R. P. Koopmans

Nonlinear Mixed Effects Modeling of the Diurnal Blood Pressure Profile in a Multiracial Population

BACKGROUNDnCardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling.nnnMETHODSnAmbulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability.nnnRESULTSnThe diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R (2) = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks.nnnCONCLUSIONSnThe developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABPM.

Pharmacokinetic–Pharmacodynamic Modeling of the Antihypertensive Effect of Eprosartan in Black and White Hypertensive Patients

Background and ObjectiveIt is well recognized that many antihypertensive drugs exhibit large interindividual variability in effect and that this wide range of patient response to antihypertensive drugs is a major problem in achieving blood pressure (BP) control. Variability in both drug concentration and drug effect may cause the heterogeneity in antihypertensive drug response. However, for most antihypertensive drugs, no clear relationship between drug concentration and its effect on BP has been reported. This study aimed to describe the relationship between eprosartan exposure and its effect on the systolic blood pressure (SBP) using population pharmacokinetic–pharmacodynamic modeling. Interindividual variability in pharmacokinetics and pharmacodynamics was quantified and the influence of covariates on this relationship was evaluated.Patients and MethodsEprosartan plasma concentrations and SBP measurements were determined in 86 mildly hypertensive patients from the ROTATE study aged 48.1xa0±xa07.6xa0years with different ethnic backgrounds (33 White Dutch, 41 Creole Surinamese, 12 Hindustani Surinamese). In 12 of these patients, pharmacokinetics were densely sampled and 24-h ambulatory BP measurements were obtained. Data were analyzed using nonlinear mixed effects modeling.ResultsEprosartan concentration–time profiles were adequately described with a two-compartment pharmacokinetic model with zero-order absorption. A log-linear relationship was used to describe the relationship between concentration and the decrease in SBP. A hypothetical effect compartment was used to describe hysteresis in the drug effect. Approximately 80xa0% of the maximum decrease in SBP was observed after 24xa0days. Interindividual variability in drug response was 65xa0% and decreased to 14xa0% when ethnicity was added as covariate. Creole Surinamese exhibited no drug response in contrast to White Dutch and Hindustani Surinamese [−2.6xa0mmxa0Hg per (ng/ml)].ConclusionsThe developed pharmacokinetic–pharmacodynamic model allows the quantification and explanation of variability in SBP between individuals with ethnicity as a useful determinant of responsiveness to eprosartan.

Biological Variation of Creatinine, Cystatin C, and eGFR over 24 Hours

BACKGROUNDnEstimated glomerular filtration rate (eGFR) is widely used in clinical practice. This study assessed the within-subject biological variation (CVI) of different eGFR equations in people with chronic kidney disease (CKD) and people without CKD. The aims of this study were (a) to determine the 24-h biological variation profiles of creatinine, cystatin C, and eGFR and (b) to determine whether CVI of creatinine, cystatin C, and eGFR changes on deterioration of glomerular filtration.nnnMETHODSnHourly blood samples were analyzed from 37 individuals (17 without CKD, 20 with CKD) during 24 h. Creatinine (enzymatic method) and cystatin C were measured using a Cobas 8000 (Roche Diagnostics). eGFR was estimated using the Modification of Diet in Renal Disease and the Chronic Kidney Disease Epidemiology Collaboration based on creatinine and/or cystatin C. Plasma samples were stored at -80 °C before analysis. Outlier and homogeneity analyses were checked before performing a nested ANOVA to determine biological variation.nnnRESULTSnCVI of creatinine was higher in people without CKD than in those with CKD (6.4% vs 2.5%) owing primarily to the more profound effect of meat consumption on creatinine variability in individuals with lower baseline creatinine concentrations. Unlike creatinine, cystatin C concentrations were unaffected by meat consumption. Cystatin C showed some diurnal rhythmic variation and less in people with CKD. Reference change values (RCVs) of all eGFR equations were within 13% to 20% in both study groups.nnnCONCLUSIONSnDespite differences in CVI of creatinine, the CVI and RCV of the eGFR equations were relatively similar for people with or without CKD.