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1.  Etravirine in CSF is highly protein bound 
Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).
Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8–2000 (plasma) and 0.78–200 (CSF) ng/mL.
Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.
Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.
PMCID: PMC3625433  PMID: 23335197
HIV; antiretroviral therapy; central nervous system; CNS; protein binding; CSF
2.  Efavirenz concentrations in CSF exceed IC50 for wild-type HIV 
HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF.
CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2–17] of therapy were 2145 ng/mL in plasma (IQR 1384–4423) and 13.9 ng/mL in CSF (IQR 4.1–21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026–0.0076; n = 69). The CSF/IC50 ratio was 26 (IQR 8–41) using the published IC50 for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV.
Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
PMCID: PMC3019085  PMID: 21098541
CNS; pharmacology; non-nucleoside reverse transcriptase inhibitors
Therapeutic drug monitoring  2014;36(4):510-518.
Optimal monitoring of vancomycin in children needs evaluation using the exposure target with area-under-the-curve of the serum concentrations vs. time over 24 hours (AUC). Our study objectives were to: (1) compare the accuracy and precision of vancomycin AUC estimations using two sampling strategies – one serum concentration sample (1S, near trough) versus two samples (2S, near peak and trough) against the rich sample (RS) method; and (2) determine the performance of these strategies in predicting future AUC against an internal validation sample (VS).
This was an retrospective cohort study using population-based pharmacokinetic modeling with Bayesian post-hoc individual estimations in NONMEM 7.2. Pediatric subjects 3 months to 21 years of age who received vancomycin ≥ 48 hours and had ≥ 3 drug samples within the first ≤ 96 hours of therapy were enrolled. Outcome measures were the accuracy, precision and internal predictive performance of AUC estimations using two monitoring strategies (i.e., 1S vs 2S) against the RS (which was derived from modeling all serum vancomycin concentrations obtained anytime during therapy), and VS (from serum concentrations obtained after 96 hours of therapy).
Analysis included 138 subjects with 712 vancomycin serum concentrations. Median age was 6.1 (interquartile range [IQR] 2.2-12.2) yr, weight 22 (13-38) kg, and baseline serum creatinine 0.37 (0.30-0.50) mg/dL. Both accuracy and precision were improved with the 2S, compared to 1S, for AUC estimations (-2.0% vs -7.6 % and 10.3% vs 12.8%, respectively) against the RS. Improved accuracy and precision were also observed for 2S when evaluated against VS in predicting future AUC.
Compared to 1S, the 2S sampling strategy for vancomycin monitoring improved accuracy and precision in estimating and predicting future AUC. Evaluating two drug concentrations in children may be prudent to ensure adequate drug exposure.
PMCID: PMC4101060  PMID: 24452067
Accuracy; Vancomycin; Pharmacokinetics; Pediatrics; Therapeutic Drug Monitoring
4.  Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications 
Drugs  2014;74(8):891-909.
Invasive fungal disease (IFD) remains life-threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD.
To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents like fluconazole, voriconazole, and micafungin require higher dosing than in adults due to faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age.
Pharmacodynamics principles of antifungals mostly rely on in vitro and in vivo models but very few pharmacodynamics studies specifically address IFD in children. Exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model.
In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.
PMCID: PMC4073603  PMID: 24872147
5.  Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection 
Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.
PMCID: PMC4000232  PMID: 24695591
Aging; Disability; Everyday functioning; Learning and memory
7.  Population Pharmacokinetics of Intravenous Acyclovir in Preterm and Term Infants 
Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population.
We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database.
The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × (postmenstrual age [PMA]/31.3 weeks)3.02. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA; 20 mg/kg every 6 hours in infants 36–41 weeks PMA.
Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in the majority of infants.
PMCID: PMC3904301  PMID: 24346595
herpes simplex virus; preterm infants; acyclovir
8.  Intestinal Fatty-Acid Binding Protein and Metronidazole Response in Premature Infants 
In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection.
