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PEDIATRICS |
From the Division of Pediatric Nephrology, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, New York (Dr Flynn); Division of Pediatric Nephrology, Columbus Children's Hospital, Ohio State University, Columbus, Ohio (Dr Nahata, Dr Mahan); and Division of Pediatric Nephrology and Hypertension, University of Texas Medical School, Houston, Texas (Dr Portman).
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Amlodipine • children • adolescents • hypertension • population pharmacokinetics
Because these properties should not change when the drug is crushed or compounded into a suspension, amlodipine has found widespread use in the treatment of hypertensive children, with many single-center reports of its use appearing in the literature over the past several years.5-11 Furthermore, given that amlodipine is extensively hepatically metabolized, with 90% of the oral dose converted to inactive metabolites, amlodipine concentrations do not seem to increase to the point of clinical significance in renal failure, making it also attractive as an agent in hypertensive children, many of whom have underlying renal disease.
Several findings from the single-center reports mentioned above raise the possibility that the pharmacokinetics of amlodipine may differ in children, especially young children, compared to adults. These include the administration of much higher doses of amlodipine to children than those used in adults and also administration of amlodipine twice daily,9 as opposed to the recommended once-daily dosing in adults, to achieve blood pressure control.1-3 To determine whether amlodipine pharmacokinetics truly differ in children compared to adults and to characterize the pharmacokinetics of amlodipine in children, a population pharmacokinetic study was conducted.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Children were eligible for enrollment if they met the following criteria: age 6 months to 17 years, ongoing treatment with amlodipine at a stable dose for at least 4 weeks, no anticipated change in amlodipine treatment, and signed consent from the parent or legal guardian and assent from the child as required by local IRBs. Children were ineligible for the study if any of the following criteria were met: concomitant treatment with another investigational drug within 1 month prior to study entry; transient, unstable, malignant, or accelerated hypertension; poor vascular access; history of noncompliance; or refusal to provide written consent/assent.
Following enrollment, subjects were seen for a screening visit. A medical history and physical examination were completed, serum chemistries (blood urea nitrogen [BUN], creatinine, bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase) and a hepatitis panel (for hepatitis A, B, and C) were obtained, and an amlodipine dosing diary was begun. Date and time of amlodipine dosing were recorded for 1 week. A second study visit for pharmacokinetic sampling was conducted at least 1 week after visit 1. At this visit, repeat serum chemistries were obtained and blood was collected for analysis of amlodipine concentrations at 4 time points.
For children receiving amlodipine in the morning, blood for amlodipine concentration was drawn 3, 5, 8, and 10 hours following the dose. For children receiving evening or late afternoon dosing, the study visit was conducted on the following day and specimens were drawn at 15, 18, 20, and 24 hours following the prior evening's dose. For children receiving twice-daily dosing, specimens were obtained according to the schedule for morning dosing, and the second dose of the day was withheld until after the 10-hour postdose specimen was drawn.
At study visit 3, which occurred 1 day after visit 2, blood was drawn approximately 24 hours after the visit 2 dose for a trough amlodipine concentration (or 12 hours after the visit 2 dose for patients dosed twice daily). A fourth study visit was conducted 1 day to 3 weeks following study visit 3, at which time another trough amlodipine concentration was obtained.
Blood pressure and other vital signs were obtained at the screening visit and at study visit 2. An oscillometric device (Dinamap® Compact BP Monitor, Critikon, Inc, Tampa, FL) was used for determination of blood pressure. Blood pressure was measured in the subject's right arm while seated. The recommendations of the National High Blood Pressure Education Program Working Group12 were followed with respect to cuff size selection.
Study medication was provided as commercially available Norvasc® (amlodipine) 2.5-mg, 5-mg, and 10-mg tablets. Subjects requiring a liquid preparation of amlodipine were provided with a compounded extemporaneous suspension prepared as previously described.13 Study drug compounding was performed by the investigational pharmacy at each clinical site. There were no amlodipine dose adjustments permitted during the study. Study coordinators maintained regular contact with subjects and their families to monitor compliance with amlodipine treatment. All concomitant medications that the patients were receiving at the time of enrollment were continued for the duration of the study.
Subjects could be withdrawn from the study at any time because of worsening hypertension, study drug-related serious adverse events (SAEs), noncompliance with the study protocol, or withdrawal of consent by the subject's parent/guardian.
