Edmund Capparelli | University of California, San Diego (original) (raw)

Papers by Edmund Capparelli

Research paper thumbnail of Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections

The Pediatric Infectious Disease Journal, 2014

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribe... more This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two of 3 children with a staphylococcal CSF infection had CSF concentrations greater than minimal inhibitory concentration at the end of the dosing interval.

Research paper thumbnail of Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics

HIV medicine, 2015

Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by ... more Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-β hydroxycortisol to cortisol (6βHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics. Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau. 6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI)...

Research paper thumbnail of Etravirine in CSF is highly protein bound

Journal of Antimicrobial Chemotherapy, 2013

Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycop... more 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.

Research paper thumbnail of Raltegravir pharmacokinetics during pregnancy

Journal of acquired immune deficiency syndromes (1999), 2014

We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and ... more We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum. International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls. Median raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.91...

Research paper thumbnail of Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

Journal of Antimicrobial Chemotherapy, 2011

Research paper thumbnail of Pharmacokinetic and Safety Evaluation of a Pediatric Formulation of Pentoxifylline for Treatment of Acute Kawasaki Disease

Pediatric Research, 2003

Purpose Is ulinastatin administration an effective treatment for Kawasaki disease? We investigate... more Purpose Is ulinastatin administration an effective treatment for Kawasaki disease? We investigated the ulinastatin administration and other factors that might influence the duration of fever and C-reactive protein (CRP) in the children sufferin g from Kawasaki disease. Method We planed multi-center and retrospective study. We investigated 80 patients in the 12 institutions from March 1998 to May 2001. Three patients were excluded because of a readministration of high-dose gamma glob u lin. 44 female and 33 men were treated by high-dose gamma globulin: a single administration of 2g/kg or ulinastatin administration with high-dose gamma globulin. Ulinastatin was infused 5000/kg x 3 per day intravenously when the patients has high tempe r at ure. Their age was 2.8 ϩ/-2.4 years old. 43 patients were treated by high-dose gamma globulin and 31 patients were treated by high-dose gamma globulin with ulinastatin. We analyzed a correlation between the duration of fever and CRP, and following f ac tor s; age, sex, maximum CRP, maximal white blood cell count, minimal albumin concentration, minimal hemoglobin concentration and treatment protocols, by multiple regression analysis. Result The duration of fever and CRP from the start of t rea tmen ts were 41 ϩ/-39 hours and 8.8 ϩ/-5.4 days. Maximal CRP value was 10.0 ϩ/-7.2 mg/dl. The duration of fever significantly correlated with age and minimal albumin concentration (regression coefficient were 4.57 and -19.1; pϽ0.02 and pϽ0.03, re spect ively). The duration of CRP was significantly correlated with age (regression coefficient was 1.05; pϽ0.0003). Neither the duration of fever nor CRP was correlated with treatment protocols with or without ulinastatin. Conclusion The a dditio nal ulinastatin treatment with high-dose gamma globulin do not influence the duration of fever and CRP in our cases.

Research paper thumbnail of CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV1-infected children

Aids, 2007

Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6... more Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Research paper thumbnail of Bayesian Estimation of Vancomycin Pharmacokinetics in Obese Children: Matched Case-Control Study

Clinical therapeutics, Jan 29, 2015

The study objective was to compare different body size descriptors that best estimate vancomycin ... more The study objective was to compare different body size descriptors that best estimate vancomycin Vd and clearance (CL). Patients between 3 months and 21 years old who received vancomycin for ≥48 hours from 2003 to 2011 were evaluated in this matched case-control study. Cases had body mass index in the ≥85th percentile; controls were nonobese individuals who were matched by age and baseline serum creatinine (SCr). Using a 1-compartment model with first-order kinetics, Bayesian post hoc individual Vd and CL were estimated. Analysis included 87 matched pairs with 389 vancomycin serum concentrations. Median ages were 10.0 (interquartile range [IQR], 4.8-15.2) years for cases (overweight and obese children) and 10.2 (IQR, 4.5-14.8) years for controls (normal-weight children). Median weights were 44.0 (IQR, 23.4-78.1) kg for cases and 31.3 (IQR, 16.8-47.1) kg for controls. Mean (SD) for the baseline SCr values were also similar between the groups: 0.51 (0.22) (IQR, 0.34-0.67) mg/dL and 0....

