Pharmacokinetic Simulation Model Research Articles

P684 Using a pharmacokinetic simulation model to determine the optimal infliximab intensification strategy to address loss of response in inflammatory bowel disease

Abstract Background The optimal dose intensification strategy to address loss of response associated with low infliximab levels remains uncertain. Favorable associations between higher infliximab levels and objective endpoints imply that post-intensification trough and treatment targets may have utility. This simulation study aimed to identify intensification strategies capable of achieving post-intensification trough thresholds associated with aspirational treatment targets in Crohn’s disease (CD) and ulcerative colitis (UC). Methods A previously published infliximab pharmacokinetic model, applied to 200 simulated patients, identified those with subtherapeutic(<3.00mg/L) trough levels after 30-weeks of standard dosing, and subsequently applied ten dose intensification strategies (Figure 1) over a further 32 weeks. The proportion of simulations achieving infliximab trough thresholds associated with endoscopic remission (CD >9.7mg/L; UC >7.5mg/L) was the primary outcome, with clinical improvement (CD >7.0mg/L; UC >3.7mg/L) and perianal fistula healing (CD >10.1mg/L) representing secondary outcomes. Outcomes were stratified by intensity of dose intensification, with five deemed intensive (>10mg/kg 8-weekly). The impact of pre-intensification antibodies to infliximab (ATI) on post-intensification trough levels was also evaluated. Results The median pre-intensification infliximab trough level was 0.91mg/L (IQR 1.31). Intensive intensification strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (UC: 34.76 v 10.56%, CD: 25.80 v 4.92%), clinical improvement (UC: 61.40 v 34.52%, CD: 39.58 v 12.12%) and perianal fistula healing (24.70 v 4.50%, all p<0.01) than standard intensification strategies (Figure 2). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest trough levels (all p<0.01). Patients simulated to have ATI prior to dose intensification had lower median infliximab trough levels at weeks 30/32 (3.38 mg/L, IQR 5.52 mg/L) compared to those without ATI (3.89 mg/L IQR 6.14 mg/L) across all dose intensification strategies (p=0.015). Conclusion This simulation-based analysis highlights the potential of using post-intensification trough level targets to guide dosing strategy and intensity. Combined high-dose, interval-shortened strategies appear to achieve higher infliximab levels, which may be important in the pursuit of stringent endpoints such as endoscopic remission and fistula healing. These findings require validation across real-world cohorts.

Viral dissemination and immune activation modulate antiretroviral drug levels in lymph nodes of SIV-infected rhesus macaques.

To understand the relationship between immunovirological factors and antiretroviral (ARV) drug levels in lymph nodes (LN) in HIV therapy, we analyzed drug levels in twenty-one SIV-infected rhesus macaques subcutaneously treated with daily tenofovir (TFV) and emtricitabine (FTC) for three months. The intracellular active drug-metabolite (IADM) levels (TFV-dp and FTC-tp) in lymph node mononuclear cells (LNMC) were significantly lower than in peripheral blood mononuclear cells (PBMC) (P≤0.005). Between Month 1 and Month 3, IADM levels increased in both LNMC (P≤0.001) and PBMC (P≤0.01), with a steeper increase in LNMC (P≤0.01). The viral dissemination in plasma, LN, and rectal tissue at ART initiation correlated negatively with IADM levels at Month 1. Physiologically-based pharmacokinetic model simulations suggest that, following subcutaneous ARV administration, ART-induced reduction of immune activation improves the formation of active drug-metabolites through modulation of kinase activity and/or through improved parent drug accessibility to LN cellular compartments. These observations have broad implications for drugs that need to phosphorylate to exert their pharmacological activity, especially in the settings of the pre-/post-exposure prophylaxis and efficacy of antiviral therapies targeting pathogenic viruses such as HIV or SARS-CoV-2 replicating in highly inflammatory anatomic compartments.

Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy.

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy.

Pharmacokinetic parameter driven outcomes model predicts a reduction in bleeding events associated with BAY 81–8973 versus antihemophilic factor (recombinant) plasma/albumin-free method in a Chinese healthcare setting

BackgroundLong-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population.MethodsHead-to-head PK profile data of BAY 81–8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year.ResultsCumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3% for BAY 81–8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81–8973 compared to rAHF-PFM. BAY 81–8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM.ConclusionBased on modeled head-to-head comparisons, differences in PK-properties between BAY 81–8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81–8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids.

Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.

Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease.

BackgroundInfliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics.MethodsThe study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed‐effects population pharmacokinetic modeling.ResultsDose‐normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10–21) compared to prepregnancy (7, 2–12; p = 0.003), the first trimester (9, 1–12; p = 0.04), or postpregnancy (6, interquartile range 3–11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7–36; p > 0.05). A one‐compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti‐infliximab antibodies, and not by pregnancy‐imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre‐ and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester.ConclusionInfliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de‐intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.

How Many Urine Samples Are Needed to Accurately Assess Exposure to Non-Persistent Chemicals? The Biomarker Reliability Assessment Tool (BRAT) for Scientists, Research Sponsors, and Risk Managers.

In epidemiologic and exposure research, biomonitoring is often used as the basis for assessing human exposure to environmental chemicals. Studies frequently rely on a single urinary measurement per participant to assess exposure to non-persistent chemicals. However, there is a growing consensus that single urine samples may be insufficient for adequately estimating exposure. The question then arises: how many samples would be needed for optimal characterization of exposure? To help researchers answer this question, we developed a tool called the Biomarker Reliability Assessment Tool (BRAT). The BRAT is based on pharmacokinetic modeling simulations, is freely available, and is designed to help researchers determine the approximate number of urine samples needed to optimize exposure assessment. The BRAT performs Monte Carlo simulations of exposure to estimate internal levels and resulting urinary concentrations in individuals from a population based on user-specified inputs (e.g., biological half-life, within- and between-person variability in exposure). The BRAT evaluates—through linear regression and quantile classification—the precision/accuracy of the estimation of internal levels depending on the number of urine samples. This tool should guide researchers towards more robust biomonitoring and improved exposure classification in epidemiologic and exposure research, which should in turn improve the translation of that research into decision-making.

Flow irregularities from syringe infusion pumps caused by syringe stiction.

The current study aimed to evaluate the extent of the slide-stick phenomenon in differently designed infusion syringes at various infusion rates and filling positions. Fluid delivery from three 50-mL infusion syringe brands (BD; Codan; Fresenius) was investigated using a flow sensor at flow rates of 0.5, 1.0, or 5.0mLh-1 , with the syringes filled with either 10, 30, or 50mL of distilled water. Two identical models (A/B) of the same infusion pump model were used. The effect of flow rate variations on the plasma concentration of a continuous epinephrine infusion in a 3kg neonate receiving a continuous infusion of 0.1μgkgmin-1 epinephrine was studied using a pharmacokinetic simulation model. Considerable variations in calculated plasma epinephrine concentration were detected between flow rates of 5 and 0.5 or 1mLh-1 for all syringe types and filling volumes. The median deviation of plasma concentration for the 5mLh-1 flow rate varied depending on assembly from 1.3% (Codan) to 1.8% (Fresenius). This was more pronounced for lower flow rates, where at 1mLh-1 the deviation varied from 3.3% (BD) to 4.8% (Fresenius) and at 0.5mLh-1 from 4.9% (BD) to 5.4% (Fresenius). Differences between filling volumes (within syringe type and flow rate) did not appear to have relevant influence on variations in calculated plasma epinephrine concentration. Infusion set rate rather than syringe brand or filling volume was a major predictor for syringe stiction-related amount of variation in the calculated plasma epinephrine concentration.

Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials.

To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19). We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2. The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for in vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose. We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in vitro. Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.

