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Objective- Although oxytocin is widely used in labor and childbirth, questions remain regarding the pharmacokinetics (PK), pharmacodynamics (PD) and dose of oxytocin in pregnant people as well as the potential effects on the fetus and newborn. The objective of the current study was to use published studies to investigate the PK/PD and dose of oxytocin in pregnancy, examine the placental transfer of oxytocin through the development of a physiologically-based PK (PBPK) model, and postulate whether the model predicts the effect(s) of oxytocin on fetuses and newborn infants. Methods- A literature review of articles related to oxytocin in the areas of PK/PD, placental transfer and its influence on newborns were reviewed and summarized. A PBPK model for oxytocin was developed to predict maternal-fetal transfer. Results- Previous studies have demonstrated a positive relationship between the plasma oxytocin concentration and uterine contractions during labor. An ex vivo study demonstrated maternal to fetal and fetal to maternal oxytocin transfer, but a clinical study investigating oxytocin concentrations in umbilical blood could not confirm these results. Previous studies have suggested that a high concentration of oxytocin is related to fetal bradycardia and possibly autism in the child. Conclusion- The current study developed a PBPK model to measure the placental transfer of oxytocin and its potential for adverse effects on the fetus and developing child. Further research is needed to determine oxytocin’s efficacy and safety in the maternal population and in their fetuses and developing children, and modeling techniques such as PBPK will contribute to that understanding.

Little is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal medications. Our objective was to develop and evaluate a novel, physiologically based pharmacokinetic modeling workflow for predicting perinatal and postnatal disposition of commonly used antiretroviral drugs administered prenatally to pregnant women living with human immunodeficiency virus. Using previously published, maternal-fetal, physiologically based pharmacokinetic models for emtricitabine, dolutegravir, and raltegravir built with PK-Sim/MoBi®, placental drug transfer was predicted in late pregnancy. The total drug amount in fetal compartments at term delivery was estimated and subsequently integrated as initial conditions in different tissues of a whole-body, neonatal, physiologically based pharmacokinetic model to predict drug concentrations in the neonatal elimination phase after birth. Neonatal elimination processes were parameterized according to published data. Model performance was assessed by clinical data. Neonatal physiologically based pharmacokinetic models generally captured the initial plasma concentrations after delivery but underestimated concentrations in the terminal phase. The mean percentage error for predicted plasma concentrations was − 71.5%, − 33.8%, and 76.7% for emtricitabine, dolutegravir, and raltegravir, respectively. A sensitivity analysis suggested that the activity of organic cation transporter 2 and uridine diphosphate glucuronosyltransferase 1A1 during the first postnatal days in term newborns is ~11% and ~30% of that in adults, respectively. These findings demonstrate the general feasibility of applying physiologically based pharmacokinetic models to predict washout concentrations of transplacentally acquired drugs in newborns. These models can increase the understanding of pharmacokinetics during the first postnatal days and allow the prediction of drug exposure in this vulnerable population.

Age-related changes in many parameters affecting drug absorption remain poorly characterized. The objective of this study was to apply physiologically based pharmacokinetic (PBPK) models in pediatric patients to investigate the absorption and pharmacokinetics of 4 drugs belonging to the Biopharmaceutics Classification System (BCS) class I administered as oral liquid formulations. Pediatric PBPK models built with PK-Sim/MoBi were used to predict the pharmacokinetics of acetaminophen, emtricitabine, theophylline, and zolpidem in different pediatric populations. The model performance for predicting drug absorption and pharmacokinetics was assessed by comparing the predicted absorption profile with the deconvoluted dose fraction absorbed over time and predicted with observed plasma concentration-time profiles. Sensitivity analyses were performed to analyze the effects of changes in relevant input parameters on the model output. Overall, most pharmacokinetic parameters were predicted within a 2-fold error range. The absorption profiles were generally reasonably predicted, but relatively large differences were observed for acetaminophen. Sensitivity analyses showed that the predicted absorption profile was most sensitive to changes in the gastric emptying time (GET) and the specific intestinal permeability. The drug's solubility played only a minor role. These findings confirm that gastric emptying time, more than intestinal permeability or solubility, is a key factor affecting BCS class I drug absorption in children. As gastric emptying time is prolonged in the fed state, a better understanding of the interplay between food intake and gastric emptying time in children is needed, especially in the very young in whom the (semi)fed condition is the prevailing prandial state, and hence prolonged gastric emptying time seems more plausible than the fasting state.

