Population pharmacokinetics of olanzapine in children.

AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.

A Randomized, Controlled Pharmacokinetic and Pharmacodynamics Trial of Ambrisentan After Fontan Surgery.

OBJECTIVES: To determine the pharmacokinetics, pharmacodynamics, and safety of the hepatically metabolized endothelin receptor antagonist, ambrisentan in children after Fontan surgery. DESIGN: Prospective, randomized, double-blind, placebo-controlled pharmacokinetic/pharmacodynamics and safety trial. SETTING: Single-center, postoperative cardiac ICU. PATIENTS: Children undergoing elective Fontan surgery. INTERVENTIONS: Subjects randomized on postoperative day number 1 to short-term (3 d) treatment with oral ambrisentan (2.5 mg in suspension, daily) versus placebo (4:1 randomization). MEASUREMENTS AND MAIN RESULTS: Plasma drug concentrations were measured at 0.5, 1, 2, 4, and 18-36 hours after the first dose. We developed a population pharmacokinetic model in NONMEM 7.2 (Icon Solutions, Ellicott City, MD) and applied the model to dose-exposure simulations. Pharmacodynamics endpoints were assessed at baseline and 3 hours after study drug administration, using postoperative hemodynamic monitoring lines. The analysis included 16 patients, 13 on ambrisentan (77 plasma samples); median age 36 months (range, 26-72 mo), weight 13.3 kg (11.1-17.6 kg), and nine males. There were no differences in baseline characteristics between ambrisentan and controls. A one-compartment model with first-order absorption and lag-time characterized the data well. Allometrically scaled weight was the only covariate retained in the final model. Typical values for clearance and volume of distribution were lower than previously reported in adults, 1 L/hr/70 kg and 13.7 L/70 kg, respectively. Simulated exposures with doses of 0.1-0.2 mg/kg approximated therapeutic exposures in adults with pulmonary arterial hypertension receiving 5 mg or 10 mg doses. Ambrisentan lowered plasma brain natriuretic peptide concentrations (452 ± 479 to 413 ± 462; p = 0.046), Fontan pressures (16.8 ± 2.9 to 15.6 ± 2.9; p = 0.01), and indexed pulmonary vascular resistance (2.3 ± 0.9 to 1.8 ± 0.6; p = 0.01) with no drug-related adverse events. CONCLUSIONS: Ambrisentan clearance is reduced following Fontan surgery, perhaps reflecting abnormal hepatic metabolism in this population. The observed safety profile appears favorable and hemodynamic effects of ambrisentan may be beneficial for Fontan patients.

Use of normalized prediction distribution errors for assessing population physiologically-based pharmacokinetic model adequacy.

Currently employed methods for qualifying population physiologically-based pharmacokinetic (Pop-PBPK) model predictions of continuous outcomes (e.g., concentration-time data) fail to account for within-subject correlations and the presence of residual error. In this study, we propose a new method for evaluating Pop-PBPK model predictions that account for such features. The approach focuses on deriving Pop-PBPK-specific normalized prediction distribution errors (NPDE), a metric that is commonly used for population pharmacokinetic model validation. We describe specific methodological steps for computing NPDE for Pop-PBPK models and define three measures for evaluating model performance: mean of NPDE, goodness-of-fit plots, and the magnitude of residual error. Utility of the proposed evaluation approach was demonstrated using two simulation-based study designs (positive and negative control studies) as well as pharmacokinetic data from a real-world clinical trial. For the positive-control simulation study, where observations and model simulations were generated under the same Pop-PBPK model, the NPDE-based approach denoted a congruency between model predictions and observed data (mean of NPDE = - 0.01). In contrast, for the negative-control simulation study, where model simulations and observed data were generated under different Pop-PBPK models, the NPDE-based method asserted that model simulations and observed data were incongruent (mean of NPDE = - 0.29). When employed to evaluate a previously developed clindamycin PBPK model against prospectively collected plasma concentration data from 29 children, the NPDE-based method qualified the model predictions as successful (mean of NPDE = 0). However, when pediatric subpopulations (e.g., infants) were evaluated, the approach revealed potential biases that should be explored.

Pitfalls of using numerical predictive checks for population physiologically-based pharmacokinetic model evaluation.