Study design
We conducted an intravenous metronidazole pharmacokinetic study, collecting ≤3 urine samples per infant for I-FABP concentration measurements. We analyzed the relationship between I-FABP concentrations and measures of metronidazole exposure and pharmacokinetics, maturational factors, and other covariates.
Twenty-six samples from 19 premature infants were obtained during metronidazole treatment. When analyzed without regard to presence of necrotic gastrointestinal disease, there were no significant associations between predictor variables and I-FABP concentrations. However, when the sample was limited to premature infants with necrotic gastrointestinal disease, an association was found between average predicted metronidazole concentration and I-FABP concentration (p=0.006).
While a predictive association between urinary I-FABP and metronidazole systemic exposure was not observed, the data suggest the potential of this endogenous biomarker to serve as a pharmacodynamic surrogate for antimicrobial treatment of serious abdominal infections in neonates and infants.
PMCID: PMC4225165  PMID: 25318626
necrotizing enterocolitis; biomarkers; pharmacokinetics; premature infants; antimicrobial agents
9.  Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design 
Although ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (≤34 or >34 weeks) and postnatal age (PNA) (≤7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of ≤34 weeks and PNA of ≤7 days, 75 mg/kg every 12 h for GA of ≤34 weeks and PNA of ≥8 and ≤28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of ≤28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.
PMCID: PMC4068432  PMID: 24614374
10.  Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants 
Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of ≤30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (≤32 mg/liter) for 75% of the dosing interval.
PMCID: PMC3993246  PMID: 24614369
11.  Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency 
Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MIC) target of ≥ 400 in children with renal insufficiency is unknown. Our objectives were to compare vancomycin clearance (CL) and initial dosing in children with normal and impaired renal function.
Using a matched case-control study in subjects ≥ 3 months old who received vancomycin ≥ 48 hr, we performed population-based modeling with empiric Bayesian post-hoc individual parameter estimations and Monte Carlo simulations. Cases, defined by baseline serum creatinine (SCr) ≥ 0.9 mg/dL, were matched 1:1 to controls by age and weight.
Analysis included 63 matched pairs with 319 serum concentrations. Mean age (± SD) was 13 ± 6 yr and weight, 51 ± 25 kg. Mean baseline SCr was 0.6 ± 0.2 mg/dL for controls, and 1.3 ± 0.5 for cases. Age, SCr, and weight were independent covariates for CL. Final model parameters and inter-subject variability (ISV) were: CL(L/hr) = 0.235*Weight0.75*(0.64/SCr)0.497*(ln(DOL)/8.6)1.19 ISV=39%, where DOL is day of life. Target AUC/MIC ≥ 400 was achieved in 80% of cases at vancomycin 45 mg/kg/day, but required 60 mg/kg/day for controls. Drug CL improved in 87% of cases due to recovery of renal function.
Due to reduced CL, a less frequent dosing at 15 mg/kg every 8 hr (i.e., 45 mg/kg/day) may be appropriate for some children with renal impairment. Close monitoring of renal function and drug concentrations is prudent to ensure adequate drug exposure, especially in those with renal impairment since recovery of renal function may occur during therapy.
PMCID: PMC4191860  PMID: 25309945
Vancomycin; Children; Pediatrics; Renal disease; Renal insufficiency; Antibiotic; Methicillin-resistant Staphylococcus aureus (MRSA); Staphylococcus aureus; Antibiotic resistance; Pharmacokinetic-pharmacodynamic; Population-based pharmacokinetic modeling; Monte Carlo simulation; Area-under-the curve
12.  Optimizing Pediatric Esmolol Dosing Using Computerized Practitioner Order Entry 
OBJECTIVES: The aims of this study were to 1) describe the cardiovascular dose-response of esmolol and dose-limiting adverse effects in pediatric patients; 2) assess an institutional guideline for protocol adherence, efficacy, and achievement of therapeutic targets for pediatric patients with tachyarrhythmias or systemic hypertension; and 3) revise the protocol accordingly.
