The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice. Clinical and experimental immunology 2016; 185 (3): 372-381
Recently, there has been considerable interest in using 4-methylumbelliferone (4-MU) to inhibit hyaluronan synthesis in mouse models of cancer, autoimmunity, and a variety of other inflammatory disorders where hyaluronan (HA) has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration, and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after one week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a one-week loading period on the drug is required for most protocols. At steady state, over 90% of the drug is present in plasma as the glucuronidated metabolite 4-methylumbelliferyl glucuronide (4-MUG), with the sulfated metabolite, 4-methylumbelliferyl sulfate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0.65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice. This article is protected by copyright. All rights reserved.
View details for DOI 10.1111/cei.12815
View details for PubMedID 27218304
Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass. Journal of clinical pharmacology 2016; 56 (9): 1084-1093
Children undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) frequently develop acute kidney injury due to renal ischemia. Theophylline, which improves renal perfusion via adenosine receptor inhibition, is a potential targeted therapy. However, children undergoing cardiac surgery and CPB commonly have alterations in drug pharmacokinetics. To help understand optimal aminophylline (salt formulation of theophylline) dosing strategies in this population, a population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM) from 71 children (median age: 5 months [90% range: 1 week - 10 years]) who underwent cardiac surgery requiring CPB and received aminophylline as part of a previous randomized controlled trial. A one-compartment model with linear elimination adequately described the pharmacokinetics of theophylline. Weight scaled via allometry was a significant predictor of clearance and volume. In addition, allometric scaled clearance increased with age implemented as a power maturation function. Compared to prior reports in non-cardiac children, theophylline clearance was markedly reduced across age. Applying the final population pharmacokinetic model, optimized empiric dosing regimens were developed via Monte Carlo simulations. Doses 50-75% lower than those recommended in non-cardiac children were needed to achieve target serum concentrations of 5-10 mg/L. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/jcph.697
View details for PubMedID 26712558
Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION 2016; 62 (5): 723-727
Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION 2016; 62: 723-727
Standard infliximab maintenance dosing of 5mg/kg every 8 weeks may be inadequate to consistently achieve sufficient drug exposure to minimize loss of response or treatment failure in pediatric Crohn's disease (CD). We aimed to determine the predicted infliximab trough concentrations in children with CD during maintenance therapy and the percentage of patients achieving target trough concentration >3g/ml.A Monte Carlo simulation analysis was constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial. We assessed maintenance dosing strategies of 5, 7.5, and 10mg/kg at dosing intervals of every 4, 6, and 8 weeks for children that differed by age, weight, albumin level, and concomitant immunomodulator therapy.Based on the index case of a 10 year old with CD receiving standard infliximab dosing with concomitant immunomodulator therapy, the median (IQR) simulated infliximab trough concentration at week 14 was 1.3 (0.5-2.7) g/ml, and 2.4 (1.0-4.8) g/ml for albumin levels of 3 and 4g/dl, respectively. Among 1000 simulated children in the model, trough concentration >3g/ml at week 14 was achieved 21% and 41% of the time for albumin levels of 3 and 4g/dl, respectively.Standard infliximab maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low. Optimized dosing strategies for individual patients are needed to achieve sufficient drug exposure during infliximab maintenance therapy.