Comparisons between observed data and model simulations represent a critical component for establishing confidence in population physiologically-based pharmacokinetic (Pop-PBPK) models. Numerical predictive checks (NPC) that assess the proportion of observed data that correspond to Pop-PBPK model prediction intervals (PIs) are frequently used to qualify such models. We evaluated the effects of three components on the performance of NPC for qualifying Pop-PBPK model concentration-time predictions: (1) correlations (multiple samples per subject), (2) residual error, and (3) discrepancies in the distribution of demographics between observed and virtual subjects. Using a simulation-based study design, we artificially created observed pharmacokinetic (PK) datasets and compared them to model simulations generated under the same Pop-PBPK model. Observed datasets containing uncorrelated and correlated observations (± residual error) were formulated using different random-sampling techniques. In addition, we created observed datasets where the distribution of subject body weights differed from that of the virtual population used to generate model simulations. NPC for each observed dataset were computed based on the Pop-PBPK model's 90% PI. NPC were associated with inflated type-I-error rates (> 0.10) for observed datasets that contained correlated observations, residual error, or both. Additionally, the performance of NPC were sensitive to the demographic distribution of observed subjects. Acceptable use of NPC was only demonstrated for the idealistic case where observed data were uncorrelated, free of residual error, and the demographic distribution of virtual subjects matched that of observed subjects. Considering the restricted applicability of NPC for Pop-PBPK model evaluation, their use in this context should be interpreted with caution.

Examining Small Intestinal Transit Time as a Function of Age: Is There Evidence to Support Age-Dependent Differences among Children?

The small intestine represents the region where the majority of drug and nutrient absorption transpires. Among adults, small intestinal transit kinetics is well delineated; however, the applicability of these values toward children remains unclear. This article serves to examine the relationship between age and mean small intestinal transit time (SITT) based on the available literature. In addition, the influence of alterations in intestinal transit time was explored among children using a model-based approach. Primary literature sources depicting SITT from children to adults were ascertained via the PubMed database. Data were limited to subjects without pathologies that could influence intestinal motility. Random-effect meta-regression models with between-study variability were employed to assess the influence of age on SITT. Three separate models with age as a linear or higher-order (i.e., second- and third-order polynomial) regressor were implemented to assess for the potential of both linear and curvilinear relationships. Examination of the influence of altered intestinal transit kinetics on the absorption of a sustained release theophylline preparation was explored among children between 8 and 14 years using physiologically based pharmacokinetic (PBPK) modeling. Age was not found to be a significant modulator of small intestinal transit within either the linear or higher-order polynomial meta-regression models. PBPK simulations indicated a lack of influence of variations in SITT on the absorption of theophylline from the examined sustained release formulation in older children. Based on the current literature, there is no evidence to suggest that mean SITT differs between children and adults.

Assessment of Age-Related Changes in Pediatric Gastrointestinal Solubility.

PURPOSE: Compound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility. METHODS: Solubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37 °C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media. RESULTS: For six of the seven compounds investigated, solubility fell outside an 80-125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II). CONCLUSION: Developmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.

A Simulation-Based Assessment of Levetiracetam Concentrations Following Fixed and Weight-Based Loading Doses: A Meta-Regression and Pharmacokinetic Modeling Analysis.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

48-hour Induction of Transdermal Buprenorphine to Extended-release Buprenorphine.

ABSTRACT: Buprenorphine extended-release (BUP-XR) provides sustained delivery of buprenorphine to control withdrawal and craving symptoms in the form of a monthly injectable and has been shown to improve health outcomes in patients with opioid use disorder. It is recommended that patients are stabilized with a transmucosal buprenorphine product, for at least 7 days per the product monograph; however, clinically, this timeline may be expedited. We report a case of a hospitalized patient with unregulated fentanyl use who underwent a successful transdermal buprenorphine induction for 48 hours to initiate BUP-XR with minimal levels of withdrawal and without precipitating opioid withdrawal. The approach described could provide a practical, patient-centered, accelerated induction strategy that, once independently validated, could considerably facilitate the use of BUP-XR.

Rapid induction of transdermal buprenorphine to subcutaneous extended-release buprenorphine for the treatment of opioid use disorder.

BACKGROUND: Buprenorphine is an effective and safe treatment for opioid use disorder, but the requirement for moderate opioid withdrawal symptoms to emerge prior to initiation is a significant treatment barrier. CASE PRESENTATION: We report on two cases of hospitalized patients with severe, active opioid use disorder, in which we initiated treatment with transdermal buprenorphine over 48 h, followed by the administration of a single dose of sublingual buprenorphine/naloxone and then extended-release subcutaneous buprenorphine. The patients did not experience precipitated withdrawal and only had mild withdrawal symptoms. CONCLUSIONS: This provides preliminary evidence for a rapid induction strategy that may improve tolerability, caregiver burden, and treatment retention as compared to previous induction strategies.