METHODS: In this prospective study, pediatric/neonatal subjects were identified using a medication utilization report in the electronic medical record and treated with esmolol for blood pressure or rhythm control at Rady Children's Hospital San Diego between November 1, 2012, and February 28, 2013. Inclusion criteria required subjects to be under intensive care and have bedside telemetry monitoring. Data collection consisted of patient demographic information, administration history of esmolol, concurrent administration of other cardiovascular medications, patient cardiovascular goals, and vital signs.
RESULTS: A total of 8 subjects representing 10 administrations of esmolol were included in the study. Whereas esmolol was found to be safe and effective overall for control of hypertension and tachyarrhythmia, protocol adherence was poor, leading to subtherapeutic dosing schemes, dose changes prior to achievement of presumed steady-state pharmacokinetics, and erratic dosing to target effect.
CONCLUSIONS: After the review, the data were revealed at a program-wide conference and consensus was reached on a new, data-driven protocol. As a result of this quality improvement initiative, the new protocol provides more precise dosing and clearly delineated therapeutic targets and is designed to reflect specific esmolol pharmacokinetics. The effort emphasizes the need to construct foundations for follow-up quality improvement efforts in intensive care pharmacology.
PMCID: PMC4341416  PMID: 25762876
computerized practitioner order entry; esmolol; pediatrics; pharmacology; quality improvement
13.  Determining Population and Developmental Pharmacokinetics of Metronidazole Using Plasma and Dried Blood Spot Samples from Premature Infants 
Limited pharmacokinetic (PK) data of metronidazole in premature infants has led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections.
We evaluated the PK of metronidazole using plasma and dried blood spot (DBS) samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N=3) study using population PK modeling (NONMEM). Monte Carlo simulations (N=1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated.
Twenty-four premature infants (111 plasma and 51 DBS samples) were enrolled: median (range) gestational age at birth 25 (23–31) weeks, postnatal age 27 (1–82) days, postmenstrual age (PMA) 31 (24–39) weeks, and weight 740 (431–1466) g. Population clearance (CL, L/h/kg) was 0.038 × (PMA/30)2.45 and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and DBS samples. Metabolic ratios correlated with CL.
Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using PMA-based dosing.
PMCID: PMC3769518  PMID: 23587979
neonate; drug; pharmacokinetics; metronidazole; dried blood spots
14.  Reduced indinavir exposure during pregnancy 
To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period.
IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6–12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6–12 weeks post-partum. PK targets were the estimated 10th percentile IDV AUC (12.9 μg ml−1 h) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg ml−1, the suggested minimum target.
Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9–40.8) years and weight 60.5 (50.0–85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml−1 at delivery. All 26 infants were confirmed HIV negative.
Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.
PMCID: PMC3769674  PMID: 23305215
antiretrovirals; HIV; pregnancy; prevention of mother-to-child transmission
15.  Auranofin Is Highly Efficacious against Toxoplasma gondii In Vitro and in an In Vivo Experimental Model of Acute Toxoplasmosis 
The mainstay of toxoplasmosis treatment targets the folate biosynthetic pathways and has not changed for the last 50 years. The activity of these chemotherapeutic agents is restricted to one lifecycle stage of Toxoplasma gondii, they have significant toxicity, and the impending threat of emerging resistance to these agents makes the discovery of new therapies a priority. We now demonstrate that auranofin, an orally administered gold containing compound that was FDA approved for treatment of rheumatoid arthritis, has activity against Toxoplasma gondii in vitro (IC50 = 0.28 µM) and in vivo (1 mg/kg).
Methods/Principal Findings
Replication within human foreskin fibroblasts of RH tachyzoites was inhibited by auranofin. At 0.4 µM, auranofin inhibited replication, as measured by percent infected fibroblasts at 24 hrs, (10.94% vs. 24.66% of controls; p = 0.0003) with no effect on parasite invasion (16.95% vs. 12.91% p = 0.4331). After 18 hrs, 62% of extracellular parasites treated with auranofin were non-viable compared to control using an ATP viability assay (p = 0.0003). In vivo, a previously standardized chicken embryo model of acute toxoplasmosis was used. Fourteen day old chicken embryos were injected through the chorioallantoic vein with 1×104 tachyzoites of the virulent RH strain. The treatment group received one dose of auranofin at the time of inoculation (1 mg/kg estimated body weight). On day 5, auranofin-treated chicken embryos were 100% protected against death (p = 0.0002) and had a significantly reduced parasite load as determined by histopathology, immunohistochemistry and by the number of parasites quantified by real-time PCR.