View details for DOI 10.1097/IWPG.0000000000001123
View details for Web of Science ID 000375334500010
View details for PubMedID 26890885
Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery AAPS JOURNAL 2016; 18 (1): 124-133
Decreased Morphine Clearance in Neonates with Hypoxic Ischemic Encephalopathy Receiving Hypothermia. Journal of clinical pharmacology 2016
Morphine is commonly used in neonates with hypothermic ischemic encephalopathy (HIE) during therapeutic hypothermia to provide comfort and analgesia. However, pharmacokinetic data to support morphine dosing in this vulnerable population are lacking. A prospective, two-center, clinical pharmacokinetic study of morphine was conducted in 20 neonates (birthweight 1.82-5.3 kg) with HIE receiving hypothermia. Morphine dosing was per standard of care at each center. Morphine and glucuronide metabolites (morphine-3-glucuronide and morphine-6-gluronide) were measured via a validated dried blood spot LC-MS/MS assay. From the available concentration data (n = 106 for morphine; n = 106 for each metabolite), a population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). The clearance of morphine and glucuronide metabolites were best predicted by birthweight allometrically scaled using an exponent of 1.23. In addition, the clearance of each glucuronide metabolite was influenced by serum creatinine. No other significant predictors of clearance or volume of distribution were found. For a 3.5 kg neonate, morphine clearance was 0.77 L/h (CV 48%) and the steady-state volume of distribution was 8.0 L (CV 49%). Compared to previous studies in full-term newborns without HIE, morphine clearance was markedly lower. Dosing strategies customized for this vulnerable population will be needed. Applying the final population pharmacokinetic model, repeated Monte Carlo simulations (n = 1000 per simulation) were performed to evaluate various morphine dosing strategies that optimized achievement of morphine concentrations between 10-40 ng/ml. An optimized morphine loading dose of 50 g/kg followed by a continuous infusion of 5 g/kg/h was predicted across birthweight. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/jcph.775
View details for PubMedID 27225747
Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction LUNG CANCER 2015; 89 (3): 280-286
Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308698ng/ml and AUC 0-24 41,03015,577 ngh/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.
View details for DOI 10.1016/j.lungcan.2015.06.011
View details for Web of Science ID 000360513200010
View details for PubMedID 26149476
Pharmacokinetics, Pharmacodynamics, and Safety of Lisinopril in Pediatric Kidney Transplant Patients: Implications for Starting Dose Selection CLINICAL PHARMACOLOGY & THERAPEUTICS 2015; 98 (1): 25-33
Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options-including angiotensin-converting enzyme inhibitors-are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-nave patients (n=13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59ml/min per 1.73m(2) ), exposure (standardized to 0.1mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-nave patients, 85% and 77% had a 6mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations.
View details for DOI 10.1002/cpt.127
View details for Web of Science ID 000358502900018
View details for PubMedID 25807932
4-Methylumbe liferone treatment and hyaluronan innibition as a therapeutic strategy in nflammation, autoimmunity, and cancer FRONTIERS IN IMMUNOLOGY 2015; 6
Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease BIOPHARMACEUTICS & DRUG DISPOSITION 2015; 36 (2): 104-114
Etomidate is a rapid-onset, short-acting hypnotic medication administered for induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants is lacking.The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery.Four neonates and sixteen infants, postnatal age 0.3 - 11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics.The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found to significantly impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 L/min/70-kg and 0.44 L/min/70-kg, respectively; central and peripheral distribution volume of 9.47 and 22.8 L/70-kg, respectively. Inter-individual variability was between 94-142% for all parameters and residual variability was 29%.The clearance of etomidate is lower in neonates and infants with congenital heart disease compared to published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/bdd.1924
View details for Web of Science ID 000351311700004
Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates. Infectious diseases and therapy 2015
The pharmacokinetics of vancomycin are highly variable among neonates, which makes dosing challenging in this population. However, adequate drug exposure is critical, especially when treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Utilization of population pharmacokinetic models and Bayesian methods offers the potential for developing individualized therapeutic approaches. To meet this need, a neonatal vancomycin population pharmacokinetic model was recently published. The current study sought to externally evaluate the predictive performance and generalizability of this model.A retrospective chart review of neonates who received vancomycin and had 1 peak and 1 trough concentrations at five Intermountain Healthcare neonatal intensive care units from 2006 to 2013 was performed and served as the external validation cohort. The published population pharmacokinetic model was implemented in NONMEM 7.2 with the structural and variance parameter values set equal to the estimates reported previously. The model was then used to predict the first peak and trough concentration for each neonate in the validation cohort and the model prediction error and absolute prediction error were calculated. Normalized prediction distribution errors (NPDE) were also evaluated.A total of 243 neonates were studied with a median postmenstrual age of 33 (range: 23-54)weeks and a median weight of 1.6 (range: 0.4-6.8)kg. The model predicted the observed vancomycin concentrations with reasonable precision. For all vancomycin concentrations, the median prediction error was -0.8 (95% CI: -1.4 to -0.4) mg/L and the median absolute prediction error was 3.0 (95% CI: 2.7-3.5) mg/L. No trends in NPDE across weight, postmenstrual age, serum creatinine, or time after dose were observed.An evaluation of a recently published neonatal vancomycin population pharmacokinetic model in a large external dataset supported the predictive performance and generalizability of the model. This model may be useful in evaluating neonatal vancomycin dosing regimens and estimating the extent of drug exposure.