BACKGROUND: Predicting drug pharmacokinetics (PK) in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal-fetal physiologically-based PK (PBPK) models for two antiretroviral drugs (ARVs), dolutegravir (DTG) and raltegravir (RAL). METHODS: PBPK models were built with the Open Systems Pharmacology software suite (PK-Sim/MoBi). Different approaches to inform placental drug transfer were applied and compared. Model performance was evaluated using in vivo DTG and RAL maternal plasma concentrations during the 2(nd) and 3(rd) trimesters and umbilical vein concentrations at delivery. All clinical in vivo data were obtained from the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s study. RESULTS: The PBPK models successfully predicted plasma concentration-time profiles of DTG and RAL in the 2(nd) and 3(rd) trimesters and most predicted PK parameters fell within a 1.33-fold error range. Predicted umbilical vein concentrations of DTG were in reasonable agreement with in vivo data but were sensitive to changes in the placental partition coefficient and transplacental clearance. CONCLUSION: Maternal-fetal PBPK modeling reliably predicted maternal PK of DTG and RAL during pregnancy. For the fetal PK, data on the unbound fraction of highly protein-bound DTG has proven to be important to adequately capture changes in total clearance in silico. More research efforts, along with clinical data, are needed to verify the predictions of fetal PK of ARVs. Overall, the findings suggest that it may be possible to use PBPK models to assess the disposition of ARVs in pregnant women and their fetuses.

Pregnancy is associated with physiological changes that may impact drug pharmacokinetics (PK). The goals of this study were to build maternal-fetal physiologically based pharmacokinetic (PBPK) models for acyclovir and emtricitabine, 2 anti(retro)viral drugs with active renal net secretion, and to (1) evaluate the predicted maternal PK at different stages of pregnancy; (2) predict the changes in PK target parameters following the current dosing regimen of these drugs throughout pregnancy; (3) evaluate the predicted concentrations of these drugs in the umbilical vein at delivery; (4) compare the model performance for predicting maternal PK of emtricitabine in the third trimester with that of previously published PBPK models; and (5) compare different previously published approaches for estimating the placental permeability of these 2 drugs. Results showed that the pregnancy PBPK model for acyclovir predicted all maternal concentrations within a 2-fold error range, whereas the model for emtricitabine predicted 79% of the maternal concentrations values within that range. Extrapolation of these models to earlier stages of pregnancy indicated that the change in the median PK target parameters remained well above the target threshold. Concentrations of acyclovir and emtricitabine in the umbilical vein were overall adequately predicted. The comparison of different emtricitabine PBPK models suggested an overall similar predictive performance in the third trimester, but the comparison of different approaches for estimating placental drug permeability revealed large differences. These models can enhance the understanding of the PK behavior of renally excreted drugs, which may ultimately inform pharmacotherapeutic decision making in pregnant women and their fetuses.

The selection of appropriate endpoints in pediatric drug development trials is a critical aspect of trial design. Given the high pediatric trial failure rate, selecting optimal trial design elements, such as the primary efficacy endpoint, is essential to ensuring increased potential for trial success. The objectives of this study were to identify the primary efficacy endpoints measured in pediatric drug development trials submitted to the US Food and Drug Administration and to relate endpoint attributes to trial and label outcome. The analysis included pediatric pivotal efficacy studies submitted from September 2007 to July 2016 for which there was a corresponding adult trial for the same indication. Two hundred and thirty-four efficacy trials on 138 unique products studied in pediatric patients were assessed. The adult and pediatric endpoints were the same in 141 of the 234 trials (60.3%), and these trials succeeded in meeting their primary endpoint more often (122 of 141 [86.5%]) than when the adult and pediatric endpoints differed (57 of 93 [61.3%]; odds ratio, 4.03; 95%CI, 2.10-7.80). Trials that included both pediatric and adult patients succeeded more frequently than those trials that did not combine pediatric and adult patients (85 of 95 versus 94 of 139, respectively; odds ratio, 4.05; 95%CI, 1.94-9.31). No differences were observed in pediatric trial success between those using subjective and objective endpoints. Using the same endpoint in the pediatric trial as was measured in the corresponding adult trial and enrolling pediatric and adult patients in the same trial were attributes associated with trial success.

