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QUANTITATIVE CLINICAL PHARMACOLOGY |
From Daiichi Sankyo, Inc, Parsippany, New Jersey (Dr Rohatagi, Dr Lee, Dr Salazar) and Pharsight Corporation, Mountain View, California (Dr Carrothers, Dr Kshirsagar, Dr Khariton). Dr Salazar is also a Fellow of the ACCP.
Address for reprints: Shashank Rohatagi, PhD, MBA, Fellow FCP, Daiichi Sankyo Pharma Development, 399 Thornal St, Edison, NJ 08837; e-mail: srohatagi{at}dsus.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: Population pharmacokinetics • amlodipine • olmesartan • exposure-response
Olmesartan medoxomil is rapidly and completely converted to olmesartan during gastrointestinal absorption.6 Studies in healthy volunteers6,7 and in subjects with hypertension6,8 have shown that the pharmacokinetics of the drug are predictable with a low potential for drug interactions, although serum drug concentrations may be elevated in patients aged 
65 years and in those with renal or hepatic insufficiency.2 Similarly, the oral clearance (CL) of amlodipine is affected by age and hepatic insufficiency.9,10
Population-based assessments of the pharmacokinetics of olmesartan previously have been conducted in a small number of healthy volunteers (n = 16)11 and in a pooled analysis of data from healthy volunteers and hypertensive patients (n = 472).12
Modeling and simulation was undertaken to support the registration and inform future phase IIIb and phase IV decision making for the fixed-dose combination of the 2 compounds. The first objective of the analysis was to model the population pharmacokinetics of amlodipine and olmesartan using data collected from 4 phase I studies and 1 phase III study to characterize and quantify the effects of covariates, including age, body weight, gender, serum creatinine (SCr), race, and subject status (ie, healthy volunteer or hypertensive patient) on the oral CL of the 2 compounds. The covariate analysis for amlodipine also included serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin levels because hepatic dysfunction affects the pharmacokinetics of the drug. The analysis aimed to determine whether coadministration of amlodipine besylate and olmesartan medoxomil modified the oral CL of the active moieties. An exposure-response model was developed to characterize trough seated diastolic blood pressure (SeDBP) after administration of a fixed-dose combination formulation of amlodipine besylate/olmesartan medoxomil, concomitant administration of the 2 drugs in single-entity tablets, and administration of each drug as monotherapy. The effects of covariates (age, race, weight, gender, and baseline SeDBP) on the parameters of the exposure-response model were characterized and quantified.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The phase I studies were conducted at MDS Pharma Services in Neptune, New Jersey, and Phoenix, Arizona. The phase III study was conducted at 172 clinical sites in the United States. An investigational review board approved each study protocol. Written informed consent was obtained from each study participant before any study-specific procedures or assessments. Studies were conducted under the principles of the World Medical Assembly Declaration of Helsinki and its most recent amendments, the US Code of Federal Regulations, and good clinical practice.
The phase I studies evaluated the pharmacokinetics of amlodipine and olmesartan after administration of amlodipine besylate and olmesartan medoxomil in healthy volunteers, including the potential for a pharmacokinetic drug-drug interaction between amlodipine and olmesartan, the bioavailability of the fixed-dose combination formulation relative to concomitant administration of the 2 drugs in commercially available single-entity products, the effect of a high-fat meal on the bioavailability of the 2 agents administered as a fixed-dose combination, and dose proportionality of the 2 agents administered in a fixed-dose combination tablet (Table I). The phase III study assessed the safety and efficacy of amlodipine besylate/olmesartan medoxomil compared with monotherapy with either agent in patients with mild to severe hypertension (Table I).
Blood pressure (BP) was measured at trough prior to dosing in the phase III study. SeDBP measurements were taken at the start (visit 3) and end (visit 7, week 8) of the relevant period. Three measurements, at least 1 minute apart, were obtained on each occasion.