Adapting a Combination of Intrinsic and Extrinsic Cellular Factors to Generate an Improved Model of Tumor Exposure and Sensitivity to Chloroquine Derivatives

In cancer clinical trials hydroxychloroquine (HCQ) is the only approved autophagy inhibitor for use in treatment. Pharmacokinetic data from clinical trials comparing tumor vs. blood concentrations of HCQ suggest that there is a significant disconnect between drug levels within these compartments [Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH (2014) “Phase I Clinical Trial and Pharmacodynamic Evaluation of Combination Hydroxychloroquine and Doxorubicin Treatment in Pet Dogs Treated for Spontaneously Occurring Lymphoma Phase I Clinical Trial and Pharmacodynamic Evaluation of Combination Hydroxychloroquine.” Autophagy 10 (8): 1415–25]. Attempts to improve prediction of drug kinetics in these compartments have been made through development of individual patient‐focused physiologically‐based models, but these models fall short in predicting dynamic tumor cell‐specific intrinsic and extrinsic factors that dictate the amount of HCQ that sequesters within its ultimate pharmacodynamic target – the lysosome. Two factors intrinsic to tumor cells suggest that HCQ exposure should be predicted on a tumor‐by‐tumor basis. The first factor being basal levels of HCQ uptake drivers in the context of lysosomal burden, broken up into overall lysosomal volume and pH in a cell population. Different cell lines exhibit different pre‐exposure lysosomal burdens, modifying their overall initial exposure to HCQ both in vitro and in tumor‐bearing mice in vivo. Basal lysosomal burden is coupled to an adaptive response to HCQ exposure as well. This adaptive response is broken up into a short‐term component, driven primarily through lysosomal swelling, and a longer‐term component wherein TFEB‐activation induces biogenesis of functional lysosomes capable of sequestering HCQ. These intrinsic components result in a continual increase in cell uptake of HCQ over a 24‐hour period, split into rapid uptake within the short term (1st hour) and a slower, steadier uptake in the long term (1–24 hours). In addition, the main extrinsic factor that modulates HCQ exposure is extracellular pH. We observed a 5‐fold decrease in total cellular drug uptake and up to 10‐fold decrease in sensitivity to HCQ in media pH 6.8 vs. 7.4 across 4 cell lines. Combining these intrinsic and extrinsic factors we generate a cell‐based pharmacokinetic simulation model capable of predicting HCQ exposure to cell lines, and then translate it to next‐generation chloroquine derivatives through modification of compound‐specific physicochemical parameters. The power of this model is in its ability to account for dynamic systems within the tumor cell, giving a more accurate picture of how the tumor interacts with the drug, accounting for a major form of HCQ resistance through the non‐homogenous acidic tumor microenvironment in vivo, and pushing forward the development of next generation lysosomotropic autophagy inhibitors that may interact with the system similarly.Support or Funding InformationNational Cancer Institute [Grant R01CA190170 Therapeutic Targeting of Autophagy‐Dependent Cancer] and by Department of Defense CDMRP Breast Cancer Research Program [Grant BC130103P1 Identifying and Targeting Autophagy Dependence to Eliminate Metastatic Breast Cancer]

Performance of modern syringe infusion pump assemblies at low infusion rates in the perioperative setting

BackgroundSyringe infusion pumps are used for the precise continuous administration of intravenous drugs. Their compliance and mechanical deficiencies have been found to cause considerable start-up delays, flow irregularities during vertical displacement, as well extensive delays of occlusion alarms at low infusion rates. The aim of this study was to evaluate the performance of several modern syringe infusion pumps at low infusion rates and the impact on drug concentration. MethodsSeven currently marketed syringe infusion pump assemblies were assessed in an in vitro study during start-up, vertical displacement manoeuvres, and infusion line occlusion at a set flow rate of 1 ml h−1. The measured data were used as input for a pharmacokinetic simulation modelling plasma concentration during a standard neonatal continuous epinephrine infusion. ResultsThe mean time from starting the infusion pump to steady-state flow varied from 89 to 1622 s. The zero-drug delivery time after lowering the pump ranged from 145 to 335 s. In all assemblies tested, occlusion alarm delays and measured flow irregularities during vertical displacement manoeuvres resulted in relevant deviations in plasma epinephrine concentration (>25%) as calculated by the pharmacokinetic simulation model. ConclusionProblems with the performance of syringe infusion pump assemblies can have considerable impact on plasma drug concentration when highly concentrated short-acting cardiovascular drugs are administered at low flow rates. The problems, which affected all assemblies tested, are mainly related to the functional principle of syringe infusion pumps and will only partially be solved by incremental improvements of existing equipment.

Physiologically based pharmacokinetic evaluation of cefuroxime in perioperative antibiotic prophylaxis.

