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.

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.

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.

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.

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.

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019.

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required. Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment. Design, Setting, and Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population. Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies. Main Outcomes and Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration. Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL). Conclusions and Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.

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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

CNS penetration and pharmacodynamics of the CHK1 inhibitor prexasertib in a mouse Group 3 medulloblastoma model.

Prexasertib (LY2606368) is a potent and selective small molecule inhibitor of cell-cycle checkpoint CHK1 and CHK2 protein kinases and is currently under clinical evaluation for treatment of pediatric malignancies. As a candidate therapy for pediatric Group 3 medulloblastoma (G3MB), prexasertib CNS penetration was evaluated in mice using cerebral microdialysis and pharmacokinetic modeling. A plasma pharmacokinetic study with a population-based design was performed in CD1 nude mice bearing G3MB orthotopically implanted in the brain and receiving a single dose of prexasertib (10 mg/kg, subcutaneously) to characterize prexasertib disposition and to establish a limited plasma sampling model for the microdialysis studies. The microdialysis studies were performed in both non-tumor bearing mice and in mice bearing G3MB receiving 10 mg/kg prexasertib subcutaneously, for up to 24 h post-dose. Plasma and extracellular fluid (ECF) concentrations were quantified using validated LC MS/MS methods, and analyzed using a population pharmacokinetic model. Model-derived prexasertib tumor/ECF to plasma partition coefficient Kp,uu (ratio of tumor/brain ECF to unbound plasma AUC0-24 h) was significantly greater in G3MB tumor-bearing mice (0.17 ±â€¯0.08) compared to non-tumor bearing mice (0.09 ±â€¯0.04, p = 0.04). A pharmacodynamic study was then performed in mice bearing G3MB (20 mg/kg, IV) to evaluate prexasertib-induced target engagement after a single dose. Phosphorylated CHK1 serine 345 (pCHK1 S345), phosphorylated Histone 2A variant (γ-H2AX), and cleaved caspase-3 were quantified in mouse G3MB tumor tissues by immunohistochemistry at different time points up to 24 h post-dose. The induction of pCHK1 S345 and γ-H2AX peaked at 2 h after the dose and was elevated above baseline for at least 6 h, reflecting relevant CHK1 inhibition and DNA damage. Cleaved caspase-3 levels increased at 24 h suggesting initiation of cell apoptosis. Adequate unbound prexasertib exposure reached the brain tumor site relative to target engagement in G3MB tumor bearing mice at a clinically relevant dosage. These results support further preclinical and clinical development of prexasertib to treat children with medulloblastoma.

Dosing of Continuous Fentanyl Infusions in Obese Children: A Population Pharmacokinetic Analysis.

Differences in fentanyl pharmacokinetics (PK) between obese and nonobese adults have previously been reported; however, the impact of childhood obesity on fentanyl PK is relatively unknown. We developed a population pharmacokinetic (PopPK) model using opportunistically collected samples from a cohort of predominately obese children receiving fentanyl per the standard of care. Using a probability-based approach, we evaluated the ability of different continuous infusion strategies to provide steady-state concentrations (Css ) within an analgesic concentration range (1-3 ng/mL). Fifty-three samples from 32 children were used for PopPK model development. Median (range) age and body weight of study participants were 13 years (2-19 years) and 52 kg (16-164 kg), respectively. The majority of children (94%) were obese. A 2-compartment model allometrically scaled by total body weight provided an appropriate fit to the data. Estimated typical clearance was 32.5 L/h (scaled to 70 kg). A fixed dose rate infusion of 1 µg/kg/h was associated with probabilities between 49% and 58% for achieving Css within target; however, the risk of achieving Css > 3 ng/mL increased with increasing body weight (15% at 16 kg vs 43% at 164 kg). A proposed model-based infusion strategy maintained consistent probabilities across the examined weight range for achieving Css within (58%) and above (20%) target. Use of an allometric relationship between weight and clearance was appropriate for describing the PK of intravenous fentanyl in our cohort of predominately obese children. Our proposed model-derived continuous infusion strategy maximized the probability of achieving target Css in children of varying weights.

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.

Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects.

BACKGROUND: Differences in plasma protein levels observed between children and adults can alter the extent of xenobiotic binding in plasma, resulting in divergent patterns of exposure. OBJECTIVE: This study aims to quantify the ontogeny of α1-acid glycoprotein in both healthy and infected subjects. METHODS: Data pertaining to α1-acid glycoprotein from healthy subjects were compiled over 26 different publications. For subjects diagnosed or suspected of infection, α1-acid glycoprotein levels were obtained from 214 individuals acquired over three clinical investigations. The analysis evaluated the use of linear, power, exponential, log-linear, and sigmoid E max models to describe the ontogeny of α1-acid glycoprotein. Utility of the derived ontogeny equation for estimation of pediatric fraction unbound was evaluated using average-fold error and absolute average-fold error as measures of bias and precision, respectively. A comparison to fraction unbound estimates derived using a previously proposed linear equation was also instituted. RESULTS: The sigmoid E max model provided the comparatively best depiction of α1-acid glycoprotein ontogeny in both healthy and infected subjects. Despite median α1-acid glycoprotein levels in infected subjects being more than two-fold greater than those observed in healthy subjects, a similar ontogeny pattern was observed when levels were normalized toward adult levels. For estimation of pediatric fraction unbound, the α1-acid glycoprotein ontogeny equation derived from this work (average fold error 0.99; absolute average fold error 1.24) provided a superior predictive performance in comparison to the previous equation (average fold error 0.74; absolute average fold error 1.45). CONCLUSION: The current investigation depicts a proficient modality for estimation of protein binding in pediatrics and will, therefore, aid in reducing uncertainty associated with pediatric pharmacokinetic predictions.

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.

Effect of an ethanol/trisodium citrate hemodialysis catheter locking solution on isolates of Candida albicans.

We conducted an in vitro study to assess the effect of a 30% ethanol/4% trisodium citrate (TSC) catheter locking solution on isolates of Candida albicans. Twelve isolates obtained from human blood cultures were tested in control solutions composed of broth and normal saline, and a test solution of 30% ethanol, 4% TSC, and broth. Colony counts were determined for control and test solutions at baseline and after 1, 24, and 48 hours of exposure. After 48 hours, the remaining test solution was filtered through a sterile filter funnel and rinsed with 10 mL of sterile water. Filters were aseptically transferred to agar plates and incubated for 24 hours. Control solutions grew well over the incubation period, as expected. In contrast, no viable growth was observed in test solutions 1 hour after instillation of the ethanol/TSC locking solution, or throughout the 48-hour study duration. Additionally, filters from test solutions displayed no growth. We conclude that a 30% ethanol/4% TSC catheter locking solution eradicated all isolates of C. albicans within 1 hour of exposure in this in vitro study, and shows promise as a new hemodialysis catheter locking solution.