These results reveal in vitro and in vivo activity of auranofin against T. gondii, suggesting that it may be an effective alternative treatment for toxoplasmosis.
Author Summary
Toxoplasma gondii is a protozoan parasite that infects at least two thirds of the world human population. Once it infects the human host, it has great predilection for the brain and the retina of the eye. It remains latent until the host's immune system weakens, and then causes organ tissue damage. There are very few treatments available that are active against this parasite, and they all fail to eradicate it from the human body. Hence, there is always a risk for recurrence and/or disabling long-term complications such as blindness or neurological abnormalities. Despite this fact, it has been over fifty years since most anti-Toxoplasma agents were initially described. Most recently, in an attempt to expedite the process of drug discovery, older drugs are making a comeback by being re-purposed for new diseases. Auranofin, which was originally designed to treat rheumatoid arthritis, has consistently shown antiparasitic activity against multiple organisms, including parasites of great public health importance such as Plasmodium, Schistosoma and Leishmania, although most of these reports are based on in vitro assays. Herein, we present our studies that demonstrate that auranofin is active against Toxoplasma gondii in vitro and in an animal model of acute Toxoplasma infection, suggesting that auranofin has great potential to become a new anti-Toxoplasma agent.
PMCID: PMC4117455  PMID: 25079790
16.  Adverse Events Associated with Meropenem versus Imipenem/Cilastatin Therapy in a Large Retrospective Cohort of Hospitalized Infants 
Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin.
We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness.
Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days vs. 40.7/1000 infant days, P<0.001). There was no difference in seizures with meropenem vs. imipenem/cilastatin (adjusted odds ratio [OR] 0.96; 95% confidence interval 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use—OR 0.68 (0.50, 0.88) and OR 0.77 (0.62, 0.95), respectively.
In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
PMCID: PMC3708263  PMID: 23838776
meropenem; imipenem/cilastatin; adverse events; infant
18.  Improved Vancomycin Dosing in Children Using Area-Under-the-Curve Exposure 
Our objectives were to: (1) determine the pharmacokinetic [PK] indices of vancomycin in pediatric patients; and (2) compare attainment of two target exposures: AUC/MIC ≥ 400 and trough concentration ≥ 15 mcg/mL.
The population-based PK modeling was performed using NONMEM 7.2 for children ≥ 3 months old who received vancomycin for ≥ 48 hr from 2003 to 2011. A one-compartment model with first-order kinetics was used to estimate clearance (CL), volume of distribution (Vd) and area-under-curve (AUC). Empiric Bayesian post-hoc individual parameters and Monte Carlo simulations (N=11,000) were performed.
Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range [IQR] 2.2–13.4) yr, weight 22.7 (12.6–46) kg, and baseline serum creatinine (SCr) 0.40 (0.30–0.60) mg/dL. Final model PK indices were: CL(L/h) = 0.248*Wt0.75*(0.48/SCr)0.361*(ln(age)/7.8)0.995; and Vd(L) = 0.636*Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39–52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥ 12 years old and 70 mg/kg/day for those < 12 years old achieved target AUC/MIC in ~ 75% and trough concentrations ≥ 15 in ~ 45% of virtual subjects. An AUC/MIC ~ 400 corresponded to trough concentration ~ 8 to 9 mcg/mL.
Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine, and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.
PMCID: PMC3632448  PMID: 23340565
Vancomycin; children; pediatrics; antibiotic; Staphylococcus aureus; pharmacokinetic; pharmacodynamic
19.  Determination of Efavirenz in Human Dried Blood Spots by Reversed-Phase High Performance Liquid Chromatography with UV Detection 
Therapeutic drug monitoring  2013;35(2):10.1097/FTD.0b013e31827fb72b.