Research paper thumbnail of Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

Antimicrobial Agents and Chemotherapy, 2015

Candida infections are a leading cause of infectious disease-related death in children supported ... more Candida infections are a leading cause of infectious disease-related death in children supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing may result in suboptimal drugexposure. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. PK data were analyzed using nonlinear mixed effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of creatinine (SCR) on CL, and ECMO on V, as follows: CL(L/h)=0.019*Weight*(SCR/0.4)(-0.29)*exp(ηCL) and V(L)=0.93*Weight*1.4(ECMO)*exp(ηV). Fluconazole V was increased in children supported with ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12mg/kg) and treatment (35mg/kg) paired with standard maintenance doses to achieve exposures similar to children not on ECMO.

Research paper thumbnail of Optimizing pediatric esmolol dosing using computerized practitioner order entry

The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG

The aims of this study were to 1) describe the cardiovascular dose-response of esmolol and dose-l... more 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. 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. A total of 8 subjects repre...

Research paper thumbnail of Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy

The Journal of antimicrobial chemotherapy, 2015

To assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standa... more To assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy. Lopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (>1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy. The median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and vo...

Research paper thumbnail of Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus

Antimicrobial agents and chemotherapy, 1998

We used population analysis techniques to determine zidovudine (ZDV) pharmacokinetic parameters i... more We used population analysis techniques to determine zidovudine (ZDV) pharmacokinetic parameters in 15 preterm neonates (mean gestational age, 29.4 weeks; mean birth weight, 1,230 g) at a mean age of 5.5 days. The values of the pharmacokinetic parameters were as follows: clearance, 2.53 +/- 0.44 ml/min/kg; volume of distribution, 1.59 +/- 0.51 liters/kg; and half-life, 7.2 +/- 1.5 h. For seven infants studied a second time, at a mean age of 17.7 days, an increase in the mean clearance (2.33 versus 4.35 ml/min/kg; P = 0.024) and a decrease in the half-life (7.3 versus 4.4 h; P = 0.003) were found. The ZDV clearance is low and the half-life is prolonged in premature neonates, but the clearance increases and the half-life decreases with postnatal age. Potentially toxic concentrations may accumulate in serum if the standard dosage for full-term infants is used. We suggest that initial ZDV dosing should be reduced to 1.5 mg every 12 h for preterm neonates.

Research paper thumbnail of Abacavir Pharmacokinetics During Chronic Therapy in HIV-1-Infected Adolescents and Young Adults

Clinical Pharmacology & Therapeutics, 2008

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficien... more The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and ≥18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Research paper thumbnail of Pharmacokinetics of zidovudine in infants: A population analysis across studies

Clinical Pharmacology & Therapeutics, 1999

Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxi... more Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxis and therapy of human immunodeficiency virus infection, the developmental pharmacology of zidovudine in the first months of life has not been fully described. We used population analysis to estimate zidovudine pharmacokinetic parameters in newborns and infants who either participated in one of five Pediatric AIDS Clinical Trials Group (PACTG) protocols or were premature infants who had zidovudine concentrations drawn for therapeutic drug monitoring. The data set consisted of 698 serum samples from 83 infants with a mean gestational age at birth of 37.5 weeks (range, 26.0 to 41.5 weeks), mean postnatal age at sampling of 19.3 days (range, 0 to 144 days), and a mean weight at sampling of 3.1 kg (range, 0.71 to 6.0 kg). With use of the program NONMEM and a two-compartment open model, the influences of demographic and clinical factors on the elimination rate constant (k10), volume of distribution of the central compartment (Vc) and bioavailability (F1) were examined. Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old. Zidovudine elimination kinetics undergo large increases during the first months of life, and the pattern of maturation is different in term and preterm infants. Higher bioavailability in younger infants is consistent with decreased first-pass metabolism associated with reduced clearance.