View details for DOI 10.1007/s40121-015-0067-9
View details for PubMedID 25998107
4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Frontiers in immunology 2015; 6: 123-?
Hyaluronan (HA) is a prominent component of the extracellular matrix at many sites of chronic inflammation, including type 1 diabetes (T1D), multiple sclerosis, and numerous malignancies. Recent publications have demonstrated that when HA synthesis is inhibited using 4-methylumbelliferone (4-MU), beneficial effects are observed in several animal models of these diseases. Notably, 4-MU is an already approved drug in Europe and Asia called "hymecromone" where it is used to treat biliary spasm. However, there is uncertainty regarding how 4-MU treatment provides benefit in these animal models and the potential long-term consequences of HA inhibition. Here, we review what is known about how HA contributes to immune dysregulation and tumor progression. Then, we review what is known about 4-MU and hymecromone in terms of mechanism of action, pharmacokinetics, and safety. Finally, we review recent studies detailing the use of 4-MU to treat animal models of cancer and autoimmunity.
View details for DOI 10.3389/fimmu.2015.00123
View details for PubMedID 25852691
Association between Vancomycin Trough Concentration and Area under the Concentration-Time Curve in Neonates ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 2014; 58 (11): 6454-6461
The Use of Betaine HCl to Enhance Dasatinib Absorption in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria AAPS JOURNAL 2014; 16 (6): 1358-1365
Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia THERAPEUTIC DRUG MONITORING 2014; 36 (5): 584-589
Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia. Therapeutic drug monitoring 2014; 36 (5): 584-589
Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05).The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.
View details for DOI 10.1097/FTD.0000000000000056
View details for PubMedID 25225917
Prevalence of Acid-Reducing Agents (ARA) in Cancer Populations and ARA Drug-Drug Interaction Potential for Molecular Targeted Agents in Clinical Development MOLECULAR PHARMACEUTICS 2013; 10 (11): 4055-4062
Gastric Reacidification with Betaine HCl in Healthy Volunteers with Rabeprazole-Induced Hypochlorhydria MOLECULAR PHARMACEUTICS 2013; 10 (11): 4032-4037
Desired Vancomycin Trough Serum Concentration for Treating Invasive Methicillin-resistant Staphylococcal Infections PEDIATRIC INFECTIOUS DISEASE JOURNAL 2013; 32 (10): 1077-1079
Vancomycin AUC/MIC >400 best predicts outcome when treating invasive MRSA infection, however trough serum concentrations are used clinically to assess the appropriateness of dosing. We used pharmacokinetic modeling and simulation to examine the relationship between vancomycin trough values and AUC/MIC in children receiving vancomycin 15mg/kg every 6h and MRSA MIC of 1 g/ml. A trough of 7-10 g/ml predicted achievement of AUC/MIC >400 for >90% of children.
View details for DOI 10.1097/INF.0b013e318299f75c
View details for Web of Science ID 000324890500013
View details for PubMedID 23652479
Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia JOURNAL OF PERINATOLOGY 2013; 33 (10): 778-782
Objective:To examine the impact of a change in the empiric gentamicin dose from 5mgkg(-1) every 24h (Q24h period) to 5mgkg every 36h (Q36h period) on target drug concentration achievement in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia.Study Design:Gentamicin drug concentrations in neonates with HIE receiving therapeutic hypothermia were examined during two time periods in a retrospective chart review. During the initial treatment period (November 2007 to March 2010; n=29), neonates received Q24h period. During the second treatment period (January 2011 to May 2012; n=23), the dose was changed to Q36h period. Cooling criteria and protocol remained the same between treatment periods. Gentamicin drug concentrations including achievement of target trough concentrations (<2mgl(-1)) were compared between treatment periods. Individual Bayesian estimates of gentamicin clearance were also compared.Result:Neonates with an elevated trough concentration >2mgl(-1) decreased from 38 to 4% with implementation of a Q36-h dosing interval (P<0.007). The mean gentamicin trough concentration was 2.00.8mgl(-1) during the Q24h period and 0.90.4mgl(-1) during the Q36h period (P<0.001). Peak concentrations were minimally impacted (Q24h 11.42.3mgl(-1) vs Q36h 10.01.9mgl(-1); P=0.05). The change in gentamicin trough concentration could not be accounted for by differences in gentamicin clearance between treatment periods (P=0.9).Conclusion:A 5mgkg(-1) every 36-h gentamicin dosing strategy in neonates with HIE receiving therapeutic hypothermia improved achievement of target trough concentration <2mgl(-1), while still providing high peak concentration exposure.Journal of Perinatology advance online publication, 23 May 2013; doi:10.1038/jp.2013.59.