AimsAdequate plasma concentrations of antibiotics during surgery are essential for the prevention of surgical site infections. We examined the pharmacokinetics of 1.5 g cefuroxime administered during induction of anaesthesia with follow‐up doses every 2.5 hours until the end of surgery. We built a physiologically based pharmacokinetic model with the aim to ensure adequate antibiotic plasma concentrations in a heterogeneous population.MethodsA physiologically based pharmacokinetic model (PK‐Sim®/MoBi®) was developed to investigate unbound plasma concentrations of cefuroxime. Blood samples from 25 thoracic surgical patients were analysed with high‐performance liquid chromatography. To evaluate optimized dosing regimens, physiologically based pharmacokinetic model simulations were conducted.ResultsDosing simulations revealed that a standard dosing regimen of 1.5 g every 2.5 hours reached the pharmacokinetic/pharmacodynamic target for Staphylococcus aureus. However, for Escherichia coli, >50% of the study participants did not reach predefined targets. Effectiveness of cefuroxime against E. coli can be improved by administering a 1.5 g bolus immediately followed by a continuous infusion of 3 g cefuroxime over 3 hours.ConclusionThe use of cefuroxime for perioperative antibiotic prophylaxis to prevent staphylococcal surgical site infections appears to be effective with standard dosing of 1.5 g preoperatively and follow‐up doses every 2.5 hours. In contrast, if E. coli is relevant in surgeries, this dosing regimen appears insufficient. With our derived dose recommendations, we provide a solution for this issue.

Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime-Avibactam Combination: A Model-Informed Strategy for its Clinical Development.

Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment. Population PK models of ceftazidime and avibactam were developed separately and incorporated body weight, disease state, ethnicity, and renal function (creatinine clearance) as covariates of clearance and volume of distribution. The clinical dosing regimen of ceftazidime/avibactam combination was determined from population PK model simulations in the patient population for dosing regimens that can achieve sufficient joint probability of target attainment for ceftazidime minimum inhibitory concentration (MIC) of 8mg/L at a fixed 4mg/L avibactam concentration (MIC ≤ 8/4mg/L); 8mg/L is the breakpoint of ceftazidime in Enterobacteriaceae and Pseudomonas aeruginosa for the target pharmacodynamic indices of ceftazidime and avibactam of 50% time at which the free ceftazidime concentration is above the MIC (fT > MIC) and 50% time at which the free avibactam is above a threshold concentration of 1mg/L (fT > CT). Whereas the static index approach does not take into account the changing potency of ceftazidime in the presence of changing avibactam concentration, a mathematical model based on kill-curve kinetics was utilized to validate the dose selection in humans. The clinical dosing regimen of 2/0.5g ceftazidime/avibactam administered every 8h as a 2-h intravenous infusion in patients with normal renal function, with dose adjustment in renal impairment, demonstrated statistical non-inferiority to carbapenem in phase III studies on the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia, including ceftazidime non-susceptible Gram-negative pathogens. The success of the phase III studies validated the dose selection and exposure target that were associated with efficacy based on a model-informed approach.

The Japanese experience and pharmacokinetics of antenatal maternal high-dose immunoglobulin treatment as a prophylaxis for neonatal hemochromatosis in siblings

Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70–90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited.Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment.Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model.Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000–3000 and 4000–5000 mg/dl, respectively.Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment.

Monte-Carlo and multi-exposure assessment for the derivation of criteria for disinfection byproducts and volatile organic compounds in drinking water: Allocation factors and liter-equivalents per day

The probability distributions of total potential doses of disinfection byproducts and volatile organic compounds via ingestion, inhalation, and dermal exposure were estimated with Monte Carlo simulations, after conducting physiologically based pharmacokinetic model simulations to takes into account the differences in availability between the three exposures. If the criterion that the 95th percentile estimate equals the TDI (tolerable daily intake) is regarded as protecting the majority of a population, the drinking water criteria would be 140 (trichloromethane), 66 (bromodichloromethane), 157 (dibromochloromethane), 203 (tribromomethane), 140 (dichloroacetic acid), 78 (trichloroacetic acid), 6.55 (trichloroethylene, TCE), and 22 μg/L (perchloroethylene). The TCE criterion was lower than the Japanese Drinking Water Quality Standard (10 μg/L). The latter would allow the intake of 20% of the population to exceed the TDI. Indirect inhalation via evaporation from water, especially in bathrooms, was the major route of exposure to compounds other than haloacetic acids (HAAs) and accounted for 1.2–9 liter-equivalents/day for the median-exposure subpopulation. The ingestion of food was a major indirect route of exposure to HAAs. Contributions of direct water intake were not very different for trihalomethanes (30–45% of TDIs) and HAAs (45–52% of TDIs).

