| 31. |
- Jones, A Wayne, et al.
(författare)
-
Magnitude and time-course of arterio-venous differences in blood-alcohol concentration in healthy men
- 2004
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 43:15, s. 1157-1166
-
Tidskriftsartikel (refereegranskat)abstract
- Background and objective: Human studies of arterio-venous (AV) differences in drug concentrations and the consequences for pharmacokinetic modelling and concentration-effect relationships are very limited. We therefore investigated the intravenous and intra-arterial concentrations of alcohol (ethanol) during the absorption, distribution and elimination stages of alcohol metabolism in healthy men. Study participants and methods: Nine male volunteers aged 26-67 years drank 0.6g alcohol/kg bodyweight in 2-15 minutes. The drink was prepared from 95% v/v alcohol, which was diluted with an alcohol-free beverage to 20% v/v. Before the start of drinking and for 6-7 hours post-administration, blood samples were drawn at 15- to 20-minute intervals from indwelling catheters in a radial artery and a cubital vein on the same arm. The blood-alcohol concentration (BAC) was determined by headspace gas chromatography, and blood-water content was measured by desiccation. Results: The peak concentration (Cmax) of alcohol in arterial blood was 0.98 g/L (SD 0.209) compared with 0.84 g/L (SD 0.176) for venous blood (p < 0.001), whereas median time to reach Cmax (tmax) was the same (35 minutes). The AV difference was greatest at 10 minutes after the end of drinking (mean 0.20 g/L [range 0.09-0.40 g/L]), decreasing as the absorption of alcohol continued. At a median time of 90 minutes post-administration (range 45-105 minutes), the AV difference was momentarily zero. At later times, the AV differences became increasingly negative and at 280 minutes post-administration the mean was -0.051 g/L (range -0.025 to -0.078 g/L). The slope of the post-absorptive phase (k0) was 0.116 g/L/h (SD 0.0167) for arterial blood compared with 0.109 g/L/h (SD 0.0185) for venous blood (p < 0.001). The extrapolated time to reach zero BAC was 391 minutes (SD 34) for arterial blood and 420 minutes (SD 41) for venous blood, the difference of 29 minutes was statistically highly significant (p < 0.001). The apparent volume of distribution of alcohol, the area under the concentration-time curves (AUC) and the water content of arterial and venous blood samples were not significantly different for the two sampling compartments. Conclusion: The arterial and venous blood-alcohol profiles were shifted in time owing to the time it takes for alcohol to equilibrate between arterial blood and tissue water. Alcohol is metabolised in the liver but not in muscle tissue, which acts as a reservoir for alcohol. The concentrations of alcohol in arterial and venous blood were the same at only one timepoint, which signifies complete equilibration of alcohol in total body water. During the entire post-absorptive phase, the concentration of alcohol in venous blood draining skeletal muscles was slightly greater than the arterial blood concentration, therefore, the AV differences were negative.
|
|
| 32. |
|
|
| 33. |
- Jönsson, Siv, et al.
(författare)
-
Role of modelling and simulation : a European regulatory perspective
- 2012
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 51:2, s. 69-76
-
Tidskriftsartikel (refereegranskat)abstract
- Modelling and simulation (M&S) of clinical data, e.g. pharmacokinetic, pharmacodynamic and clinical endpoints, is a useful approach for more efficient interpretation of collected data and for extrapolation of knowledge to the entire target population. This type of documentation is included in the majority of marketing authorization applications for new medicinal products. This article summarizes the current status of regulatory review with respect to the role of M&S in Europe from the perspective of the Swedish Medical Products Agency. At present, regulatory bodies in Europe encourage the application of the M&S approach during drug development. However, there is a lack of consensus and transparent guidance documents. The main regulatory usage is in the evaluation of dose choices in sub-populations and as support for the dosing regimen in general. The regulatory review of conestat alfa illustrates how the dose recommendation was revised during the approval procedure based on M&S information. A survey of marketing authorization applications for new medicinal products approved in 2010 revealed that the use of the information gained from M&S documentation varies with respect to both regulatory review and the applicants' presentation of the data in the submitted dossier. Increased utilization and broadened application of M&S is anticipated in pharmaceutical development, where one area of focus is medicines for paediatric patients. Accordingly, the regulatory agencies will need to increase their capability to assess and utilize this type of information, and an interactive process among regulatory agencies is warranted to provide more unified regulatory assessment and guidance. Moreover, applicants are encouraged to expand on the usage of exposure-response models to map the systemic exposure range that yields safe and efficacious treatment and to improve the presentation of the gained knowledge in summary documents of the marketing authorization applications.
|
|
| 34. |
- Kip, Anke E., et al.