Previously published methods for determination of efavirenz (EFV) in human dried blood spots (DBS) employ costly and complex liquid chromatography/mass spectrometry. We describe the validation and evaluation of a simple and inexpensive high-performance liquid chromatography (HPLC) method for EFV quantification in human DBS and dried plasma spots (DPS), using ultraviolet (UV) detection appropriate for resource-limited settings.
100μl of heparinized whole blood or plasma were spotted onto blood collection cards, dried, punched, and eluted. Eluates are injected onto a C-18 reversed phase HPLC column. EFV is separated isocratically using a potassium phosphate and ACN mobile phase. UV detection is at 245nm. Quantitation is by use of external calibration standards. Following validation, the method was evaluated using whole blood and plasma from HIV-positive patients undergoing EFV therapy.
Mean recovery of drug from dried blood spots is 91.5%. The method is linear over the validated concentration range of 0.3125 – 20.0μg/mL. A good correlation (Spearman r=0.96) between paired plasma and DBS EFV concentrations from the clinical samples was observed, and hematocrit level was not found to be a significant determinant of the EFV DBS level. The mean observed CDBS/Cplasma ratio was 0.68. A good correlation (Spearman r=0.96) between paired plasma and DPS EFV concentrations from the clinical samples was observed. The mean percent deviation of DPS samples from plasma samples is 1.68%.
Dried whole blood spot or dried plasma spot sampling is well suited for monitoring EFV therapy in resource limited settings, particularly when high sensitivity is not essential.
PMCID: PMC3848783  PMID: 23503446
Efavirenz; Dried Blood Spots; Dried Plasma Spots; HPLC
20.  External evaluation of population pharmacokinetic models of vancomycin in neonates: the transferability of published models to different clinical settings 
Vancomycin is one of the most evaluated antibiotics in neonates using modeling and simulation approaches. However no clear consensus on optimal dosing has been achieved. The objective of the present study was to perform an external evaluation of published models, in order to test their predictive performances in an independent dataset and to identify the possible study-related factors influencing the transferability of pharmacokinetic models to different clinical settings.
Published neonatal vancomycin pharmacokinetic models were screened from the literature. The predictive performance of six models was evaluated using an independent dataset (112 concentrations from 78 neonates). The evaluation procedures used simulation-based diagnostics [visual predictive check (VPC) and normalized prediction distribution errors (NPDE)].
Differences in predictive performances of models for vancomycin pharmacokinetics in neonates were found. The mean of NPDE for six evaluated models were 1.35, −0.22, −0.36, 0.24, 0.66 and 0.48, respectively. These differences were explained, at least partly, by taking into account the method used to measure serum creatinine concentrations. The adult conversion factor of 1.3 (enzymatic to Jaffé) was tested with an improvement in the VPC and NPDE, but it still needs to be evaluated and validated in neonates. Differences were also identified between analytical methods for vancomycin.
The importance of analytical techniques for serum creatinine concentrations and vancomycin as predictors of vancomycin concentrations in neonates have been confirmed. Dosage individualization of vancomycin in neonates should consider not only patients' characteristics and clinical conditions, but also the methods used to measure serum creatinine and vancomycin.
PMCID: PMC3612725  PMID: 23148919
dosing regimen; external evaluation; neonates; population pharmacokinetics; serum creatinine; vancomycin
21.  Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration 
Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC90).
Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography–tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir.
Twenty-nine matched CSF–plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma.
Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.
PMCID: PMC3566670  PMID: 23143899
HIV; antiretroviral therapy; central nervous system; protein binding
22.  Lopinavir Exposure With an Increased Dose During Pregnancy 
Use of standard adult lopinavir/ritonavir (LPV/RTV) dosing (400/100 mg) during the third trimester of pregnancy results in reduced LPV exposure. The goal of this study was to determine LPV exposure during the third trimester of pregnancy and 2 weeks postpartum with a higher LPV/RTV dose.