Measurement of Amlodipine Concentrations
Amlodipine content was determined in plasma by PPD Development (Richmond, VA).14 All blood samples were of sufficient volumes so that 0.5 mL of plasma could be obtained. Heparinized plasma samples were kept frozen at –20°C prior to analysis. Solid-phase extraction of amlodipine from human plasma and a commercially available internal standard (Damocles10, Inc, Thorndale, Pa; Lot CA#88150-42-9) was performed using a 96-well Waters Oasis MCX extraction plate. The extraction was carried out using a TOMTEC Quadra 96 Model 320.
Following extraction of amlodipine, extracts were dried and reconstituted in 50:50 methanol/water. A 100-µL plasma aliquot was required for the analysis. Following reconstitution, specimens were analyzed using a liquid chromatography/mass spectrophotometer method using positive ion Turbo IonSpray with multiple-reaction monitoring detection. The lower limit of quantification was 0.100 ng/mL. A Leap Technologies CTC A200SE liquid chromatographic autosampler, HP 1100 LC pump, and HP Zorbax analytical column (part 860975-905) were used for the liquid chromatography. A Sciex API 3000 mass spectrometer was used for the mass spectroscopy.
Linearity of the procedure was evaluated by analysis of 9 calibration standards over a range of 0.100 to 50.0 ng/mL using a linear weighted least squares regression algorithm to plot the peak area ratio of amlodipine to internal standard versus concentration. Linearity was indicated by an average correlation coefficient of 0.9991. Intra-assay precision and accuracy were evaluated for 5 human plasma quality control pools. Each quality control pool was analyzed multiple times on 1 assay day. Interassay precision and accuracy were evaluated for 3 of the quality control pools on 5 separate analytical runs. Based on these analyses, the interday and intraday coefficient of variation for the analytical method was less than 10%.
Adverse Event/Safety Monitoring
Assessment of adverse events (AEs) took place at every study visit. Observed or volunteered AEs that occurred during the study were classified by severity (mild, moderate, or severe), by body system, and by the investigator's assessment of relationship to study treatment. Adverse events were recorded as treatment related if described as having a probable, possible, or uncertain relationship to study treatment. Laboratory tests that resulted in discontinuation of treatment or change in dose of study drug were also recorded as AEs and the relationship to treatment assessed by the investigator.
Serious adverse events were defined as any adverse drug experience that resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in a persistent or significant disability or incapacity, or resulted in a congenital anomaly/birth defect. All subjects who received at least 1 dose of study drug were included in safety analyses.
Population Pharmacokinetic Model Development
Population pharmacokinetic analysis was conducted by Globomax LLC (Hanover, MD) using NONMEM (double precision, Version V, Level 1.1) and the NMTRAN preprocessor. The first-order conditional method with interaction (FOCEI) implemented in NONMEM was used throughout this analysis.
The population pharmacokinetic analysis consisted of several major steps—(1) base pharmacokinetic model building, (2) covariate model building, and (3) model reduction—to obtain the final model. A 1-compartment model with first-order absorption and first-order elimination was assumed.15 The model used to describe the data consisted of 3 components: the structural pharmacokinetic model, the between-subject (interindividual) variability in parameter estimates, and the random, residual error in the data that cannot be explained by the model. The structural pharmacokinetic model comprised 3 fixed-effect parameters: clearance (CL/F), apparent volume of distribution (V/F), and the absorption rate constant (ka). Initially, exponential error models were used to describe the interindividual variability terms and were included on all 3 pharmacokinetic parameters in the model, and the initial residual error model used consisted of 2 components: an additive and a proportional component. Once an appropriate base pharmacokinetic model had been developed, individual parameters were generated in NONMEM and their relationship with covariates graphically explored.
Covariates that were evaluated included anthropometric variables, including weight, height, body surface area (BSA), and body mass index (BMI); age, race and gender; and clinical laboratory values recorded at visit 2, including serum creatinine, calculated creatinine clearance, SGOT, SGPT, alkaline phosphatase, total protein, and albumin. Gender, race, and BMI were modeled as categorical covariates. The other covariates were modeled as continuous variables. Linear models of continuous covariates were centered about the median of the distribution of the respective covariate in this population. Equations used to calculate pediatric variables are listed in Appendix A.