The analytical methods used for the phase III study and 3 of the phase I studies were developed and implemented by 2 separate laboratories. An aliquot of human plasma (EDTA) containing the analyte and internal standard was extracted using a liquid-liquid procedure. The extracted samples were analyzed by a high-performance liquid chromatography (HPLC) system equipped with an AB/MDS Sciex API 4000 mass spectrometer. Positive ions were monitored in the multiple-reaction monitoring (MRM) mode. For olmesartan assay, the MRM transitions were 447.2/207.1 for olmesartan and 461.2/207.1 for internal standard (RNH-6272, a structural analog of olmesartan). For amlodipine assay, the MRM transitions were 409.1/238.1 for amlodipine and 418.1/238.1 for internal standard (d9-amlodipine). Human plasma (EDTA), free of significant interference, was used to prepare calibration standard and quality control (QC) samples. For both compounds, a set of 9 nonzero calibration standards, ranging from 1.00 to 400 ng/mL for olmesartan (50-10 000 pg/mL for amlodipine), and QC samples at 4 different concentrations—3.00 ng/mL, 50 ng/mL, 300 ng/mL, and 1200 ng/mL (150 pg/mL, 1500 pg/mL, 7500 pg/mL, and 30 000 pg/mL for amlodipine)—were prepared and subsequently stored at a nominal temperature of –20°C. A 
weighted linear regression model was then used to calculate slope, intercept, and correlation coefficient. Study sample, QC, and back-calculated results were then obtained by fitting the peak area ratio to the weighted regression equation for the relevant standards. Between-batch precision (% coefficient of variation [CV]) and accuracy (%Bias) results for QC samples prepared at low, medium, and high QC concentrations are summarized in the individual bioanalysis reports. The accuracy of sample dilution was verified by the performance of dilution QC samples. At least 50% of the diluted QC samples must have been within ±15% of the nominal concentration for the dilution scheme to be accepted.
Pharmacokinetic Sampling
Intensive pharmacokinetic sampling was conducted after 10 days of treatment in the drug-drug interaction study and after a single oral dose of study medication in the other phase I trials. Blood samples were collected up to 72 hours postdose for analysis of olmesartan and up to 144 hours postdose for analysis of amlodipine. In the phase III trial, trough steady-state samples were collected predose. Maximum plasma concentrations (Cmax) at steady state were determined in samples collected 0.5 to 2 hours postdose for olmesartan and 4 to 10 hours postdose for amlodipine.
Pharmacokinetic Data Analysis and Model Development
Graphic representation of the data was performed using S-PLUS software, Version 6.2. All pharmacokinetic and exposure-response analyses were done with NONMEM Version V, Level 1.1,13 with the first-order (FO) method for the pharmacokinetic models and the first-order with conditional estimation (FOCE) method for the exposure-response model.
The development of the population pharmacokinetic model commenced with an exploratory pharmacokinetic data analysis of model relationships, determination of an appropriate structural model, optimization of intersubject random effect matrices, performance of covariate analysis by forward selection and stepwise backward elimination, and establishment of a tentative final pharmacokinetic model (criteria for selection described later). The model then underwent assessment for quality, parameter estimates and standard errors, intra- and interpatient variability estimates, distribution of interindividual variability terms (
, independent normally distributed random effects with mean 0 and variance 
2), and diagnostic plots to validate a final pharmacokinetic model. The approach was based on the US Food and Drug Administration (FDA) Guidance for Industry Population Pharmacokinetics.14
The pharmacokinetic data were analyzed through the generation of drug concentration versus time profiles for each subject in each study. Continuous covariates were plotted against each subject number to identify correlations. Box plots of continuous covariates, sorted by categorical covariates, were also created to identify potential relationships.
Various compartmental models and combinations of interindividual and residual error models were assessed in describing the plasma concentration-time data for olmesartan and amlodipine. One- and 2-compartment structural models were evaluated based on graphic evaluation of plasma concentration versus time profiles.
A clinically significant interaction between the 2 drugs was defined as one that caused at least a 1.25-fold change in oral CL of 1 agent (ie, the ratio of the CI for monotherapy/CI for combination therapy outside of the bioequivalence range of 80%–125%).
The exposure-response modeling included the analysis of the intercept (ie, placebo effect) and identification of covariates that influenced it. Modeling of drug effects focused on modeling the relationship between exposure (as measured by the area under the concentration–time curve [AUC]) and change from baseline in SeDBP. Two different structural models were investigated for this purpose:
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After covariate relationships were established, a model incorporating all exposure-response data was built to determine the structural form of the exposure-response interaction, if any.