The Pediatric AIDS Clinical Trials Group Protocol 1026s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving LPV/RTV 400/100 mg twice daily during the second trimester and 533/133 mg twice daily during the third trimester through 2 weeks postpartum. Intensive steady state 12-hour pharmacokinetic profiles were performed during the third trimester and at 2 weeks postpartum and were optional during the second trimester. LPV and RTV were measured by reverse-phase high-performance liquid chromatography with a detection limit of 0.09 µg/mL.
Twenty-six HIV-infected pregnant women were studied. Median LPV area under the plasma concentration-time curve (AUCs) for the second trimester, third trimester, and postpartum were 57, 88, and 152 µg·h−1·mL−1, respectively. Median minimum LPV concentrations were 1.9, 4.1, and 8.3 µg/mL.
The higher LPV/RTV dose (533/133 mg) provided LPV exposure during the third trimester similar to the median AUC (80 µg·h−1·mL−1) in nonpregnant adults taking standard doses. However, the AUC on this increased dose at 2 weeks postpartum was considerably higher. These data suggest that the higher LPV/RTV dose should be used in third trimester pregnant women; that it should be considered in second trimester pregnant women, especially those who are protease inhibitor experienced; and that postpartum LPV/RTV dosing can be reduced to standard dosing by 2 weeks after delivery.
PMCID: PMC3912695  PMID: 18989231
HIV; lopinavir; mother-to-child transmission; pharmacokinetics; pregnancy
23.  Developmental Pharmacokinetic Changes of Lamivudine in Infants and Children 
Journal of clinical pharmacology  2011;52(12):1824-1832.
Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in infants and children in combination antiretroviral therapy to treat human immunodeficiency virus (HIV) infection. Developmental changes in lamivudine pharmacokinetic disposition were assessed by combining data from 7 studies of lamivudine (Pediatric AIDS Clinical Trials Group 300, 353, 356, 358, 386, 1056, and 1069) representing subjects across the pediatric age continuum. A population pharmacokinetic model was developed to identify factors that influence lamivudine disposition. Age and Thai race were independent predictors of apparent clearance (CL/F), whereas the use of a fixed drug combination formulation (GPO-VIR) was an independent predictor of bioavailability, with CL/F more than doubling from birth to adolescence. Serum creatinine was not associated with CL/F. Monte Carlo simulations were used to compare the lamivudine exposure achieved with World Health Organization (WHO) weight band and Food and Drug Administration (FDA) label dosing recommendations. WHO dosing yielded higher exposure during the first few months of life, but this difference was less pronounced between 6 months and 14 years of age. Overall, both FDA and WHO dosing provided similar AUC values to those previously reported in HIV-infected adults. Lamivudine WHO weight band dosing results in therapeutic exposure in infants and children and may improve drug dosing in resource-limited countries.
PMCID: PMC3369109  PMID: 22180560
Clinical research; infectious diseases; pediatrics; pharmacokinetics and drug metabolism; virology
24.  Safety and Effectiveness of Meropenem in Infants With Suspected or Complicated Intra-abdominal Infections 
The safety and effectiveness of meropenem in young infants with suspected or confirmed intra-abdominal infections were evaluated. was well tolerated in this cohort of critically-ill infants, and the majority of infants treated with meropenem (84%) met the definition of therapeutic success.
Background. Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections.
Methods. Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score.
Results. Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%.
Conclusions. Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success.
Clinical Trials Registration. NCT00621192.
PMCID: PMC3491861  PMID: 22955430
25.  Pharmacokinetics and Safety of Fluconazole in Young Infants Supported with Extracorporeal Membrane Oxygenation 
Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the PK of fluconazole in infants on ECMO.
Infants <120 days old received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
Ten infants were enrolled. After dose 1 (n=9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg, and the median exposure in the first 24 hours (AUC0–24) was 322 h*mg/L. After multiple doses (n=7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg, and the AUC0–24 was 352 h*mg/L. After dose 1, 78% of infants achieved the prophylaxis target, while only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (−2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (rho= − 0.05). There were no adverse events related to fluconazole.
Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.
PMCID: PMC3444624  PMID: 22627870
fluconazole; Candida; extracorporeal membrane oxygenation; pharmacokinetics; infants

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