The statistical significance of each covariateparameter relationship was tested individually in a stepwise parameter addition method in NONMEM. Each step of the model-building process involved testing the effect of a covariate on the appropriate model parameter in a separate model run. When comparing alternative hierarchical models, differences in the NONMEM objective function (which is equal to minus twice the maximum logarithm of the likelihood of the data) are approximately chi-square distributed with n degrees of freedom (df), where n is the difference in the number of parameters between the 2 hierarchical models. This comparison (likelihood ratio test) resulted in a significant change (P < .05) when the objective function value increased by at least 3.84 units for 1 df. Based on these criteria, covariates that resulted in a significant decrease in the objective function were identified. At the end of the model-building process, all significant covariates were then incorporated into 1 model, which was designated as the "full" NONMEM model.
After the full model was defined, the statistical significance of each covariate-parameter relationship was tested individually in a stepwise deletion method. During the stepwise deletion phase, significance of parameters was assessed at the P < .001 level. A particular covariate parameter in the full model was fixed to its null value, and the model was run to obtain a new objective function. The parameter was then returned to the model, the next covariate parameter was fixed to 0, and a new objective function was determined. This was repeated for each covariate parameter. The least significant parameter (smallest change in objective function) was then removed from the model. This entire cycle was repeated in a stepwise fashion until only significant parameters remained in the "final" NONMEM model.
Statistics
Except where otherwise noted, data in this report are expressed as mean ± standard deviation or as percentages. Further data analysis (other than the pharmacokinetic calculations) was performed using SPSS for Windows 11.5 (SPSS, Inc, Chicago). Statistical significance for all analyses was set at P < .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Mean age of the 74 enrolled subjects was 10.4 ± 4.4 years, with a range of 1 to 17 years. There were 49 males and 25 females. Age and anthropometric characteristics of the subjects by gender are displayed in Table I. The range of weights was large in both sexes (13-142 kg in males and 6-101 kg in females), and the maximum values indicate that obesity was common in this subject population: 32 subjects (43.2%) were classified as obese according to the definition of a subject's BMI being 
95th percentile.16 Of these 32 subjects, 18 were male and 14 were female. Most subjects recruited into this study were white (56%) or black (36%).
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The mean duration of time from when the subjects were first diagnosed with hypertension to study entry was 3.4 years, with a range of 0.1 to 16.8 years. Although information was collected regarding medical conditions other than hypertension, specific information regarding the underlying cause of each subject's hypertension was not recorded. However, there were a wide variety of concomitant conditions documented in the subjects' medical histories, including glomerulonephritis or nephrotic syndrome in 15 subjects, obesity in 18 subjects, urologic malformations in 15 subjects, and a history of solid organ or tissue transplant in 14 subjects.
The median duration of treatment with amlodipine prior to study enrollment was 283 days, with a range of 24 to 1976 days. The median duration of amlodipine dosing during the study was 17 days, with a range of 7 to 90 days. The mean amlodipine dose was 0.17 ± 0.13 mg/kg/d, with a range of 0.03 to 0.77 mg/kg/d. Absolute amlodipine doses ranged from 1.3 to 20 mg/d. Of the subjects, 61 out of 74 (82%) received amlodipine once daily. Only 3 subjects in the study took amlodipine in a liquid formulation.
Population Pharmacokinetics
The final data set used in the NONMEM analysis consisted of 405 plasma concentrations from 73 subjects (on average, 5-6 samples per subject). The subject who received a renal transplant prior to study visit 2 did not provide samples for pharmacokinetic analysis and so was not included in this analysis.
Figure 1 shows the plasma concentrations plotted against time after dose for individuals dosed once a day (Figure 1A) and twice a day (Figure 1B). It can be seen from Figure 1B that there are 5 concentration-time points that are considerably higher than the rest. All of these concentrations were measured in 1 subject (39) who received amlodipine at a dose of 0.26 mg/kg/d; even after dose normalization, this subject still had higher plasma concentrations relative to other subjects.
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All 3 pharmacokinetic parameters were associated with a moderate to high degree of variability, with %CV estimates of 51%, 61%, and 45% for CL/F, V/F, and ka, respectively. Finally, the residual error was initially modeled with both an additive and a proportional component. The additive component of the residual error model tended toward 0 and was removed from the model, leaving only the proportional error in the model (22 %CV), a level of residual variability often seen in sparsely sampled population studies.
The influence of covariates was examined using this base model. Covariates that were significant in the model-building step (using a drop in the objective function of 3.84, P < .05, to define significance) were gender, protein (or albumin), race, creatinine clearance, and any of the estimates for body size (ie, age, weight, height, BMI, BSA, or ideal body weight [IBW]) for clearance and estimates for body size, SGPT, and creatinine clearance for volume.