View details for DOI 10.1038/jp.2013.59
View details for Web of Science ID 000325087700008
View details for PubMedID 23702622
Gentamicin Pharmacokinetics and Dosing in Neonates with Hypoxic Ischemic Encephalopathy Receiving Hypothermia PHARMACOTHERAPY 2013; 33 (7): 718-726
STUDY OBJECTIVE: To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations. DESIGN: Population pharmacokinetic study using retrospective medical record data. SETTING: Tertiary neonatal intensive care unit. PATIENTS: A total of 29 full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring MEASUREMENT AND MAIN RESULTS: Patient demographics and gentamicin concentration data were retrospectively collected over a 2-year period. A population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). Using the developed model, Monte Carlo simulations were performed to evaluate the probability of achieving target peak (>6mg/L) and trough (<2mg/L) gentamicin concentrations for various potential dosing regimens. A one-compartment model best described the available gentamicin concentration data. Birthweight and serum creatinine significantly influenced gentamicin clearance. For the typical study neonate (birthweight 3.3kg, serum creatinine 0.9mg/dl), clearance was 0.034L/hour/kg and volume was 0.52L/kg. At a 24-hour dosing interval, Monte Carlo simulations predicted target gentamicin peak and trough concentrations could not be reliably achieved at any dose. At a 36-hour dosing interval, a dose of 4-5mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than90% of neonates. CONCLUSIONS: Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed.
View details for DOI 10.1002/phar.1263
View details for Web of Science ID 000326278200007
View details for PubMedID 23553582
Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 2013; 75 (2): 463-475
To evaluate pharmacogenetic factors as contributors to the variability of unbound mycophenolic acid (MPA) exposure in adult allogeneic haematopoietic cell transplantation (alloHCT) recipients.A population-based pharmacokinetic (PK) model of unbound MPA was developed using non-linear mixed-effects modelling (nonmem). Previously collected intensive unbound MPA PK data from 132 adult alloHCT recipients after oral and intravenous dosing of the prodrug mycophenolate mofetil (MMF) were used. In addition to clinical covariates, genetic polymorphisms in UGT1A8, UGT1A9, UGT2B7 and MRP2 were evaluated for their impact on unbound MPA PK.Unbound MPA concentration-time data were well described by a two compartment model with first order absorption and linear elimination. For the typical patient (52 years of age, creatinine clearance 86 ml min(-1)), the median estimated values [coefficient of variation, %, (CV)] of systemic clearance, intercompartmental clearance, central and peripheral volumes of MPA were 1610 l h(-1) (37.4%), 541 l h(-1) (75.6%), 1230 l (37.5%), and 6140 l (120%), respectively. After oral dosing, bioavailability was low (0.56) and highly variable (CV 46%). No genetic polymorphisms tested significantly explained the variability among individuals. Creatinine clearance was a small but significant predictor of unbound MPA CL. No other clinical covariates impacted unbound MPA PK.In adult alloHCT recipients, variability in unbound MPA AUC was large and remained largely unexplained even with the inclusion of pharmacogenetic information. Targeting unbound MPA AUC in a patient will require therapeutic drug monitoring.
View details for DOI 10.1111/j.1365-2125.2012.04372.x
View details for Web of Science ID 000313554200017
View details for PubMedID 22765258
Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is pH-Dependent Solubility the Achilles Heel of Targeted Therapy? CLINICAL PHARMACOLOGY & THERAPEUTICS 2012; 92 (2): 203-213
A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).