Although blood pressure varies diurnally, the sampling scheme of the phase III study was not rich enough to enable modeling diurnal variation. Because the AUC values were used to correlate exposure to response, and because the distribution of sampling times did not vary by arm, the assessment of the placebo-adjusted effect on blood pressure would not be affected.
Subject Covariate Analysis
Factors included in the analyses for amlodipine and olmesartan were body weight, age, SCr, health status, sex, race, and concomitant medication. Serum ALT, AST, and total bilirubin levels were also included in the amlodipine analysis. For the assessment of actual covariate effects, a statistically significant change in the objective function (
= 0.05) was used to determine whether the effect existed. In addition, any effect was required to be well estimated such that the 95% confidence intervals (CIs) for the estimate did not include 0.
In the forward selection process, covariates were screened one at a time in NONMEM to ascertain whether any covariates modified the parameters for the monotherapy models. Continuous covariates were included in the model as follows:
 | (1) |
i is the value of the parameter for the ith individual, Typical is the typical value of the parameter in the population, Covi is the value of the covariate for the individual, Covmedian is the median value of the covariate in the study population, and eff is the effect of the covariate on the parameter.
Categorical covariates were introduced into the model as follows:
 | (2) |
Parameter-covariate relationships were included in a full tentative pharmacokinetic model if the covariate contributed at least a 3.84 change in the objective function ( = 0.05 for 1 degree of freedom, chi-squared). Covariates were then excluded from the model using a simple backward elimination method if the covariate relationship did not contribute at least a 6.63 change in the objective function ( = 0.01 for 1 degree of freedom, chi-squared).
Model Assessment and Validation
Graphic plots of population-predicted and individual-predicted values versus observed concentrations were constructed, and residuals (differences between the logarithm of the measured and predicted concentrations) were examined to determine if model bias existed. The precision of the parameter estimation was evaluated as a percent of the standard error (SE) of the mean (SE of parameter estimate/parameter estimate*100%). Potential relationships between structural model parameters and covariates were examined graphically after accounting for all statistically significant covariate relationships to determine if any trends remained.
To verify that the models adequately described the central tendency and spread of the data, we overlaid plots of actual data with model predictions (mean, 95% CI) to determine the fraction of the data that lay within the model prediction interval.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Pharmacokinetic Model
Population Pharmacokinetic Analysis for Olmesartan
The pharmacokinetic data for olmesartan were best described by a 2-compartment linear model with first-order absorption and elimination and an absorption time lag. This result agrees with the biexponential decline seen in the plasma concentration versus time data and also with the findings of a previous population pharmacokinetic analysis.12
The parameters included in the final covariate model for the CL of olmesartan are shown in Table III. According to the model, CL was significantly (P < .05) affected by sex, body weight, renal function (as measured by SCr), and subject status (ie, healthy volunteer or hypertensive patient) according to the following equation:
 | (3) |
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The model estimates that a male patient with a baseline SCr of 1 mg/dL and body weight of 86 kg, the median values for the study population, would have a CL of 5.9 L/h. A healthy male volunteer with similar SCr and body weight would have a CL of 7.6 L/h. CL in female patients would be approximately 15% lower than in men. Each 10% decrease in body weight from the median of 86 kg would translate into a 3.3% decrease in CL, and each 10% increase in SCr would translate into a 2.7% decrease in CL. The residual error model indicated that separate additive terms were required for the phase I and phase III subsets in addition to the proportional error term that was applicable to all studies.
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Figure 2A depicts 3 model qualification plots for olmesartan concentration, overlaid with observed concentrations by study design (single- and multiple-dose phase I studies and the phase III study). Across the plots, 82% to 94% of the data fell within the 95% CI of the model predictions, supporting the validity of the model. A posterior-predictive check for AUC in the intensively sampled studies showed that approximately 90% of the observed AUCs fell within the 95% prediction interval of the model.
