Application of the Convection–Dispersion Equation to Modelling Oral Drug Absorption

Models of systemic drug absorption after oral administration are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict drug concentrations in blood plasma frequently yields a considerable mismatch between predicted and measured concentration profiles. This is particularly true for the upswing of the plasma concentration after oral administration. The current investigation explores an alternative model to describe the absorption rate based on the convection–dispersion equation describing the transport of chemicals through the GI tract. This equation is governed by two parameters, transport velocity and dispersion coefficient. One solution of this equation for a specific set of initial and boundary conditions was used to model absorption of paracetamol in a 22-year-old man after oral administration. The GI-tract passage rate in this subject was influenced by co-administration of drugs that stimulate or delay gastric emptying. The transport-limited absorption function is more accurate in describing the plasma concentration versus time curve after oral administration than the first-order model. Additionally, it provides a mechanistic explanation for the observed curve through the differences in GI-tract passage rate

Extensions to the Visual Predictive Check to facilitate model performance evaluation

The Visual Predictive Check (VPC) is a valuable and supportive instrument for evaluating model performance. However in its most commonly applied form, the method largely depends on a subjective comparison of the distribution of the simulated data with the observed data, without explicitly quantifying and relating the information in both. In recent adaptations to the VPC this drawback is taken into consideration by presenting the observed and predicted data as percentiles. In addition, in some of these adaptations the uncertainty in the predictions is represented visually. However, it is not assessed whether the expected random distribution of the observations around the predicted median trend is realised in relation to the number of observations. Moreover the influence of and the information residing in missing data at each time point is not taken into consideration. Therefore, in this investigation the VPC is extended with two methods to support a less subjective and thereby more adequate evaluation of model performance: (i) the Quantified Visual Predictive Check (QVPC) and (ii) the Bootstrap Visual Predictive Check (BVPC). The QVPC presents the distribution of the observations as a percentage, thus regardless the density of the data, above and below the predicted median at each time point, while also visualising the percentage of unavailable data. The BVPC weighs the predicted median against the 5th, 50th and 95th percentiles resulting from a bootstrap of the observed data median at each time point, while accounting for the number and the theoretical position of unavailable data. The proposed extensions to the VPC are illustrated by a pharmacokinetic simulation example and applied to a pharmacodynamic disease progression example

Explaining variability in ciclosporin exposure in adult kidney transplant recipients

International audienc

Marginal increase of sunitinib exposure by grapefruit juice

Clinical Oncolog

Dutch guideline on total hip prosthesis

Contains fulltext : 97840.pdf (publisher's version ) (Open Access

Mitotane has a strong and a durable inducing effect on CYP3A4 activity

Objective The effects of mitotane on the pharmacokinetics (PK) of co-administered drugs are mostly unknown. The aim of the present study was to describe the effects of mitotane on the PK of the phenotypic probe midazolam and of the tyrosine kinase inhibitor sunitinib. Design A serendipitous observation was made in two of nine patients who volunteered in a sunitinib pharmacokinetic study. Both patients were diagnosed with adrenocortical carcinoma (ACC) and were exposed to mitotane. The sunitinib PK study was designed to determine the relationship between CYP3A4 activity and sunitinib exposure using 7.5 mg midazolam orally as a phenotypic probe. Patient and methods Serial blood samples for PK analysis of midazolam, 1-hydroxy-midazolam, and sunitinib were collected at steady-state sunitinib PK (between days 14 and 20). To confirm this observation in the mitotane-exposed patients, midazolam PK was evaluated in two additional patients with ACC and mitotane treatment. Results The four mitotane-treated patients showed highly induced CYP3A4 activity, even after interrupting mitotane therapy months before study entry, reflected by decreased midazolam exposure compared with the other seven patients (mean AUC(0)(-)(12 h) (95% CI): 7.6 (5.5-9.7) vs 139.0 (95.1-182.9) μg×h/l respectively P=0.001) and increased 1-hydroxy-midazolam exposure (mean AUC(0)(-)(12 h) (95% CI): 409.6 (290.5-528.7) vs 35.0 (26.4-43.6) μg×h/l, P=0.008). Sunitinib exposure was decreased in the two patients who were co-treated with mitotane (267 and 268 μg×h/l versus 1344 (1079-1609) (mean (95% CI)) μg×h/l). Conclusion Mitotane has a strong and long-lasting inducing effect on CYP3A4 activity, which will result in clinically relevant interactions with multiple drugs since many drugs are metabolized by this enzym