View details for DOI 10.1038/clpt.2012.73
View details for Web of Science ID 000306596300017
View details for PubMedID 22739140
Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women AIDS 2012; 26 (7): 833-841
To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa.In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/?l randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity.NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations.Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h in women without 3+ rash (P = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (P = 0.046). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/?l (P = 0.003).In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4 cell count at least 250 cells/?l was significantly associated with NVP toxicity.
View details for DOI 10.1097/QAD.0b013e328351a521
View details for Web of Science ID 000302813000008
View details for PubMedID 22301417
Impact of a Hospitalwide Increase in Empiric Pediatric Vancomycin Dosing on Initial Trough Concentrations PHARMACOTHERAPY 2011; 31 (9): 871-876
To evaluate the impact of a hospitalwide increase in the recommended vancomycin starting dose from 45 to 60 mg/kg/day on initial vancomycin trough concentrations in children suspected of having an invasive methicillin-resistant Staphylococcus aureus (MRSA) infection.Retrospective medical record review.Dedicated children's hospital located in a tertiary care, academic medical center.A total of 182 children aged 1 month-12 years with normal renal function who had suspected MRSA infections treated with vancomycin during two different starting dose recommendation periods: 45 mg/kg/day divided every 8 hours during July 2006-June 2007 (low-dose group [88 children]) and 60 mg/kg/day divided every 6 hours during July 2008-June 2009 (high-dose group [94 children]).Data on patient demographics, vancomycin doses, and initial vancomycin trough concentrations were collected. No significant demographic differences were noted between patients in the low-dose and high-dose groups. The mean SD initial vancomycin trough level increased from 7 5 ?g/ml in the low-dose group to 9 5 ?g/ml in the high-dose group (p<0.001). The percentage of patients with an initial trough level less than 5 ?g/ml declined from 38% (33/88 children) in the low-dose group to 17% (16/94 children) in the high-dose group (p<0.001), whereas the percentage of patients with an initial trough concentration in the potentially adverse range (> 20 ?g/ml) did not change between the two groups (2% vs 2%, p=0.9). Less than 14% (13/94 children) achieved a trough level in the range of 15-20 ?g/ml in the high-dose group.An increase in the recommended vancomycin starting dose to 60 mg/kg/day decreased the likelihood of an initial low vancomycin trough level (< 5 ?g/ml), with no increase in the proportion of patients with trough levels in a potentially toxic range. The 60-mg/kg/day dose did not consistently achieve a vancomycin trough of 15-20 ?g/ml, a goal suggested by some experts for adults. Comparative effectiveness studies are needed to directly evaluate vancomycin dosing regimens and clinical outcomes for children with invasive MRSA infections.
View details for Web of Science ID 000295749400007
View details for PubMedID 21923588
Effect of Single-Dose Rifampin on the Pharmacokinetics of Warfarin in Healthy Volunteers CLINICAL PHARMACOLOGY & THERAPEUTICS 2010; 88 (4): 540-547
Based on in vitro rat and human hepatocyte uptake studies showing inhibition of warfarin uptake in the presence of the nonspecific organic anion-transporting polypeptide (OATP) inhibitor rifampin, a clinical study was conducted in 10 healthy volunteers to examine the in vivo relevance of OATP hepatic uptake on the pharmacokinetics of warfarin. In a randomized, single-dose, two-period, crossover design, subjects received a 7.5-mg dose of warfarin, either alone or immediately following a 600-mg intravenous dose of rifampin. Rifampin did not significantly alter the R- or S-warfarin area under the concentration-time curves (AUCs) from 0 to 12 h (period of hepatic OATP inhibition by rifampin) or the maximum plasma concentration (C(max)) value. AUC(0-?) was decreased on days rifampin was administered, for both R-warfarin (25% reduction; P < 0.001) and S-warfarin (15% reduction; P < 0.05). No differences were seen in the area under the international normalized ratio (INR)-time curve. Our study suggests that hepatic uptake via OATPs may not be clinically important in the pharmacokinetics of warfarin.