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 | (4) |
The parameters for the final covariate model for the CL of amlodipine are shown in Table III. The model estimates that a 50-year-old subject with a serum ALT of 17 IU/L and body weight of 86 kg would have a CL of 22.9 L/h. Each 10% decrease in body weight would translate into a 2.1% decrease in CL, each 10% increase in age would translate into a 3.7% decrease in CL, and each 10% increase in serum ALT level would translate into a 1.4% decrease in CL. The residual error model indicated that an additive term was required for the phase III study in addition to the proportional error term that was applicable to all studies.
Goodness-of-fit plots for the base (ie, no covariate effects modeled) amlodipine 1-compartment model showed the model to be appropriate. The individual- and population-predicted plasma amlodipine concentrations matched the observed (measured) plasma amlodipine concentrations, demonstrating that the model adequately described the data (Figure 1B; weighted and raw residuals versus the population predictions and time are available online). Figure 1B also illustrates the weighted and raw residuals versus the population predictions and versus time.
The goodness-of-fit plot for subsets of amlodipine data stratified for the presence (combination therapy) or absence (monotherapy) of olmesartan again showed that the predicted concentrations matched the observed concentrations satisfactorily (available online). Goodness-of-fit plots stratified by phase showed the differences in residual error (available online).
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Population Interaction Analysis
Neither compound influenced the CL of the other according to the prespecified definition of a clinically significant interaction: at least a 1.25-fold change in the CL of 1 compound after coadministration of the other.
The sensitivity analysis of covariate effects on the CL of olmesartan and amlodipine is shown in Figure 3A,B. Each bar represents the influence of a single covariate on typical CL, with the most influential variables at the top. The vertical reference line is the CL in a typical subject. Additional analyses of both of the final population pharmacokinetic models were performed to determine if covariate effects on CL were modified by coadministration of olmesartan medoxomil and amlodipine besylate. These analyses showed that the covariate effects for olmesartan (subject status, gender, body weight, and SCr) and for amlodipine (body weight, age, and serum ALT) were not modified by coadministration. As seen in Table II, the covariate distributions were similar in the olmesartan and amlodipine subsets, so there was no concern for confounding of the other covariate effects by the respective codrugs.
Exposure-Response Analysis for SeDBP
A final exposure-response model for change in SeDBP from baseline examined the antihypertensive effects of amlodipine and olmesartan to their systemic exposures (AUCAML and AUCOLM, respectively). Exploratory plots (Figure 4) and model exploration indicated that a linear model was preferable for modeling the dependence of SeDBP on amlodipine exposure based on the monotherapy data set. In contrast, an Emax model best described the dependence of SeDBP on olmesartan. Body weight, age, sex, and race were investigated as possible covariates on the placebo and drug effect.
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When the drug effects are small relative to baseline, then the interaction term is also small, and the modeled combined effect is similar to the simple additive sum of the 2 monotherapy effects. As the monotherapy drug effects increase, the similarity slowly decreases. As an example, consider a theoretical subject in which amlodipine besylate 10 mg/day reduced SeDBP by 10 mm Hg and in which olmesartan medoxomil 40 mg/day reduced SeDBP by 12 mm Hg. The model would predict a drug effect of (–10) + (–12) + 0.05*(–10)*(–12) = –16 mm Hg for combination therapy with amlodipine besylate/olmesartan medoxomil 10/40 mg/day. Assuming a baseline DBP of 100 mm Hg, this would compare to a drug effect of (–10) + (–12) + 0.01*(–10)*(–12) = –20.8 mm Hg if there was complete pharmacological independence.
The final model for change from baseline in SeDBP was this:
 | (5) |
an additive random effect, and 
the residual error. Black race significantly modified both of the drug effect models, increasing the slope in the amlodipine model and decreasing Emax in the olmesartan model. No other covariate relationships were significant.
Compared with other races, subjects of black race had an approximately 20% greater reduction in SeDBP after equivalent exposure to amlodipine but had only half of the maximal reduction in SeDBP after equivalent exposure to olmesartan, as demonstrated in the following 2 equations:
 | (6) |
 | (7) |
The placebo effect was estimated as a –3.59 mm Hg reduction in SeDBP, with Hispanic subjects showing a larger placebo effect than non-Hispanic subjects. Patients with a higher baseline SeDBP also experienced a larger placebo effect (an approximate additional 3 mm Hg decrease per 10 mm Hg of additional baseline SeDBP).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Effect sizes were consistent between the current and prior analyses, with all 4 common covariates (subject status, sex, body weight, and baseline SCr) falling within ±20% of the previous estimates. The effect of age in the prior study was minimal, with an approximate 1.3% decrease in CL per 10% increase in age.12 Because age was correlated with SCr in this study, any effects of age on olmesartan CL were most likely incorporated into the effect of SCr.