The various estimates of body size were all highly correlated. However, actual body weight proved to be sufficient and was incorporated into the full model to represent body size. A similar high correlation was observed for age and height and for serum protein and serum albumin levels. The covariate with the biggest change in the objective function and the better model diagnostics (lower weighted residuals, bigger reduction in interindividual variability in clearance, and more precise parameter estimates as indicated by %RSE values) was chosen for inclusion in the full model. Thus, height and serum protein were included as covariates in the full model.
The equation for apparent clearance in the full model included the following covariates: weight, height, creatinine clearance, gender, race = black, and protein level; the equation for volume included the following covariates: weight, creatinine clearance, height, and SGPT level. A backward elimination process using a more stringent criterion for selection of covariates was employed to further determine significant covariates. Using this process, only creatinine clearance and sex remained significant covariates for clearance, and only weight retained significance for volume. Creatinine clearance and actual body weight were also highly correlated in this study. To determine if the effects of these 2 covariates were similar, the final model was run in which creatinine clearance was replaced by weight as a covariate on clearance. The population parameter estimates and the significant covariates for the final model with either creatinine clearance (model 1) or weight (model 2) as covariates on clearance are shown in Table II. The individual model-predicted versus observed concentration-time data for both models are shown in Figure 2. These scatterplots show that the models are similar at predicting concentrations of amlodipine. In addition, the parameter estimates for both models are similar, and the effect of adding either covariate on interindividual variability and residual variability is also similar.
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The population values of CL/F for a subject at the median weight for the study population of 45 kg were 23.7 L/h and 17.61 L/h for males and females, respectively, as compared with estimates of 26.5 L/h and 19.28 L/h for males and females with the median value for CrCL of 97 mL/min. These estimates are similar to the reported estimate for clearance in the literature for adults of 24.8 L/h.15
The coefficients of the model for CL/F were estimated with good precision using both models. Inclusion of these covariates in the model for CL/F explained some of the random interindividual variance in CL/F, as indicated by a reduction in the %CV estimate to 41% or 43% for the final models compared with 51% in the base model. Estimates of all other model parameters were similar in both final models. The average estimate of V/F for a subject with the median value for weight in this population of 45 kg was 1130 for weight (model 2) versus 1150 L using creatinine clearance (model 1). This estimate is similar to the reported population estimate for volume in the literature for adults of 1120 L.15 The coefficients of the model for V/F were estimated with good precision in both models. Inclusion of weight in the model for V/F explained some of the random interindividual variance in V/F, as indicated by the %CV estimate of 49% for the final models compared with 61% in the base model. Inclusion of significant covariates on CL/F and V/F had little impact on the estimation of ka in this study; the population estimate was comparable with the estimate obtained in the base model, 0.790 h–1 versus 0.850 h–1, and was relatively imprecise. Finally, inclusion of these covariates in the model had no effect on the estimation of residual random variability in this study (22 %CV in both the base model and the final models).
There were 3 subjects (11, 39, and 65) whose plasma amlodipine dose-normalized concentrations were noticeably higher than other subjects. Excluding each of these subjects one at a time from the data set of the final model parameter estimates produced minimal changes in CL/F and V/F. Therefore, the data from these subjects were not excluded from the final data set used to develop the final model.
The model with weight included in clearance was selected as the final model and was evaluated using simulated data. Figure 3 shows the results of the model evaluation procedure in which the 10th, 20th, 50th, 80th, and 90th percentiles from the simulated data were plotted with the observed concentration-time data. This figure shows that the model represents the majority of the concentration-time data points for subjects in this study, as the data points fall between the 10th and 90th percentiles of the simulated data based on the final model (in which weight was included in clearance). It can be seen that the concentration-time data for subjects 11, 39, and 65 are consistently above the 90th percentile from the simulated data. However, as discussed above, and because the model represents the majority of the data, the influence of these high concentration-time points does not appear to be large.
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Safety
Of the 74 enrolled subjects, 1 was discontinued due to an adverse event unrelated to study drug (hospitalization for dehydration and hyperglycemia), and another received a renal transplant after study visit 1 and was lost to further follow-up in the study. Amlodipine was temporarily discontinued in 1 additional subject because of an adverse event unrelated to study drug (seizure and urinary tract infection).
Six treatment-related adverse events occurred in 4 subjects (5.4%). These included headache (4), nausea (1), and dizziness (1). Three were considered to be mild in intensity; 1 was moderate and 2 severe. The 2 severe treatment-related adverse events, nausea and dizziness, occurred in the same subject and resolved on the same day as they were initially reported without specific intervention.