View details for DOI 10.1038/clpt.2010.142
View details for Web of Science ID 000282064000027
View details for PubMedID 20703222
Prediction of Vancomycin Pharmacodynamics in Children With Invasive Methicillin-Resistant Staphylococcus aureus Infections: A Monte Carlo Simulation CLINICAL THERAPEUTICS 2010; 32 (3): 534-542
Due to the emergence of community-associated strains, the prevalence of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections has increased substantially in pediatric patients. A vancomycin AUC(0-24)/MIC index >400 best predicts treatment outcomes for invasive MRSA infection in adults. Data on whether recommended vancomycin doses in children achieve this break point are lacking.This study aimed to assess the likelihood that currently recommended vancomycin doses in children achieve AUC(0-24)/MIC >400.Vancomycin AUC(0-24)/MIC predictions were conducted across a range of dosages (40-70 mg/kg/d) using a Monte Carlo simulation (n = 5000). AUC(0-24) was calculated as daily dose divided by vancomycin clearance, and daily dose was fixed for a given simulation. Three literature-reported estimates in children were used to define vancomycin clearance and its variance. For the MIC distribution of MRSA isolates, susceptibility data were obtained from the University of California, San Francisco Children's Hospital, San Francisco, California (n = 180; 40% < or =0.5 mg/L; 59% = 1 mg/L; and 1% = 2 mg/L).Using the recommended empiric dosage of 40 mg/kg/d, 58% to 66% of children were predicted to achieve AUC(0-24)/MIC >400. Increasing the vancomycin dosage to 60 mg/kg/d substantially increased the likelihood (88%-98%) of achieving this pharmacodynamic target. On sensitivity analysis, a dosage of 40 mg/kg/d was more strongly influenced by small changes in MIC compared with 60 mg/kg/d.Recommended empiric vancomycin dosing in children (40 mg/kg/d) was not predicted to consistently achieve the pharmacodynamic target of AUC(0-24)/MIC >400 for invasive MRSA infections. A vancomycin dosage of 60 mg/kg/d was predicted to optimize achievement of this target in children.
View details for DOI 10.1016/j.clinthera.2010.03.005
View details for Web of Science ID 000276632600010
View details for PubMedID 20399990
Current Recommended Dosing of Vancomycin for Children With Invasive Methicillin-Resistant Staphylococcus aureus Infections Is Inadequate PEDIATRIC INFECTIOUS DISEASE JOURNAL 2009; 28 (5): 398-402
Vancomycin area-under-the-concentration-time-curve (AUC) for 24 hours divided by the minimum inhibitory concentration (MIC) (AUC24/MIC) >400 optimally treats invasive methicillin-resistant Staphylococcus aureus (MRSA) infections in adults. It is unknown whether recommended vancomycin dosing regimens for children achieve this value.AUC24/MIC was calculated in children using vancomycin doses of 40 and 60 mg/kg/d. AUC24 was calculated as daily dose/vancomycin clearance. Vancomycin clearance in children was estimated by 2 approaches: (1) previously literature-reported vancomycin clearance, and (2) calculated vancomycin clearance using previously derived predictor models and a hypothetical population of healthy children. Representative MIC of hospital MRSA isolates was used (0.5, 1.0, and 2.0 microg/mL).The MIC50/90 for pediatric MRSA isolates in the previous year was 1.0 microg/mL. With a dose of 40 mg/kg/d, both approaches consistently predicted AUC24/MIC <400 when MIC was 1.0 microg/mL. At 60 mg/kg/d, AUC24/MIC >400 was more readily achieved when MIC was 1.0 microg/mL, however, an MIC of 2.0 microg/mL resulted in AUC24/MIC <400 for both dosing regimens.A vancomycin dose of 40 mg/kg/d in children is unlikely to achieve the recommended pharmacodynamic target of AUC24/MIC >400 for invasive MRSA infections even when MIC is 1.0 microg/mL. A starting dose of 60 mg/kg/d should be used in settings where isolates with MIC of 1.0 are common. Alternatives to vancomycin should strongly be considered for patients with MIC > or =2.0 microg/mL.
View details for DOI 10.1097/INF.0b013e3181906e40
View details for Web of Science ID 000265619400008
View details for PubMedID 19295465
Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers JOURNAL OF PAIN 2007; 8 (1): 19-25
In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain.Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.
View details for DOI 10.1016/j.jpain.2006.05.010
View details for Web of Science ID 000244025700003
View details for PubMedID 17113353