Clinical trial enrichment involves prospectively incorporating trial design elements that increase the probability of detecting a treatment effect. The use of enrichment strategies in pediatric drug development has not been systematically assessed. We analyzed the use of enrichment strategies in pediatric trials submitted to the US Food and Drug Administration from 2012–2016. In all, 112 efficacy studies associated with 76 drug development programs were assessed and their overall success rates were 78% and 75%, respectively. Eighty-eight trials (76.8%) employed at least one enrichment strategy; of these, 66.3% employed multiple enrichment strategies. The highest trial success rates were achieved when all three enrichment strategies (practical, predictive, and prognostic) were used together within a single trial (87.5%), while the lowest success rate was observed when no enrichment strategy was used (65.4%). The use of enrichment strategies in pediatric trials was found to be associated with trial and program success in our analysis.

The 21(st) Century Cures Act was passed in December, 2016, and included a number of provisions to facilitate drug approval. Considerable discussion was generated related to some aspects of the Act, especially to the use of surrogate endpoints (SEs) as a means to shorten the time required prior to receiving US Food and Drug Administration (FDA) approval.(1) The objective of this analysis was to identify the use and outcomes of SEs and clinical endpoints in pediatric drug development trials.

Tremendous efforts have been directed to investigate the ontogeny of drug transporters in the fetus, neonates, infants, and children based on their importance for understanding drug pharmacokinetics. During development (i.e. in the fetus and newborn infant), there is a special interest in transporters expressed in the placenta which modulate placental drug transfer. Many of these transporters can decrease or increase drug concentrations in the fetus and at birth stressing the relevance of elucidating the expression in the placenta and potential gestational age-dependent changes therein. Hence, the main objective of this review was to summarize the current knowledge about expression and ontogeny of transporters in the human placenta in healthy pregnant women. Additionally, various in vitro, ex vivo and in silico models that can be used to investigate placental drug transfer, namely placental cancer cell lines, ex vivo cotyledon perfusion experiments and physiologically based pharmacokinetic (PBPK) models, are discussed together with their advantages and shortcomings. A particular focus was placed on PBPK models because these models can integrate different types of information, such as expression data, ontogeny information and observations obtained from the ex vivo cotyledon perfusion experiment. Such a mechanistic modeling framework may leverage the available information and ultimately help to improve the knowledge about the adequacy and safety of pharmacotherapy in pregnant women and their fetus.

The experience with the use of monoclonal antibodies and Fc‐fusion proteins (mAb/Fc) in the pediatric population is limited. The objective of this study is to review those factors impacting the clinical efficacy and product safety of mAb/Fc products in pediatric patients during drug development. We reviewed the list of biologic products in the US Food and Drug Administration's Purple Book as of March 2018 with a focus on mAb/Fc products that are indicated for use in both adults and pediatric patients. Of 68 mAb/Fc products in the Purple Book (excluding biosimilars), 20 products have approved indications in both adults and children. Thirteen products had concurrent approval for both adult and pediatric populations. The sample size of pediatric studies generally ranged from approximately 2% to 70% of the sample size of adult studies with the same indication. In general, pediatric dosing regimens were found to be more based on body weight and weight tiered than the regimens for adults. Modeling and simulation techniques comprised mainly population pharmacokinetic and pharmacodynamic models. A review of the immunogenicity incidence did not reveal any notable difference in the 5 products having data on both pediatric and adult patients. In conclusion, most of the mAb/Fc products have a different weight‐based dosing regimen for pediatric patients versus adults. An understanding of the comparative experience in drug development for mAb/Fc products between adult and pediatric patients coupled with the application of advanced modeling and simulation methods should assist future development of new mAb/Fc products for pediatric patients.