Erratum to "A large unruptured ectopic pregnancy" [Radiology Case Reports 16 (2021) 1204-1206].

[This corrects the article DOI: 10.1016/j.radcr.2021.02.048.].

Scribes with PGY-1 Residents on Inpatient Medicine Teams: Effect on Time Spent in Meaningful Work.

Background: The high documentation demands and limited time in direct patient care in the first year of internal medicine residency represent concerns for burnout and low job satisfaction in this important year of training. Objective: To assess the effect of scribes on the time PGY-1 residents spent on various work tasks. Methods: Participants were 24 PGY-1 internal medicine residents on two inpatient medicine teams at one site for 6 months (September 2019-February 2020). Residents were assigned a scribe during the first or second 2 weeks of a 4-week rotation and had no scribe for the other 2 weeks. Time study observers documented resident work activities. Residents ranked the meaningfulness of work activities via survey at the end of each 2-week period. Results: Of 24 residents, 18 (75%) completed the survey at both time points. Residents ranked patient care as the most meaningful and EHR work as the least meaningful work activity. EHR work claimed the largest percentage of time, with or without a scribe (mean, 33.2% and 39%, respectively). With a scribe, residents spent significantly less time (-5.8%, P < 0.0001) in EHR work and significantly more time (1.3%, P = 0.0267) in direct patient care and coordinating patient care (3.0%, P < 0.0001). Conclusions: The presence of a scribe with PGY-1 internal medicine residents on inpatient teams resulted in a significantly greater percentage of total work time spent in work they considered most meaningful and a significantly lower percentage of total work time in work they considered least meaningful.

48-hour Induction of Transdermal Buprenorphine to Sublingual Buprenorphine/Naloxone: The IPPAS Method.

Buprenorphine is an effective medication for the treatment of opioid use disorder. However, the traditional method of buprenorphine induction requires a period of abstinence and the development of at least moderate withdrawal, which can be barriers in starting treatment. We present the case of a hospitalized patient with opioid use disorder using unregulated fentanyl, who underwent a transdermal buprenorphine induction over 48 hours to initiate sublingual buprenorphine/naloxone on the third day. The patient experienced minimal levels of withdrawal and did not experience precipitated withdrawal. The ease of use of this novel induction method over previously published induction protocols can greatly improve the accessibility of buprenorphine for patients and healthcare staff.

Pharmacokinetics and Proposed Dosing of Levetiracetam in Children With Obesity.

OBJECTIVE: Characterize levetiracetam pharmacokinetics (PK) in children with obesity to inform dosing. METHODS: Children 2 to <21 years old receiving standard of care oral levetiracetam across two opportunistic studies provided blood samples. Levetiracetam plasma PK data were analyzed with a nonlinear mixed-effects modeling approach. Indirect measures for body size and covariates were tested for model inclusion. Individual empirical Bayesian estimates using the final model parameters were compared by obesity status. Monte Carlo simulation using total body weight was performed in children with normal estimated glomerular filtration rate to identify dosing for children with obesity that resulted in comparable exposures to normal weight adults and children after receiving label dosing. RESULTS: The population PK model was developed from 341 plasma concentrations from 169 children. A 1-compartment model best fit the data with fat-free mass as a significant covariate. Compared with children with normal weight, children with obesity had significantly lower body weight-normalized clearance (median [range], 4.77 [1.49-10.44] and 3.71 [0.86-13.55] L/h/70 kg, respectively). After label dosing with the oral formulation in children with obesity 4 to <16 years old, maximum and minimum steady-state concentrations were higher (25% and 41%, respectively [oral solution] and 27% and 19%, respectively [tablet]) compared with children with normal weight. Comparable exposures between children with and without obesity were achieved with weight-tiered dosing regimens of <75 kg or ≥75 kg. CONCLUSIONS: Weight-tiered dosing for levetiracetam oral solution and tablets for children with obesity 4 to <16 years old results in more comparable exposures to children of normal weight.

Understanding the Impact of Age-Related Changes in Pediatric GI Solubility by Multivariate Data Analysis.

