Demystifying physiologically based pharmacokinetic modelling among non-modelers towards model-informed medicine use in under-served populations.

Physiologically based pharmacokinetic (PBPK) models represent computational technology to characterize drug behavior within the context of detailed human physiology. Today, PBPK is routinely used in drug development and regulatory approval to support decisions on how a medicine can be used under certain clinical conditions. As such, PBPK has the potential to enhance medicine use for populations that are often under-served globally in drug development and clinical care, namely pediatric patients, pregnant and lactating women.

Getting the dose right using physiologically-based pharmacokinetic modeling: dexamethasone to prevent post-extubation stridor in children as proof of concept.

Introduction: Critically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities.

[Adequate medication doses for pregnant women and their unborn children].

Most women use medication during pregnancy. The disposition of drugs may be altered due to changes in pregnant women's bodies. This may call for pregnancy-adjusted doses for certain medications.

Pragmatic physiologically-based pharmacokinetic modeling to support clinical implementation of optimized gentamicin dosing in term neonates and infants: proof-of-concept.

Introduction: Modeling and simulation can support dosing recommendations for clinical practice, but a simple framework is missing. In this proof-of-concept study, we aimed to develop neonatal and infant gentamicin dosing guidelines, supported by a pragmatic physiologically-based pharmacokinetic (PBPK) modeling approach and a decision framework for implementation.

Methods: An already existing PBPK model was verified with data of 87 adults, 485 children and 912 neonates, based on visual predictive checks and predicted-to-observed pharmacokinetic (PK) parameter ratios.

Physiologically-Based Pharmacokinetic Modeling for Drug Dosing in Pediatric Patients: A Tutorial for a Pragmatic Approach in Clinical Care.

It is well-accepted that off-label drug dosing recommendations for pediatric patients should be based on the best available evidence. However, the available traditional evidence is often low. To bridge this gap, physiologically-based pharmacokinetic (PBPK) modeling is a scientifically well-founded tool that can be used to enable model-informed dosing (MID) recommendations in children in clinical practice.

Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling.

Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine and emtricitabine compound models in Simcyp (v21) were verified in adult populations with and without CKD and in non-CKD paediatric populations.

Feasibility of a Pragmatic PBPK Modeling Approach: Towards Model-Informed Dosing in Pediatric Clinical Care.

Background And Objective: More than half of all drugs are still prescribed off-label to children. Pharmacokinetic (PK) data are needed to support off-label dosing, however for many drugs such data are either sparse or not representative. Physiologically-based pharmacokinetic (PBPK) models are increasingly used to study PK and guide dosing decisions.

Physiologically Based Pharmacokinetic (PBPK) Model-Informed Dosing Guidelines for Pediatric Clinical Care: A Pragmatic Approach for a Special Population.

Physiologically based pharmacokinetic (PBPK) modeling can be an attractive tool to increase the evidence base of pediatric drug dosing recommendations by making optimal use of existing pharmacokinetic (PK) data. A pragmatic approach of combining available compound models with a virtual pediatric physiology model can be a rational solution to predict PK and hence support dosing guidelines for children in real-life clinical care, when it can also be employed by individuals with little experience in PBPK modeling. This comes within reach as user-friendly PBPK modeling platforms exist and, for many drugs and populations, models are ready for use.

Off-Label, but on-Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy.

Many drugs are still prescribed off-label to the pediatric population. Although off-label drug use not supported by high level of evidence is potentially harmful, a comprehensive overview of the quality of the evidence pertaining off-label drug use in children is lacking. The Dutch Pediatric Formulary (DPF) provides best evidence-based dosing guidelines for drugs used in children.

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

Background And Objective: Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.

Methods: Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8).

Placental transfer and vascular effects of pharmaceutical drugs in the human placenta ex vivo: A review.

At least 80% of pregnant woman in Europe use at least one medication during their pregnancy. The majority of these drugs are prescribed off-label. A better understanding of drug transport and effects in the placenta can provide an improved pharmacological basis to rationalize drug and dose selection for prescription.

Best Evidence-Based Dosing Recommendations for Dexmedetomidine for Premedication and Procedural Sedation in Pediatrics: Outcome of a Risk-Benefit Analysis By the Dutch Pediatric Formulary.

Background: Dexmedetomidine is currently off-label for use in pediatric clinical care worldwide. Nevertheless, it is frequently prescribed to pediatric patients as premedication prior to induction of anesthesia or for procedural sedation. There is ample literature on the pharmacokinetics, efficacy and safety of dexmedetomidine in this vulnerable patient population, but there is a general lack of consensus on dosing.

The Effect of Pregnancy on the Pharmacokinetics of Total and Unbound Dolutegravir and Its Main Metabolite in Women Living With Human Immunodeficiency Virus.

Background: Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents.

Methods: Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.

Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling.

Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG).

Review article: direct-acting antivirals for the treatment of HCV during pregnancy and lactation - implications for maternal dosing, foetal exposure, and safety for mother and child.

Background: With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct-acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended.

Aim: To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation METHODS: A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation.

Placental disposition of the immunosuppressive drug tacrolimus in renal transplant recipients and in ex vivo perfused placental tissue.

Currently, tacrolimus is the most potent immunosuppressive agent for renal transplant recipients and is commonly prescribed during pregnancy. As data on placental exposure and transfer are limited, we studied tacrolimus placental handling in samples obtained from renal transplant recipients. We found transfer to venous umbilical cord blood, but particularly noted a strong placental accumulation.

Prediction of Fetal Darunavir Exposure by Integrating Human Ex-Vivo Placental Transfer and Physiologically Based Pharmacokinetic Modeling.

Background: Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship.

Objective: The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term.

Selection for growth rate or against back fat thickness in pigs is associated with changes in growth hormone axis plasma protein concentration and mRNA level.

Selection for increased growth rate or decreased back fat thickness results in concomitant changes in endocrine and metabolic status. Growth hormone (GH) changes in blood plasma concentration related to selection for growth rate and fat deposition were reported in pigs. The molecular mechanisms regulating selection-induced changes in GH plasma concentration remain largely unknown.