Research paper thumbnail of Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection

Clinical Pharmacology and Therapeutics, 2001

Background: Previous studies of dapsone pharmacokinetics in children have been too small to allow... more Background: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. Methods: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. Results: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L

Research paper thumbnail of Personalized Therapeutics: HIV Treatment in Adolescents

Clinical Pharmacology & Therapeutics, 2008

Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of p... more Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends on multiple factors. The continued use of higher (weight-or surface-based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV-infected adolescents.

Research paper thumbnail of Acetaminophen-Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen Overdose

Clinical Pharmacology & Therapeutics, 2008

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children pres... more Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k e ), elimination half-lives (t ½ ), and maximum concentration of adducts (C max ) of the subjects. The mean (±SD) k e and half-life were 0.486 ± 0.084 days −1 and 1.47 ± 0.30 days, respectively, and the C max was 1.2 (±2.92) nmol/ml serum. The model-derived, predicted

Research paper thumbnail of Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency

Journal of pharmacology & clinical toxicology, 2014

Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MI... more 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*Weight(0.75)*(0.64/SCr)(0.497...

Research paper thumbnail of Population Pharmacokinetics of Dapsone in HIV-Infected Children

Pediatric Research, 1999

Background: Prior investigations of dapsone pharmacokinetics in children have included population... more Background: Prior investigations of dapsone pharmacokinetics in children have included populations too small to allow assessment of the impact of demographic and clinical factors on dapsone pharmacokinetic parameters. Methods: We measured serum concentrations ...

Research paper thumbnail of Nevirapine Concentration in Nonstimulated Saliva: An Alternative to Plasma Sampling in Children with Human Immunodeficiency Virus Infection

Therapeutic Drug Monitoring, 2007

The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since... more The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since the introduction of NVP as part of the preferred first-line antiretroviral regimen for human immunodeficiency virus (HIV)-infected children in resource-limited settings. Adequate trough concentrations of NVP predict successful therapy, whereas subtherapeutic levels are correlated with virologic failure and development of resistance. The aim of this study was to determine the extent of agreement between total and free plasma NVP concentrations and nonstimulated saliva NVP concentrations and to evaluate the feasibility of saliva sampling as an alternative tool for therapeutic drug monitoring of NVP in children. The study was designed as an observational cohort analysis. NVP concentrations were obtained in paired plasma and saliva samples of pediatric patients receiving antiretroviral therapy, including NVP. NVP plasma and saliva concentrations were determined by a tandem-mass spectrometric method. The intraclass correlation coefficient and Bland-Altman analysis were used to evaluate agreement and to assess pattern in any discrepancies between measurements. For the random paired plasma and saliva NVP sampling, 19 African-American children (8 boys, 11 girls) with a median age of 8.0 years were enrolled. Two male subjects were recruited for the 12 hour NVP plasma and saliva pharmacokinetics study. The intraclass correlations between saliva and serum measurements of NVP concentrations indicated &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90% agreement between these two modes of measurement. The saliva concentrations reflected the free concentrations very closely but were on average 34% higher. The Bland-Altman plots indicated that the discrepancy between saliva and plasma measures is consistent across the range of average NVP concentrations. Our study results strongly indicate agreement between saliva and plasma NVP concentrations in pediatric patients with HIV infection, on the basis of Bland-Altman analysis. Nonstimulated NVP saliva concentrations can be used as an alternative noninvasive, reliable, cost-effective method for direct measurement of adherence and application of therapeutic drug monitoring in NVP therapy.

Research paper thumbnail of Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections

The Pediatric Infectious Disease Journal, 2014

This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribe... more This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two of 3 children with a staphylococcal CSF infection had CSF concentrations greater than minimal inhibitory concentration at the end of the dosing interval.