Women generally have lower body weight, serum ALT, and SCr than men. A typical woman with body weight of 85.6 kg and SCr of 0.98 mg/dL enrolled in the phase III study would have an 18% higher exposure than a typical man with body weight of 102.1 kg and SCr of 1.17 mg/dL, which is similar to the 17% difference between a woman and man of identical bodyweight and SCr.
A 1-compartment model with additive plus proportional error and a lag time on absorption was found to be the best structural model for amlodipine, which is consistent with previous studies.15,16 Body weight, age, and baseline serum ALT significantly affected the CL of amlodipine. Lower CL and higher exposure occurs in subjects with higher baseline ALT, more advanced age, and/or lower body weight. Previous estimates of 24.6 L/h for CL and 21.0 to 36.1 L/kg for the volume of the central compartment16 compare well with the estimates of 22.9 L/h and 1530 L in this analysis. A recent analysis of data from 74 children and adolescents with hypertension concluded that the pharmacokinetics of amlodipine were best described by a 1-compartment model with first-order absorption and elimination and produced estimates of 23.7 L/h for CL in boys, 17.6 L/h for CL in girls, and 1150 L for central volume.15 Weight also exerted a significant influence on CL in children and adolescents, similar to the results of the present analysis.
Advanced age is associated with increased exposures to amlodipine and olmesartan. For amlodipine, the association between age and drug exposure is explained, in part, by differences in weight and, to a lesser extent, by differences in serum ALT. For olmesartan, the association between age and drug exposure is explained by differences in body weight and SCr. The greater part of the association of amlodipine exposure and age is due to an effect of age on CL of the drug, which is independent of age-related differences in body weight and other covariates. Age did not modify the BP response at equivalent exposures (black race was the only modifying covariate in this analysis). This suggests that a greater BP response in older than younger patients may be explained by the higher drug exposure in the older age group, similar to the effect of gender on drug exposure and BP response described above.
Coadministration of amlodipine besylate with olmesartan medoxomil does not alter the pharmacokinetics of either agent.17,18 In the present analysis, concomitant administration of the 2 drugs did not modify the influence of covariates on the CL of either amlodipine or olmesartan.
Exposure-response modeling showed that steady-state AUC of both amlodipine and olmesartan was a valid predictor of change in SeDBP. An earlier olmesartan exposure-response analysis also found AUC to have an Emax-type relationship for prediction of changes in 24-hour ambulatory DBP.19
The placebo effect for 
SeDBP in this study was approximately –3.5 mm Hg, which is similar to that reported in a prior analysis.20 The impact of baseline SeDBP on the placebo effect is expected, as patients with higher baseline values have a greater potential for clinical improvement.
The negative effect of black race on the maximum effect of olmesartan is consistent with previous reports that subjects of black race have less activation of the renin-angiotensin system and, hence, a lesser response to ARBs when compared with Caucasians.21
The impact of coadministration of amlodipine besylate and olmesartan medoxomil on exposure-response was modeled as a fraction of the product of the drug effects. For subjects receiving both drugs, the effect was higher than in subjects receiving either of the 2 drugs alone, with patients realizing 80% to 100% of the calculated benefit after adding the effect of monotherapy at each of the respective AUCs. The self-regulation of blood pressure22 may be attenuating the additive effect.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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In the exposure-response model, black race decreased the maximal possible effect of olmesartan on BP and increased the effect of amlodipine on BP without influencing pharmacokinetic parameters. The drug effect of combination therapy, defined on the basis of exposure to both compounds, was greater than monotherapy with either agent.
Financial disclosure: Editorial assistance was provided by Blair Jarvis, MSc. Development of this manuscript was supported by Daiichi Sankyo, Inc. The authors wish to thank Helen Kastrissios, Pharsight Corporation, for her assistance with the pharmacokinetic models.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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1. Norvasc [prescribing information]. New York: Pfizer Labs; 2005.