The aim of this study was to understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in newborns and young infants in comparison to adults. Multivariate statistical analysis was used to understand drug solubilization as a function of drug's physicochemical properties and the composition of gastrointestinal fluids. The solubility of seven poorly soluble compounds was assessed in adult and age-specific fasted and fed state biorelevant media. Partial least squares regression (PLS-R) was used to assess the influence of (i) drug physicochemical properties and (ii) age-related changes in simulated GI fluids, as well as (iii) their interactions, on the pediatrics-to-adult solubility ratio (Sp/Sa (%)). For five out of seven of the compounds investigated, Sp/Sa (%) values fell outside of the 80-125% limits in at least one of the pediatric media. Lipophilicity was responsible for driving drug solubility differences between adults and children in all the biorelevant media investigated, while drug ionization was most relevant in the fed gastric media, and the fasted/fed intestinal media. The concentration of bile salts and lecithin in the fasted and fed intestinal media was critical in influencing drug solubility, while food composition (i.e., cow's milk formula vs. soy formula) was a critical parameter in the fed gastric state. Changes in GI fluid composition between younger pediatric patients and adults can significantly alter drug luminal solubility. The use of pediatric biorelevant media can be helpful to identify the risk of altered drug solubilization in younger patients during drug development.

Hydroxychloroquine PK and exposure-response in pregnancies with lupus: the importance of adherence for neonatal outcomes.

OBJECTIVE: Evaluate the impact of pregnancy physiology and medication non-adherence on serum hydroxychloroquine (HCQ) pharmacokinetics (PK) and exposure-response in SLE. METHODS: We conducted a PK analysis using data from two observational pregnancy registries. We enrolled pregnant women with SLE taking HCQ at least 3 months prior to, and throughout pregnancy, and excluded those with multiple gestations. Using the PK model, we conducted dosing simulations and imputed 0%/20%/40%/60% non-adherence to evaluate the impact of adherence versus physiological changes on HCQ concentrations. We compared the effect of pregnancy-average non-adherent concentrations (≤100 ng/mL vs >100 ng/mL) on preterm birth using adjusted logistic regression. RESULTS: We enrolled 56 women who had 61 pregnancies. By the third trimester, mean apparent HCQ clearance increased by 59.6%. At a dosage of 400 mg/day, fully adherent patients are expected to have HCQ concentrations ≤100 ng/mL only 0.3% of the time, compared with 24.2% when 60% of doses are missed. Persistently low HCQ concentrations throughout pregnancy were associated with a significantly higher odds of preterm birth, controlling for lupus nephritis and race (OR 11.2; 95% CI 2.3 to 54.2; p=0.003). CONCLUSIONS: We observed significant changes in HCQ PK during pregnancy, resulting in a shortening in the drug's half-life by 10 days; however, medication non-adherence had a more pronounced effect on HCQ exposure compared with physiological changes alone. Moreover, pregnant women with non-adherent HCQ concentrations had significantly higher rates of preterm birth. Accordingly, optimising adherence in pregnancy may be more clinically meaningful than adjusting HCQ dosage to account for physiological changes. PK modelling indicates that serum HCQ concentrations ≤100 ng/mL are suggestive of non-adherence regardless of trimester and may help identify pregnancies at risk for poor outcomes.

A large unruptured ectopic pregnancy.

Ectopic pregnancy carries a significant mortality risk in the first trimester given the increased likelihood of rupture of large embryos. In this report, an otherwise asymptomatic woman presented with amenorrhea and a positive urine pregnancy test. Results included an elevated beta-human chorionic gonadotropin (B-hCG) of 39,947 IU/L and Transvaginal ultrasound suggestive of a 3.9 cm unruptured fallopian tube ectopic pregnancy. She underwent emergent salpingectomy without complications, confirming a 10 week, 6 days gestational age pregnancy. This exceptional case of an unruptured ectopic with crown rump length (CRL) above 2 cm illustrates the importance of early diagnosis due to the often unremarkable presentation.

Health care workers attitudes toward COVID-19 vaccination and the effect on personal and professional life.