There were 7 serious adverse events reported in 5 subjects. Six of these were considered to be related to other illnesses, and 1 was considered to be related to concomitant treatment with a medication other than amlodipine (prednisone); this event led to discontinuation of treatment with study drug. No serious adverse events were considered to be study drug related, and no others led to discontinuation of study drug.
Sixty subjects (81.1%) received treatment with concomitant medications during the study. The most common categories of concomitant medications were antihypertensive agents other than amlodipine (48.6%), corticosteroids (39.2%), immunosuppressive agents (36.5%), and antibiotics (27%).
Baseline clinical laboratory data were available for all 74 subjects. There were 5 subjects with laboratory test abnormalities at baseline, including 2 with an elevated BUN, 1 with an elevated creatinine, 1 with low sodium, and 1 with elevated potassium. Sixty-one subjects provided follow-up laboratory data during the study; reasons for there being no follow-up laboratory data in the remaining subjects (31%) were not available. Nineteen subjects developed laboratory test abnormalities during treatment with study drug, including 15 with an elevated BUN, 6 with an elevated creatinine, 1 with low sodium, and 3 with elevated potassium. No laboratory test abnormality that occurred during the study was felt to be clinically significant, and none resulted in discontinuation from the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Indeed, prior studies of amlodipine in hypertensive children have suggested that significant pharmacokinetic differences may exist between adults and children. In several single-center studies, investigators noted that young children received significantly greater doses on a mg-per-kg basis to achieve control of blood pressure than adults,9,11,22 and in at least 2 studies, twice-daily dosing of amlodipine was used in some children to achieve adequate blood pressure control.9,22 Furthermore, at least 1 study showed a statistically significant inverse relationship between dose of amlodipine in mg/kg and age, suggesting that younger children may require higher doses of amlodipine than older children and adults to achieve effective blood pressure control,9 which the authors speculated was because of increased clearance in younger children.
The findings of this study appear to support these clinical observations. Amlodipine pharmacokinetic parameters were similar to those in adults for children with body weights comparable to adults. However, for children with low body weights—namely, toddlers and young children younger than 6 years of age—amlodipine pharmacokinetic parameters were significantly different, with greater weight-adjusted clearance and volume of distribution than in the older/larger subjects. These apparent decreases in pharmacokinetic parameters associated with maturation throughout the pediatric age range have been noted previously for other medications when parameters are normalized based on weight.23 Given the greater hepatic-to-body size ratio in young children compared to older children and adults, it is tempting to speculate that this effect is directly related to the known hepatic metabolism of amlodipine.4 However, it should be noted that there were a relatively small number of subjects (11) in the youngest age/lowest body weight group. This makes it difficult to definitively conclude that amlodipine metabolism is different in younger than in older children and adults.
In addition to body weight, creatinine clearance was also found to be a significant covariate of apparent amlodipine clearance in this study. Creatinine clearance, calculated using the Schwartz equation,24 has 2 components: a body size component (height) and a physiological component (serum creatinine). As amlodipine is primarily metabolized in the liver,4 it is reasonable to assume that it is the body size component of the Schwartz equation that is exacting an influence here. Thus, the model with weight was taken to be the final model.
Amlodipine plasma concentrations were similar in children whether amlodipine was dosed once or twice daily. This suggests that, as in adults, amlodipine may provide adequate blood pressure control in children when dosed once daily. Indeed, the recently published multicenter amlodipine efficacy study demonstrated that amlodipine produced significant reductions in blood pressure in children when given once daily.25 Therefore, based on the findings of the present study in combination with those of the efficacy study, there does not appear to be justification for twice-daily dosing of amlodipine in children.
Although no subject was discontinued from the study because of adverse events related to study drug, it is difficult to draw conclusions regarding the safety of amlodipine treatment due to the lack of a control group and short duration of treatment with amlodipine. Similar reasons make it impossible to attribute the increases in BUN or serum creatinine that occurred during the study to amlodipine treatment. However, as many single-center studies have demonstrated,5-11 and as confirmed by the multicenter efficacy study,24 it is probably reasonable to conclude that amlodipine is safe for the treatment of hypertensive children, many of whom have underlying conditions such as chronic kidney disease that may benefit from blood pressure reduction.