Research paper thumbnail of Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics

HIV medicine, 2015

Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by ... more Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-β hydroxycortisol to cortisol (6βHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics. Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau. 6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI)...

Research paper thumbnail of Etravirine in CSF is highly protein bound

Journal of Antimicrobial Chemotherapy, 2013

Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycop... more 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.

Research paper thumbnail of Raltegravir pharmacokinetics during pregnancy

Journal of acquired immune deficiency syndromes (1999), 2014

We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and ... more We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum. International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls. Median raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.91...

Research paper thumbnail of Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

Journal of Antimicrobial Chemotherapy, 2011

Research paper thumbnail of Pharmacokinetic and Safety Evaluation of a Pediatric Formulation of Pentoxifylline for Treatment of Acute Kawasaki Disease

Pediatric Research, 2003

Purpose Is ulinastatin administration an effective treatment for Kawasaki disease? We investigate... more Purpose Is ulinastatin administration an effective treatment for Kawasaki disease? We investigated the ulinastatin administration and other factors that might influence the duration of fever and C-reactive protein (CRP) in the children sufferin g from Kawasaki disease. Method We planed multi-center and retrospective study. We investigated 80 patients in the 12 institutions from March 1998 to May 2001. Three patients were excluded because of a readministration of high-dose gamma glob u lin. 44 female and 33 men were treated by high-dose gamma globulin: a single administration of 2g/kg or ulinastatin administration with high-dose gamma globulin. Ulinastatin was infused 5000/kg x 3 per day intravenously when the patients has high tempe r at ure. Their age was 2.8 ϩ/-2.4 years old. 43 patients were treated by high-dose gamma globulin and 31 patients were treated by high-dose gamma globulin with ulinastatin. We analyzed a correlation between the duration of fever and CRP, and following f ac tor s; age, sex, maximum CRP, maximal white blood cell count, minimal albumin concentration, minimal hemoglobin concentration and treatment protocols, by multiple regression analysis. Result The duration of fever and CRP from the start of t rea tmen ts were 41 ϩ/-39 hours and 8.8 ϩ/-5.4 days. Maximal CRP value was 10.0 ϩ/-7.2 mg/dl. The duration of fever significantly correlated with age and minimal albumin concentration (regression coefficient were 4.57 and -19.1; pϽ0.02 and pϽ0.03, re spect ively). The duration of CRP was significantly correlated with age (regression coefficient was 1.05; pϽ0.0003). Neither the duration of fever nor CRP was correlated with treatment protocols with or without ulinastatin. Conclusion The a dditio nal ulinastatin treatment with high-dose gamma globulin do not influence the duration of fever and CRP in our cases.

Research paper thumbnail of CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV1-infected children

Aids, 2007

Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6... more Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Research paper thumbnail of Bayesian Estimation of Vancomycin Pharmacokinetics in Obese Children: Matched Case-Control Study

Clinical therapeutics, Jan 29, 2015

The study objective was to compare different body size descriptors that best estimate vancomycin ... more The study objective was to compare different body size descriptors that best estimate vancomycin Vd and clearance (CL). Patients between 3 months and 21 years old who received vancomycin for ≥48 hours from 2003 to 2011 were evaluated in this matched case-control study. Cases had body mass index in the ≥85th percentile; controls were nonobese individuals who were matched by age and baseline serum creatinine (SCr). Using a 1-compartment model with first-order kinetics, Bayesian post hoc individual Vd and CL were estimated. Analysis included 87 matched pairs with 389 vancomycin serum concentrations. Median ages were 10.0 (interquartile range [IQR], 4.8-15.2) years for cases (overweight and obese children) and 10.2 (IQR, 4.5-14.8) years for controls (normal-weight children). Median weights were 44.0 (IQR, 23.4-78.1) kg for cases and 31.3 (IQR, 16.8-47.1) kg for controls. Mean (SD) for the baseline SCr values were also similar between the groups: 0.51 (0.22) (IQR, 0.34-0.67) mg/dL and 0....