2. Benicar [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc; 2006.
3. Salazar D, Lee J, Shenouda M, Rohatagi S. Lack of pharmacokinetic (PK) drug interaction between olmesartan medoxomil (OM) and amlodipine besylate (AM) during coadministration [abstract]. Presented: at American Society of Hypertension (ASH) Annual Meeting; May 2007; Chicago, IL.
4. Haworth S, Heyrman R, Singh Bathala M, et al. The bioavailability (BAV) of a fixed-dose combination of olmesartan medoxomil (OM) and amlodipine besylate (AM) is unaffected by food [abstract]. Presented at: American Society of Hypertension (ASH) Annual Meeting; May 2007; Chicago, IL.
5. Rohatagi S, Haworth S, Heyrman R, et al. Low and high doses of a fixed-dose combination of olmesartan medoxomil (OM) and amlodipine besylate (AM) are bioequivalent (BEQ) to free combination of the agents [abstract]. Presented at: American Society of Hypertension (ASH) Annual Meeting; May 2007; Chicago, IL.
6. Laeis P, Puchler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction. J Hypertens Suppl. 2001;19: S21-S32.[CrossRef][Medline] [Order article via Infotrieve]
7. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol. 2001;41: 515-527.[Abstract]
8. von Bergmann K, Laeis P, Puchler K, Sudhop T, Schwocho LR, Gonzalez L. Olmesartan medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan medoxomil. J Hypertens Suppl. 2001;19: S33-S40.[Medline] [Order article via Infotrieve]
9. Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J. 1989;118: 1100-1103.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Abernethy DR, Gutkowska J, Lambert MD. Amlodipine in elderly hypertensive patients: pharmacokinetics and pharmacodynamics. J Cardiovasc Pharmacol. 1988;12(suppl 7): S67-S71.[Web of Science][Medline] [Order article via Infotrieve]
11. Csajka C, Buclin T, Fattinger K, Brunner HR, Biollaz J. Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers. Clin Pharmacokinet. 2002;41: 137-152.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Yoshihara K, Gao Y, Shiga H, Wada DR, Hisaoka M. Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients. Clin Pharmacokinet. 2005;44: 1329-1342.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Beal SL, Sheiner LB, eds. NONMEM User's Guides. Hanover, MD: GloboMax, LLC; 1989-1998.
14. US Department of Health and Human Sciences, Food and Drug Administration. Guidance for Industry Population Pharmacokinetics. Available at: http://www.fda.gov/cder/guidance/1852fnl.pdf. Accessed October 2007.
15. Flynn JT, Nahata MC, Mahan JD Jr, Portman RJ. Population pharmacokinetics of amlodipine in hypertensive children and adolescents. J Clin Pharmacol. 2006;46: 905-916.
16. Meredith PA, Elliott HL. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet. 1992;22: 22-31.[Web of Science][Medline] [Order article via Infotrieve]
17. Kreutz R, Pulcher K. Combination therapy of olmesartan medoxomil with amlodipine or atenolol maintains steady state pharamcokinetics of each drug unchanged. J Hypertens. 2004;22(suppl 2): S244.
18. Rump LC, Sellin L, Laeis P. Combination of the angiotensin II-receptor antagonist olmesartan medoxomil with amlodipine: pharmacokinetics, safety and tolerability in healthy male subjects. J Hypertens. 2004;22(suppl 1): 145S.[CrossRef]
19. Gao C, Lertratanakul A. Data on file. Parsippany, NJ: Daiichi Sankyo, Inc; 2002.
20. Gualdiero P, Niebauer J, Addison C, Clark SJ, Coats AJ. Clinical features, anthropometric characteristics, and racial influences on the `white-coat effect' in a single-centre cohort of 1553 consecutive subjects undergoing routine ambulatory blood pressure monitoring. Blood Press Monit. 2000;5: 53-57.[Web of Science][Medline] [Order article via Infotrieve]
21. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003;163: 525-541.
22. Guyton AC. Blood pressure control: special role of the kidneys and body fluids. Science. 1991;252: 1813-1816.
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