Shareen Cox

Inosine monophosphate dehydrogenase (IMPDH) activity as a pharmacodynamic biomarker of mycophenolic acid effects in pediatric kidney transplant recipients.

Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)–induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)–guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra‐ and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC0–12 h) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model (EC50 = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pretransplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-Onset Systemic Lupus Erythematosus

OBJECTIVES Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity. METHODS MPA-PK [area under the curve from 0-12 hours (AUC(0-12))] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Assessment Group (BILAG) index. RESULTS A total of 19 AUC(0-12) and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC(0-12)) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC(0-12) and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC(0-12) of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002). CONCLUSION Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC(0-12) of at least 30 mg h/L is required for cSLE improvement.

UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

Background: Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)–based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance–associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy. Methods: MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C. Results: Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05). Conclusion: Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.

Propofol Clearance in Morbidly Obese Children and Adolescents

Background and ObjectiveGiven the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics.MethodsA prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM® was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors.ResultsTwenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9–18 years), a mean total body weight (TBW) of 125 kg (range 70–184 kg) and a mean body mass index of 46kg/m2 (range 31–63 kg/m2) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min)= 1.70 × (TBW/70)0.8]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable.ConclusionIn the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function.Trial registration number (clinicaltrials.gov)NCT00948597

Propofol clearance in morbidly obese children and adolescents: influence of age and body size.

BACKGROUND AND OBJECTIVE Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. METHODS A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM(®) was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. RESULTS Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46 kg/m(2) (range 31-63 kg/m(2)) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min) = 1.70 × (TBW/70)(0.8)]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. CONCLUSION In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function.

Population pharmacokinetics of felbamate in children.

Information about the pharmacokinetics of felbamate in children is limited. Even though it is claimed that monitoring of felbamate concentrations is unnecessary, many neurologists have requested therapeutic drug monitoring (TDM) for various reasons. This study used the NONMEM program to describe the pharmacokinetics and the influence of other anticonvulsants on the pharmacokinetics of felbamate. Felbamate, carbamazepine (CBZ), phenytoin (PHY), valproate (VPA), and barbiturate serum levels were obtained by our TDM service as requested by the clinician. The clearance and volume of distribution of felbamate were 41.1 ml/h/kg and 908 ml/kg, respectively. CBZ and PHY increased the clearance 49 and 40% while VPA decreased it 21%. Barbiturate had no significant effect. Clearance also decreased with age.

Clinical use of a simultaneous HPLC assay for indinavir, saquinavir, ritonavir, and nelfinavir in children and adults.

&NA; Protease inhibitor (PI) monitoring may improve the care of human immunodeficiency virus (HIV)‐infected patients; however, pediatric data are limited. A high‐performance liquid chromatographic (HPLC) assay developed for the simultaneous determination of indinavir, ritonavir, saquinavir, and nelfinavir in 0.2 mL of plasma was used to quantify PI concentrations in HIV patients. The reliability, sensitivity, and specificity of the assay were first verified in stored adult samples. Later, blood collected prospectively from patients aged 2.9 to 42 years of age (10 adults aged 24 to 42 and 15 children aged 2.9 to 18 years) was tested. Nondetectable (below 25‐50 ng/mL) concentrations (ND) were found in 33% of adult samples and 24% of pediatric samples. Four patients taking from 13.7 to 28 mg/kg/d of ritonavir (mean of 21.3) had concentrations ranging from ND to 11.4 μg/mL, quite different from predicted values. Correctable, important clinical problems including drug‐drug interactions, drug administration problems, and confirmed noncompliance were identified and corrected using modern therapeutic drug monitoring (TDM) techniques. Routine PI monitoring and interpretation (TDM) could improve the care of adult and pediatric HIV patients; especially in patients who do not respond as expected to treatment, develop viral resistance or toxicity, and have questionable compliance.

Effects of unbound mycophenolic acid on inosine monophosphate dehydrogenase inhibition in pediatric kidney transplant patients.

Background: Mycophenolic acid (MPA) is a key immunosuppressive drug that acts through inhibition of inosine monophosphate dehydrogenase (IMPDH). MPA is commonly measured, as part of therapeutic drug monitoring, as the total concentration in plasma. However, it has been postulated that the free (unbound) fraction of MPA (fMPA) is responsible for the immunosuppressive effects. In this study, a sensitive low volume high-performance liquid chromatography (HPLC) assay was developed to measure fMPA concentrations to explore the relationship between fMPA and IMPDH activity. Methods: To obtain fMPA concentrations, plasma samples were filtrated using Centrifree ultrafiltration devices. The ultrafiltrate was analyzed by HPLC using a Kinetex C18 column (2.6 &mgr;m, 3.0 × 75 mm). fMPA concentrations were compared with the total MPA concentrations available in 28 pediatric kidney transplant patients at 3 consecutive occasions after transplantation. The relationship between fMPA and IMPDH activity was analyzed using an Emax model. Results: The HPLC assay, using 25 &mgr;L of the ultrafiltrates, was validated over a range from 2.5 to 1000 &mgr;L with good accuracy, precision, and reproducibility. Total and free MPA concentrations were well correlated (R2 = 0.85, P < 0.0001), although large intraindividual and interindividual variability in the bound MPA fractions was observed. The overall relationship between fMPA concentrations and IMPDH inhibition using the Emax model was comparable with that of total MPA, as previously reported. The model estimated EC50 value (164.5 &mgr;L) is in good agreement with reported in vitro EC50 values. Conclusions: This study provides a simple HPLC method for the measurement of fMPA and a pharmacologically reasonable EC50 estimate. The good correlation between the total and free MPA concentrations suggests that routine measurement of fMPA to characterize mycophenolate pharmacokinetic and pharmacodynamic does not seem warranted, although the large variability in the bound fractions of MPA warrants further study.

Population pharmacokinetic–pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents

Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model‐based dosing guidelines.

Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1.

Background: Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. Methods: Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC–UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. Results: Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. Conclusions: This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children.