INTRODUCTION: While the discovery of the Coronavirus disease 2019 (COVID-19) vaccine renewed the hope to restore normal life, the attitude of Health Care Workers (HCWs) towards vaccination and its impact on their life are yet to be evaluated. METHODS: We conducted a cross-sectional study from late January to mid-February at the MedStar Health Hospitals in Baltimore, Maryland. Eligible HCWs completed the questionnaires anonymously. The primary outcomes were attitudes of HCWs towards vaccination and the impact on HCWs' comfort and anxiety in caring for patients, sleep, mood, attendance of social gatherings, and utilization of health clubs, before and after vaccination. RESULT: A total of 300 respondents completed the questionnaires. The mean age was 37.2 years with 37.7% physicians and 45.7% registered nurses. Of the respondents only, 15.7% refused vaccination. The most common reason for refusal was concerns for long-term adverse effects, cited by 59.5%. Following vaccination, comfort level in caring for patients with COVID-19 and other illnesses improved (6.3 (2.8) to 8.2 (2.0), p < 0.005, and 8.4 (2.4) to 9.1 (1.0), p < 0.005, respectively). Additionally, a significant decrease in anxiety was noted in HCWs caring for patients with COVID-19 and other illnesses (5.0 (3.3) vs. 3.5 (3.2), p < 0.005 and 2.7 (3.3) vs. 2.3 (3.4), p = 0.001, respectively). Significant improvement in mood scores (6.9 (2.4) vs. 7.7 (2.1), p < 0.005) and comfort level at social gatherings (4.3 (3.2) vs. 6.3 (3.0), p < 0.005) were also noted. CONCLUSION: Vaccination against COVID-19 resulted in overall improvement in HCWs physical and mental wellbeing.

Simultaneous SPECT imaging with 123I and 125I - a practical approach to assessing a drug and its carrier at the same time with dual imaging.

Radiolabeling of a drug with radioactive iodine is a good method to determine its pharmacokinetics and biodistribution in vivo that only minimally alters its physicochemical properties. With dual labeling, using the two radioactive iodine isotopes 123I and 125I, two different drugs can be evaluated at the same time, or one can follow both a drug and its drug delivery system using a single photon emission computed tomography (SPECT) imager. One difficulty is that the two radioisotopes have overlapping gamma spectra. Our aim was therefore to develop a technique that overcomes this problem and allows for quantitative analysis of the two radioisotopes present at varied isotope ratios. For this purpose, we developed a simple method that included scatter and attenuation corrections and fully compensated for 123I/125I crosstalk, and then tested it in phantom measurements. The method was applied to the study of an orally administered lipid formulation for the delivery of fenofibrate in rats. To directly compare a traditional study, where fenofibrate was determined in plasma samples to SPECT imaging with 123I-labeled fenofibrate and 125I-labeled triolein over 24 h, the drug concentrations were converted to standardized uptake values (SUVs), an unusual unit for pharmaceutical scientists, but the standard unit for radiologists. A generally good agreement between the traditional and the radioactive imaging method was found in the pharmacokinetics and biodistribution results. Small differences are discussed in detail. Overall, SPECT imaging is an excellent method to pilot a new formulation with just a few animals, replaces blood sampling, and can very quickly highlight potential administration problems, the excretion pathways and the kinetics. Furthermore, dual labeling with the two radioisotopes 123I and 125I clearly shows if a drug and its drug delivery system stay together when traveling through the body, if slow drug release takes place, and where degradation/excretion of the components occurs.

Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development.

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest. Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV. Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration. Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2-13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development. Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.

Pharmacokinetics of Ceftazidime in Children and Adolescents with Obesity.

PURPOSE: The aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies. METHODS: A population PK model was developed using opportunistically collected plasma samples. For each dosing strategy, model-based probability of target attainment (PTA) estimates were computed for study participants using empirical Bayes estimates. In addition, the effects of body size and renal function on PTA were evaluated using stochastic model simulations with virtually generated subjects. RESULTS: Twenty-nine participants, 24 of whom were obese, contributed data towards the analysis. The median (range) age, body weight, and body mass index of participants were 12.2 years (2.3-20.6), 59.2 kg (8.4-121), and 25.2 kg/m2 (13.8-42.9), respectively. Administration of 50 mg/kg intravenously (IV) every 8 hours (q8h; max 6 g/day) or 40 mg/kg IV q6h (max 6 g/day) resulted in PTA values of ≥ 90% (minimum inhibitory concentration 8 mg/L) for the subset of obese participants with estimated glomerular filtration rates (GFR) ≥ ~ 80 mL/min/1.73 m2. However, for both regimens, stochastic model simulations denoted lower PTA values (< 90%) with increasing body weight for virtual subjects with GFR ≥ 120 mL/min/1.73 m2. Alternatively, permitting for a maximum daily dose of 8 g/day using a 40 mg/kg IV q6h regimen provided PTA values that were near or above target (90%) for virtual subjects between 10 to 120 kg with GFR ≥ 80 mL/min/1.73 m2. CONCLUSION: Our analysis suggests administration of 40 mg/kg IV q6h (max 8 g/day) maximizes PTA in children and adolescents with obesity and GFR ≥ 80 mL/min/1.73 m2. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01431326.