An Innovative, Collaborative, and Strategic Approach to Proactively Evaluate and Update Drug Interactions Based on Prescribing Information of Newly Approved Medicinal Products.

Drug-drug interaction (DDIs) are evaluated using pharmacokinetic (PK) simulation models, clinical studies, and scientific publications throughout drug development. DDIs with Norvir (ritonavir) and combination products (eg, Kaletra [lopinavir/ritonavir]) containing ritonavir as a PK enhancer are relevant, because these drugs could affect exposures of CYP3A4 substrates. Application of algorithms proactively identified recently approved drugs, which potentially cause adverse outcomes when given with drugs containing ritonavir. An evidence-based medicine technology platform was used to identify newly approved products. PK-related information from the products' prescribing information was reviewed to identify DDIs with ritonavir. Algorithms were used to further evaluate PK, clinical, and postmarketing information pertinent to the interaction to determine if prescribing information required revision. From January 1, 2014, through December 31, 2015, 39 newly approved drugs were identified as having potential interactions with Norvir and/or Kaletra. Ten drugs were excluded, 19 drugs went through initial screening, and 10 drugs underwent in-depth algorithm-based analyses for DDIs. No changes to prescribing information for Norvir or Kaletra were recommended from evaluation of the DDIs. Regulatory concurrence with AbbVie decisions was 93.1% (27/29, 93.1%); in 6.9% (2/29, 6.9%) of the evaluated interactions, at least 1 local regulatory authority disagreed with recommendations, requiring label changes to incorporate the DDI information. This proactive algorithmic approach identifies and complements existing methods used to detect DDIs with newly approved products. Additionally, this approach facilitates timely communication of risks to patients and healthcare providers via label revisions, publications, or other regulatory communications.

Prediction of Ocular Drug Distribution from Systemic Blood Circulation.

Systemically circulating drugs may distribute to ocular tissues across the blood-ocular barriers. Ocular distribution is utilized in the treatment of ocular diseases with systemic medications, but ocular delivery of systemic drugs and xenobiotics may also lead to adverse ocular effects. Ocular distribution after systemic drug administration has not been predicted or modeled. In this study, distribution clearance between vitreous and plasma was obtained from a previous QSPR model for clearance of intravitreal drugs. These values were used in a pharmacokinetic simulation model to describe entry of unbound drug from plasma to vitreous. The simulation models predicted ocular distribution of 10 systemic drugs in rabbit eyes within 1.96 mean fold error and the distribution of cefepime from plasma to vitreous in humans. This is the first attempt to predict ocular distribution of systemic drugs. Reliable predictions were obtained using systemic concentrations of unbound drug, computational value of ocular distribution clearance, and a simple pharmacokinetic model. This approach can be used in drug discovery to estimate ocular drug exposure at an early stage.

Prediction of nomegestrol acetate pharmacokinetics in healthy female adolescents and adults by whole-body physiology-based pharmacokinetic modelling and clinical validation