Limitations of this study have been alluded to above. In addition to the small number of subjects in the youngest age group, no pharmacokinetic simulations were carried out to test whether frequency of dosing had any effect on amlodipine pharmacokinetics. Furthermore, although we tested the final pharmacokinetic model using simulated data, boot-strapping or data-splitting approaches were not used to assess the model's internal validity. Despite these limitations, we feel that these data provide unique insights into amlodipine pharmacokinetics in children and adolescents and raise important questions that merit further study.
In conclusion, this study demonstrates that amlodipine clearance and volume of distribution in older children with body weights comparable to adults are similar to values previously described in adults. However, young children have significantly higher weight-normalized clearance values than older children and adults. Whether or not this confirms that younger children require higher doses on a mg/kg basis to maintain blood pressure control cannot be said conclusively because of the small number of young children enrolled in this study.
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Dr Nahata is a fellow of the American College of Clinical Pharmacology. At the time of the study, Dr Joseph T. Flynn and Dr Milap C. Nahata were paid consultants to Pfizer, Inc, the manufacturer of amlodipine and sponsor of the study.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Pfizer Labs. Norvasc® prescribing information. New York: Pfizer, Inc; 2004.
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5. Khattak S, Rogan JW, Saunder EF, Theis JG, Arbus GS, Koren G. Efficacy of amlodipine in pediatric bone marrow transplant patients. Clin Pediatr. 1998;37: 31-35.
6. Pfammatter, JF, Clericetti-Affolter C, Trittmann AC, Busch K, Laux-End R, Bianchetti MG. Amlodipine once-daily in systemic hypertension. Eur J Pediatr. 1998;157: 618-621.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Tallian KB, Nahata MC, Turman MA, Mahan JD, Hayes JR, Mentser MI. Efficacy of amlodipine in pediatric patients with hypertension. Pediatr Nephrol. 1999;13: 304-310.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Rogan JW, Lyszkiewicz DA, Blowey D, Khattak S, Arbus GS, Koren G. A randomized prospective crossover trial of amlodipine in pediatric hypertension. Pediatr Nephrol. 2000;14: 1083-1087.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
9. Flynn JT, Smoyer WE, Bunchman TE. Treatment of hypertensive children with amlodipine. Am J Hypertens. 2000;13: 1061-1066.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. von Vigier RO, Franscini LMD, Bianda NDF, Pfister R, Casaulta-Aebischer C, Bianchetti MG. Antihypertensive efficacy of amlodipine in children with chronic kidney diseases. J Hum Hypertens. 2001;15: 387–391.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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12. National High Blood Pressure Education Program Working Group. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. Pediatrics. 1996;98: 649-658.
13. Nahata MC, Morosco RS, Hipple TF. Stability of amlodipine besylate in two liquid dosage forms. J Am Pharm Assoc. 1999;39: 375-377.
14. Jenkins RG, Miller JH, Zhang Z. Project CDG validation report, "LC/MS/MS analysis of amlodipine in human plasma," PPD Development, Richmond, Va, December 1999. Also see http://www.ppdi.com/pdf/val_list.pdf for an updated list of validated assays performed by PPD Development. Accessed March 14, 2006.
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16. Himes JH, Dietz WH. Guidelines for overweight in adolescent preventive services: recommendations from an expert committee. Am J Clin Nutr. 1994;59: 307-316.
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19. Public Law 105-115: Food and Drug Administration Modernization Act of 1997. Adopted November 21, 1997. Available at: http://www.fda.gov/opacom/7modact.html.
20. Public Law 107-109: Best Pharmaceuticals for Children Act. Adopted January 4, 2002. Available at: http://www.fda.gov/cder/pediatric.
21. Public Law 108-155: Pediatric Research Equity Act of 2003. Adopted January 7, 2003. Available at: http://www.fda.gov/cder/pediatric.
22. Gitomer JJ, Grimm EM, Bonilla-Felix MA, Swinford RD, Ferris ME, Portman RJ. The safety and efficacy of the calcium channel blocker (CCB) amlodipine in the treatment of secondary hypertension in children [abstract]. Pediatr Res. 1998;43: 308A.
23. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Drug therapy: developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349: 1157-1167.
24. Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children and adolescents. Pediatr Clin N Am. 1987;34: 571-590.[Web of Science][Medline] [Order article via Infotrieve]
25. Flynn JT, Newburger JW, Daniels SR, Sanders SP, Portman RJ, Hogg RJ. A randomized, placebo-controlled trial of amlodipine in children with hypertension. J Pediatr. 2004;145: 353-359.[CrossRef][Web of Science][Medline]
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