BackgroundPhysiologic changes associated with pregnancy may have a large impact on drug disposition. The goal of this study was to build PBPK maternal-fetal models to predict the fetal exposure to antiviral drugs including emtricitabine and acyclovir.MethodsPBPK models were built in the Open Systems Pharmacology Software Suite version 7.3 (www.open-systems-pharmacology.org). The maternal-fetal PBPK model structure was developed in MoBi and exported to PK-Sim for population simulations. Placental transfer was parameterized based on data from ex vivo cotyledon perfusion experiments. The predictive performance of the PBPK models was evaluated via comparison with in vivo data. The pregnancy data for those drugs were from in vivo maternal and fetal blood samples taken at delivery.ResultsIn the acyclovir ex vivo experimental data simulation, the fitted was 0.056 L/h (95% confidence interval: 0.043 - 0.069 L/h) and the fitted was 0.49 (95% confidence interval: 0.39 - 0.59). The predicted ratio between acyclovir in vivo concentrations in the umbilical vein plasma and the maternal plasma ranged from 0.37 - 0.77, whereas the observed ratios were slightly higher and ranged from 0.61 - 1.1.1 The previously published, and CLpl (1.49 1/h) parameters2 were applied to the emtricitabine maternal-fetal PBPK model, and the emtricitabine concentrations in the umbilical cord were adequately predicted.ConclusionThese results increase the confidence in applying PBPK models to predict maternal and fetal drug exposure. Improved maternal-fetal PBPK models may streamline and accelerate the performance of pharmacokinetic and safety studies for drugs in pregnant women.ReferencesFrenkel LM, et al. Pharmacokinetics of acyclovir in the term human pregnancy and neonate. Am J Obstet Gynecol 1991;164:569–76.De Sousa Mendes M, et al. Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models. Brit J Clin Pharmacol 2016;81:646–57.Disclosure(s)The opinions expressed in this article are those of the authors and should not be interpreted as the position of the U.S. Food and Drug Administration or of the National Institutes of Health. The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective To examine the differences in the adverse drug reaction (ADR) profile of antipsychotic and antidepressant agents between pediatric and adult patients in studies submitted to the Food and Drug Administration (FDA) during the drug development process. Study design Clinical trials in adult and pediatric patients were conducted by sponsors as part of the drug development programs for antipsychotic and antidepressant agents, and ADR information was collected as part of those trials and submitted to the FDA. Data collection was conducted by reviewing publicly available FDA-authored reviews and FDA-approved product labels for 10 drugs with an antipsychotic or an antidepressant indication from 2007 to 2017. Results There were 308 drug and ADR combinations for the 10 drugs and drug combinations with 113 (36.7%) having a significantly different incidence in pediatric patients compared with adults. Sixty-eight (60.2%) of these ADRs had a significantly higher incidence in pediatric patients than in adults. Sedation was higher in 6 of the 10 drugs and drug combinations with risk differences ranging from 9.6 to 36.6%. Conclusions This analysis indicates that there were significant differences between the pediatric and adult safety profiles of antipsychotic and antidepressant drugs. Sedation was the major ADR associated with the use of atypical antipsychotic drugs in pediatric patients. Clinicians caring for children should consider the ADR profile when prescribing antipsychotics and antidepressants in pediatric patients.

Pharmacogenetics holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic effect while minimizing adverse effects. As more pharmacogenetic information accumulates, the prospect of reducing or discontinuing the intensive therapeutic drug monitoring of immunosuppressants looks attractive. However, the long process of developing useful clinical information from basic information on the genes of interest is at a very early stage, and our present information does not supercede pharmacokinetic or blood concentration monitoring of immunosuppressants. The most extensive blood concentration/dose information available is on tacrolimus and its dosing related to CYP3A5 and ABCB1 gene polymorphisms. Although CYP3A5 genotype is definitely associated with tacrolimus dosing, the only recommendation presently published is for an arbitrary doubling of the starting tacrolimus dose in CYP3A5 expressors. For cyclosporine, sirolimus, and corticosteroids, the presently available pharmacogenetic information does not permit pharmacokinetic predictions. The pharmacodynamics of immunosuppressants, as evidenced by effects on acute rejection or adverse drug effects, have considerably more potential for prediction by pharmacogenetic models. Drug-resistant rejection, nephrotoxicity, steroid resistance and osteonecrosis, and even patient survival may ultimately be predicted by models incorporating multiple gene polymorphisms and other critical patient information. At this point, treatment algorithms can be developed that will allow us to individualize a transplant patient's immunosuppressive therapy.