ObjectiveNomegestrol acetate (NOMAC), a selective progestogen, and 17β-estradiol (E2), which is identical to endogenous oestrogen, are components of a new monophasic combined oral contraceptive — NOMAC/E2. This study aimed to compare pharmacokinetics (PK) of NOMAC in adolescent and adult women following a single dose of NOMAC/E2. Study designHealthy postmenarcheal adolescent (14–17years) and adult (18–50years) women received a single dose of NOMAC/E2 (2.5mg/1.5mg) in this single-centre, open-label, parallel-group Phase 1 study (EudraCT# 2008-002142-38). Blood samples were obtained for PK analysis, and concentrations of NOMAC, E2 and its metabolite estrone (E1) were determined for up to 129h following dosing to obtain PK data. An independent whole-body physiology-based pharmacokinetic (WB-PBPK) simulation model of NOMAC based on an independent Phase 3 dataset was used to scale NOMAC concentration–time plots to adolescents. ResultsOverall, 52 women were screened, of whom 30 (15 adolescents and 15 adults) were enrolled. No statistically significant differences were observed between the adolescent and adult groups for the clinically evaluated NOMAC PK parameters [maximum concentration (Cmax), area under the curve (AUC) and half-life (t1/2)]. The PK of E2 and E1 showed extensive overlap between both age groups. The WB-PBPK model accurately predicted NOMAC AUC and Cmax values in both groups. ConclusionsNo differences were observed in the clinically evaluated PK parameters for NOMAC between adolescent and adult women after a single dose of NOMAC/E2. The WB-PBPK model accurately predicted NOMAC PK data (EudraCT# 2008-002142-38). ImplicationsPK studies in adolescents are challenging because of ethical considerations. The whole-body physiology-based model described here complements classic noncompartmental and population PK approaches. The utility of this method is its ability to expand to adolescent postmenarcheal girls by using virtual postmenarcheal adolescent population data and applying physiological scaling.

24-hour human urine and serum profiles of bisphenol A: Evidence against sublingual absorption following ingestion in soup

Extensive first-pass metabolism of ingested bisphenol A (BPA) in the gastro-intestinal tract and liver restricts blood concentrations of bioactive BPA to <1% of total BPA in humans and non-human primates. Absorption of ingested BPA through non-metabolizing tissues of the oral cavity, recently demonstrated in dogs, could lead to the higher serum BPA concentrations reported in some human biomonitoring studies. We hypothesized that the extensive interaction with the oral mucosa by a liquid matrix, like soup, relative to solid food or capsules, might enhance absorption through non-metabolizing oral cavity tissues in humans, producing higher bioavailability and higher serum BPA concentrations. Concurrent serum and urine concentrations of d6-BPA, and its glucuronide and sulfate conjugates, were measured over a 24hour period in 10 adult male volunteers following ingestion of 30μg d6-BPA/kg body weight in soup. Absorption of d6-BPA was rapid (t1/2=0.45h) and elimination of the administered dose was complete 24h post-ingestion, evidence against any tissue depot for BPA. The maximum serum d6-BPA concentration was 0.43nM at 1.6h after administration and represented <0.3% of total d6-BPA. Pharmacokinetic parameters, pharmacokinetic model simulations, and the significantly faster appearance half-life of d6-BPA-glucuronide compared to d6-BPA (0.29h vs 0.45h) were evidence against meaningful absorption of BPA in humans through any non-metabolizing tissue (<1%). This study confirms that typical exposure to BPA in food produces picomolar to subpicomolar serum BPA concentrations in humans, not nM concentrations reported in some biomonitoring studies.

Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development

The aims of this research were to (1) create a curated universal database of intravitreal volumes of distribution (Vss, ivt) and clearances (CLivt) of small molecular weight compounds and macromolecules and (2) to develop quantitative structure property relationship (QSPR) and pharmacokinetic models for the estimation of vitreal drug concentrations based on the compound structure.Vss, ivt and CLivt values were determined from the available literature on intravitreal drug administration using compartmental models and curve fitting. A simple QSPR model for CLivt of small molecular weight compounds was obtained with two descriptors: LogD7.4 and hydrogen bond donor capacity. The model predicted the internal and external test sets reliably with a mean fold error of 1.50 and 1.33, respectively (Q2Y=0.62). For 80% of the compounds the Vss, ivt was 1.18–2.28ml; too narrow range for QSPR model building. Integration of the estimated Vss, ivt and predicted CLivt parameters into pharmacokinetic simulation models allows prediction of vitreous drug concentrations after intravitreal administration.The present work presents for the first time a database of CLivt and Vss, ivt values and the dependence of the CLivt values on the molecular structure. The study provides also useful in silico tools to investigate a priori the intravitreal pharmacokinetic profiles for intravitreally injected candidate compounds and drug delivery systems.