to Mitigate Efavirenz-Induced Decrease in Levonorgestrel Exposure with a Contraceptive Implant

doi: 10.3390/pharmaceutics16081050

Figure Lengend Snippet: Simulated median plasma concentrations 1 month to 5 years after levonorgestrel (LNG) implant placement administered alone or with daily oral efavirenz (EFV) and superimposed mean published data for 150 mg LNG alone or with 600 mg EFV [ , ].

Article Snippet: Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction.

Techniques: Clinical Proteomics

Journal: Pharmaceutics

Article Title: A Physiologically-Based Pharmacokinetic Simulation to Evaluate Approaches to Mitigate Efavirenz-Induced Decrease in Levonorgestrel Exposure with a Contraceptive Implant

doi: 10.3390/pharmaceutics16081050

Figure Lengend Snippet: Simulated median total ( left ) and unbound ( right ) one-year levonorgestrel (LNG) plasma concentration as a function of percent unbound to plasma proteins ( x -axis), implant dose (150 mg or 300 mg) and presence of efavirenz (EFV) 600 mg. Reference concentrations are those associated with the typical percent unbound (1.3%) for LNG 150 mg in the absence of EFV.

Article Snippet: Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction.

Techniques: Clinical Proteomics, Concentration Assay

Journal: Pharmaceutics

Article Title: A Physiologically-Based Pharmacokinetic Simulation to Evaluate Approaches to Mitigate Efavirenz-Induced Decrease in Levonorgestrel Exposure with a Contraceptive Implant

doi: 10.3390/pharmaceutics16081050

Figure Lengend Snippet: Simulated median total (left-axis) and unbound (right-axis) levonorgestrel (LNG) plasma concentration at one-year post-implant placement as a function of LNG dose and efavirenz (EFV) exposure. ‘Fold increase’ refers to varying magnitudes of EFV exposure (average plasma concentrations) associated with 600 mg for putative differing genetic subgroups relative to the general (Reference) population.

Article Snippet: Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp ® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction.

Techniques: Clinical Proteomics, Concentration Assay

Journal: Toxins

Article Title: Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

doi: 10.3390/toxins16060259

Figure Lengend Snippet: Predicted geometric mean values of pharmacokinetic parameters of AFB1 (+90% confidence interval (CI)) obtained using physiologically based pharmacokinetic modeling in a Black South African (BSA) population (in orange) and a North European Caucasian (NEC) population (in blue) exposed to (i) 30 ng aflatoxin B1 (AFB1) alone and co-exposure to both 30 ng of AFB1 and 600 mg of efavirenz (EFV) during 24 h.

Article Snippet: Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ ].

Techniques:

Journal: Toxins

Article Title: Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

doi: 10.3390/toxins16060259

Figure Lengend Snippet: Predicted geometric mean values of pharmacokinetic parameters of AFB1 (+90% confidence interval (CI)) obtained using physiologically based pharmacokinetic modelling in a Black South African (BSA) population (in orange) and a North European Caucasian (NEC) population (in blue) exposed to (ii) 30-day dosing of 30 ng AFB1 alone and co-exposure to 30 ng of AFB1 and 600 mg EFV during 30 days.

Article Snippet: Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ ].

Techniques:

Journal: Toxins

Article Title: Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

doi: 10.3390/toxins16060259

Figure Lengend Snippet: Predicted geometric mean values of pharmacokinetic parameters of AFB1 (+90% confidence interval (CI)) obtained using physiologically based pharmacokinetic modelling in a Black South African (BSA) population (in orange) and a North European Caucasian (NEC) population (in blue) exposed to (iii) a single AFB1 exposure alone on day 30 and daily administration of 600 mg of EFV for 30 days and single exposure to 30 ng AFB1 on the day.

Article Snippet: Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ ].

Techniques:

Journal: Toxins

Article Title: Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

doi: 10.3390/toxins16060259

Figure Lengend Snippet: Predicted geometric mean values of pharmacokinetic parameters of AFB1 (+90% confidence interval (CI)) obtained using physiologically based pharmacokinetic modelling in a Black South African (BSA) population (in orange) and a North European Caucasian (NEC) population (in blue) exposed to (iv) 30 ng of AFB1 alone and co-exposure to 30 ng of AFB1 and 600 mg of EFV, 300 mg of lamivudine (LAM) and 300 mg of tenofovir (TFV) on a daily basis over 30 consecutive days.

Article Snippet: Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ ].

Techniques:

Journal: Toxins

Article Title: Exploring the Impact of Efavirenz on Aflatoxin B1 Metabolism: Insights from a Physiologically Based Pharmacokinetic Model and a Human Liver Microsome Study

doi: 10.3390/toxins16060259

Figure Lengend Snippet: Overview of the different dosing schemes used in physiologically based pharmacokinetic (PBPK) modelling in a Black South African (BSA) population and a North European Caucasian (NEC) population exposed to four different scenarios being ( i ) a single dose of 30 ng aflatoxin B1 (AFB1) alone or co-administration of a single dose of 30 ng AFB1 and 600 mg efavirenz (EFV); ( ii ) 30-day dosing of 30 ng AFB1 alone or co-administration of 30 ng AFB1 and 600 mg EFV during 30 days; ( iii ) no EFV and a single dose of 30 ng AFB1 alone on day 30 or daily administration of 600 mg of EFV for 30 days and a single dose of 30 ng AFB1 on day 30; and ( iv ) 30-day dosing of 30 ng AFB1 alone or co-administration of 30 ng AFB1 and 600 mg of EFV, 300 mg of lamivudine (LAM) and 300 mg of tenofovir (TFV) on a daily basis over 30 consecutive days. The number of subjects in the simulated population is shown with #; y/o is an abbreviation for years old.

Article Snippet: Since human in vivo trials with AFB1 are not allowed due to ethical constraints, a physiologically based pharmacokinetic (PBPK) model was built for AFB1 using SimCYP ( SimCYP Ltd., a Certara company, Sheffield, UK, version 21) [ ].

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: 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