Research paper thumbnail of Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

Antimicrobial Agents and Chemotherapy, 2015

Candida infections are a leading cause of infectious disease-related death in children supported ... more Candida infections are a leading cause of infectious disease-related death in children supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing may result in suboptimal drugexposure. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. PK data were analyzed using nonlinear mixed effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of creatinine (SCR) on CL, and ECMO on V, as follows: CL(L/h)=0.019*Weight*(SCR/0.4)(-0.29)*exp(ηCL) and V(L)=0.93*Weight*1.4(ECMO)*exp(ηV). Fluconazole V was increased in children supported with ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12mg/kg) and treatment (35mg/kg) paired with standard maintenance doses to achieve exposures similar to children not on ECMO.

Research paper thumbnail of Optimizing pediatric esmolol dosing using computerized practitioner order entry

The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG

The aims of this study were to 1) describe the cardiovascular dose-response of esmolol and dose-l... more 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. 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. A total of 8 subjects repre...

Research paper thumbnail of Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy

The Journal of antimicrobial chemotherapy, 2015

To assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standa... more To assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy. Lopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (>1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy. The median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and vo...

Research paper thumbnail of Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus

Antimicrobial agents and chemotherapy, 1998

We used population analysis techniques to determine zidovudine (ZDV) pharmacokinetic parameters i... more We used population analysis techniques to determine zidovudine (ZDV) pharmacokinetic parameters in 15 preterm neonates (mean gestational age, 29.4 weeks; mean birth weight, 1,230 g) at a mean age of 5.5 days. The values of the pharmacokinetic parameters were as follows: clearance, 2.53 +/- 0.44 ml/min/kg; volume of distribution, 1.59 +/- 0.51 liters/kg; and half-life, 7.2 +/- 1.5 h. For seven infants studied a second time, at a mean age of 17.7 days, an increase in the mean clearance (2.33 versus 4.35 ml/min/kg; P = 0.024) and a decrease in the half-life (7.3 versus 4.4 h; P = 0.003) were found. The ZDV clearance is low and the half-life is prolonged in premature neonates, but the clearance increases and the half-life decreases with postnatal age. Potentially toxic concentrations may accumulate in serum if the standard dosage for full-term infants is used. We suggest that initial ZDV dosing should be reduced to 1.5 mg every 12 h for preterm neonates.

Research paper thumbnail of Abacavir Pharmacokinetics During Chronic Therapy in HIV-1-Infected Adolescents and Young Adults

Clinical Pharmacology & Therapeutics, 2008

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficien... more The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and ≥18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Research paper thumbnail of Pharmacokinetics of zidovudine in infants: A population analysis across studies

Clinical Pharmacology & Therapeutics, 1999

Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxi... more Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxis and therapy of human immunodeficiency virus infection, the developmental pharmacology of zidovudine in the first months of life has not been fully described. We used population analysis to estimate zidovudine pharmacokinetic parameters in newborns and infants who either participated in one of five Pediatric AIDS Clinical Trials Group (PACTG) protocols or were premature infants who had zidovudine concentrations drawn for therapeutic drug monitoring. The data set consisted of 698 serum samples from 83 infants with a mean gestational age at birth of 37.5 weeks (range, 26.0 to 41.5 weeks), mean postnatal age at sampling of 19.3 days (range, 0 to 144 days), and a mean weight at sampling of 3.1 kg (range, 0.71 to 6.0 kg). With use of the program NONMEM and a two-compartment open model, the influences of demographic and clinical factors on the elimination rate constant (k10), volume of distribution of the central compartment (Vc) and bioavailability (F1) were examined. Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old. Zidovudine elimination kinetics undergo large increases during the first months of life, and the pattern of maturation is different in term and preterm infants. Higher bioavailability in younger infants is consistent with decreased first-pass metabolism associated with reduced clearance.