Population pharmacokinetic analysis for simultaneous determination of Bmax and KD In Vivo by positron emission tomography

Purpose: Changes in GABAA-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABAA-receptor properties, characterized by Bmax and KD. Procedures: Following an injection of [C-11]FMZ (dose range: 1-2,000 μg) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain. Results: Application of this method in control rats resulted in estimates of Bmax and K D (14.5 ± 3.7 ng/ ml and 4.68 ± 1.5 ng/ml, respectively). Conclusions: The proposed population PK model allowed for simultaneous estimation of Bmax and KD for a group of animals using single injection PET experiments per animal

Use and Usability Of Custom-Made Knee-Ankle-Foot Orthoses In Polio Survivors with Knee Instability: A Cross-Sectional Survey

OBJECTIVE: To investigate the use of custom-made knee-ankle-foot orthoses in daily life and differences in usability factors of knee-ankle-foot orthoses between users and discontinued users. DESIGN: Cross-sectional survey study. SUBJECTS: A total of 163 polio survivors provided with a knee-ankle-foot orthosis at an outpatient clinic of a university hospital. METHODS: Use and usability of knee-ankle-foot orthoses in daily life were assessed with a postal questionnaire. Usability factors were formulated using the International Organization for Standardization (ISO) 9241-11 standard. RESULTS: A total of 106 respondents (65%) returned the questionnaire. Of these, 98 were eligible for analysis. Seventy-four respondents (76%) reported using their knee-ankle-foot orthosis. Compared with discontinued users (24%), users experienced more limitations when walking without an orthosis (p = 0.001), were more often experienced with wearing a previous orthosis (p < 0.001) and were more often prescribed with a locked rather than a stance-control knee-ankle-foot orthosis (p = 0.015). Furthermore, users reported better effectiveness of their knee-ankle-foot orthosis (p < 0.001), more satisfaction with goals of use and knee-ankle-foot orthosis-related aspects (p < 0.001). CONCLUSION: The majority of polio survivors used their custom-made knee-ankle-foot orthoses in daily life. Factors related to continued use, such as walking ability without orthosis, expectations of the orthosis, previous orthosis experience and type of knee-ankle-foot orthosis provided, should be considered and discussed when prescribing a knee-ankle-foot orthosis in polio survivors

USE AND USABILITY OF CUSTOM-MADE KNEE-ANKLE-FOOT ORTHOSES IN POLIO SURVIVORS WITH KNEE INSTABILITY: A CROSS-SECTIONAL SURVEY

Objective: To investigate the use of custom-made knee-ankle-foot orthoses in daily life and differences in usability factors of knee-ankle-foot orthoses between users and discontinued users. Design: Cross-sectional survey study. Subjects: A total of 163 polio survivors provided with a knee-ankle-foot orthosis at an outpatient clinic of a university hospital. Methods: Use and usability of knee-ankle-foot orthoses in daily life were assessed with a postal questionnaire. Usability factors were formulated using the International Organization for Standardization (ISO) 9241-11 standard. Results: A total of 106 respondents (65%) returned the questionnaire. Of these, 98 were eligible for analysis. Seventy-four respondents (76%) reported using their knee-ankle-foot orthosis. Compared with discontinued users (24%), users experienced more limitations when walking without an orthosis (p = 0.001), were more often experienced with wearing a previous orthosis (p < 0.001) and were more often prescribed with a locked rather than a stance-control knee-ankle-foot orthosis (p = 0.015). Furthermore, users reported better effectiveness of their knee-ankle-foot orthosis (p < 0.001), more satisfaction with goals of use and knee-ankle-foot orthosis-related aspects (p < 0.001). Conclusion: The majority of polio survivors used their custom-made knee-ankle-foot orthoses in daily life. Factors related to continued use, such as walking ability without orthosis, expectations of the orthosis, previous orthosis experience and type of knee-ankle-foot orthosis provided, should be considered and discussed when prescribing a knee-anklefoot orthosis in polio survivors

Nonlinear mixed effects modeling of the diurnal blood pressure profile in a multiracial population

Cardiac 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. Ambulatory 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. The 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. The 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 ABP