Research paper thumbnail of Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection

Clinical Pharmacology and Therapeutics, 2001

Background: Previous studies of dapsone pharmacokinetics in children have been too small to allow... more Background: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. Methods: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. Results: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L

Research paper thumbnail of Personalized Therapeutics: HIV Treatment in Adolescents

Clinical Pharmacology & Therapeutics, 2008

Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of p... more Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends on multiple factors. The continued use of higher (weight-or surface-based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV-infected adolescents.

Research paper thumbnail of Acetaminophen-Associated Hepatic Injury: Evaluation of Acetaminophen Protein Adducts in Children and Adolescents With Acetaminophen Overdose

Clinical Pharmacology & Therapeutics, 2008

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children pres... more Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k e ), elimination half-lives (t ½ ), and maximum concentration of adducts (C max ) of the subjects. The mean (±SD) k e and half-life were 0.486 ± 0.084 days −1 and 1.47 ± 0.30 days, respectively, and the C max was 1.2 (±2.92) nmol/ml serum. The model-derived, predicted

Research paper thumbnail of Population-Based Pharmacokinetic Modeling of Vancomycin in Children with Renal Insufficiency

Journal of pharmacology & clinical toxicology, 2014

Vancomycin dosing to achieve the area-under-the-curve to minimum inhibitory concentration (AUC/MI... more 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*Weight(0.75)*(0.64/SCr)(0.497...

Research paper thumbnail of Population Pharmacokinetics of Dapsone in HIV-Infected Children

Pediatric Research, 1999

Background: Prior investigations of dapsone pharmacokinetics in children have included population... more Background: Prior investigations of dapsone pharmacokinetics in children have included populations too small to allow assessment of the impact of demographic and clinical factors on dapsone pharmacokinetic parameters. Methods: We measured serum concentrations ...

Research paper thumbnail of Nevirapine Concentration in Nonstimulated Saliva: An Alternative to Plasma Sampling in Children with Human Immunodeficiency Virus Infection

Therapeutic Drug Monitoring, 2007

The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since... more The monitoring of nevirapine (NVP) concentrations in pediatric patients has gained interest since the introduction of NVP as part of the preferred first-line antiretroviral regimen for human immunodeficiency virus (HIV)-infected children in resource-limited settings. Adequate trough concentrations of NVP predict successful therapy, whereas subtherapeutic levels are correlated with virologic failure and development of resistance. The aim of this study was to determine the extent of agreement between total and free plasma NVP concentrations and nonstimulated saliva NVP concentrations and to evaluate the feasibility of saliva sampling as an alternative tool for therapeutic drug monitoring of NVP in children. The study was designed as an observational cohort analysis. NVP concentrations were obtained in paired plasma and saliva samples of pediatric patients receiving antiretroviral therapy, including NVP. NVP plasma and saliva concentrations were determined by a tandem-mass spectrometric method. The intraclass correlation coefficient and Bland-Altman analysis were used to evaluate agreement and to assess pattern in any discrepancies between measurements. For the random paired plasma and saliva NVP sampling, 19 African-American children (8 boys, 11 girls) with a median age of 8.0 years were enrolled. Two male subjects were recruited for the 12 hour NVP plasma and saliva pharmacokinetics study. The intraclass correlations between saliva and serum measurements of NVP concentrations indicated &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;90% agreement between these two modes of measurement. The saliva concentrations reflected the free concentrations very closely but were on average 34% higher. The Bland-Altman plots indicated that the discrepancy between saliva and plasma measures is consistent across the range of average NVP concentrations. Our study results strongly indicate agreement between saliva and plasma NVP concentrations in pediatric patients with HIV infection, on the basis of Bland-Altman analysis. Nonstimulated NVP saliva concentrations can be used as an alternative noninvasive, reliable, cost-effective method for direct measurement of adherence and application of therapeutic drug monitoring in NVP therapy.