(författare)
-
Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs
- 2018
-
Ingår i: Clinical Pharmacokinetics. - : Springer. - 0312-5963 .- 1179-1926. ; 57:2, s. 151-176
-
Forskningsöversikt (refereegranskat)abstract
- This review describes the pharmacokinetic properties of the systemically administered antileishmanial drugs pentavalent antimony, paromomycin, pentamidine, miltefosine and amphotericin B (AMB), including their absorption, distribution, metabolism and excretion and potential drug-drug interactions. This overview provides an understanding of their clinical pharmacokinetics, which could assist in rationalising and optimising treatment regimens, especially in combining multiple antileishmanial drugs in an attempt to increase efficacy and shorten treatment duration. Pentavalent antimony pharmacokinetics are characterised by rapid renal excretion of unchanged drug and a long terminal half-life, potentially due to intracellular conversion to trivalent antimony. Pentamidine is the only antileishmanial drug metabolised by cytochrome P450 enzymes. Paromomycin is excreted by the kidneys unchanged and is eliminated fastest of all antileishmanial drugs. Miltefosine pharmacokinetics are characterized by a long terminal half-life and extensive accumulation during treatment. AMB pharmacokinetics differ per drug formulation, with a fast renal and faecal excretion of AMB deoxylate but a much slower clearance of liposomal AMB resulting in an approximately ten-fold higher exposure. AMB and pentamidine pharmacokinetics have never been evaluated in leishmaniasis patients. Studies linking exposure to effect would be required to define target exposure levels in dose optimisation but have only been performed for miltefosine. Limited research has been conducted on exposure at the drug's site of action, such as skin exposure in cutaneous leishmaniasis patients after systemic administration. Pharmacokinetic data on special patient populations such as HIV co-infected patients are mostly lacking. More research in these areas will help improve clinical outcomes by informed dosing and combination of drugs.
|
|
| 35. |
- Korell, Julia, et al.
(författare)
-
A population pharmacokinetic model for low-dose methotrexate and its polyglutamated metabolites in red blood cells.
- 2013
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 52:6, s. 475-85
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Measurement of intracellular concentrations of methotrexate (MTX) and its polyglutamated metabolites (MTXGlu(2-5)) in red blood cells (RBCs) has been suggested as a potential means of monitoring low-dose MTX treatment of rheumatoid arthritis (RA). However, a possible correlation between RBC MTX and MTXGlu2-5 concentrations and clinical outcomes of MTX treatment in RA is debated. A better understanding of the dose-concentration-time relationship of MTX and MTXGlu(2-5) in RBCs by population pharmacokinetic modelling is desirable and will facilitate assessing a potential RBC concentration-effect relationship in the future.AIM: The purpose of this analysis was to describe the pharmacokinetics of MTX and MTXGlu(2-5) in RBCs. Secondary objectives included investigation of deglutamation reactions and the loss of MTX and MTXGlu(2-5) from the RBC.METHODS: A model was developed using NONMEM(®) version 7.2 based on RBC data obtained from 48 patients with RA receiving once-weekly low-dose MTX treatment. This model was linked to a fixed two-compartment model that was used to describe the pharmacokinetics of MTX in the plasma. A series of five compartments were used to describe the intracellular pharmacokinetics of MTX and MTXGlu(2-5) in RBCs. Biologically plausible covariates were tested for a significant effect on MTX plasma clearance and the intracellular volume of distribution of all MTX species in RBCs ([Formula: see text]). The developed model was used to test hypotheses related to the enzymatic deglutamation of MTXGlu(2-5) and potential loss of MTXGlu(2-5) from RBCs.RESULTS: The final RBC pharmacokinetic model required the intracellular volumes of distribution for the parent and metabolites to be set to the value estimated for the parent drug MTX alone, and the rate constants describing the polyglutamation steps were fixed at literature values. Significant covariates included effect of body surface area-adjusted estimated glomerular filtration rate on renal plasma clearance and effect of allometrically scaled total body weight with a fixed exponent of 0.75 on non-renal plasma clearance of MTX. The only significant covariate with an effect on [Formula: see text] was mean corpuscular volume (MCV). The model supported single deglutamation steps and a single mechanism of MTX and MTXGlu(2-5) loss from RBCs.CONCLUSIONS: The developed model enabled acceptable description of the intracellular kinetics of MTX and MTXGlu(2-5) in RBCs. In the future it can form the basis of a full pharmacokinetic-pharmacodynamic model to assess the time-RBC concentration-effect relationship of low-dose MTX treatment in RA.
|
|
| 36. |
- Krekels, Elke H. J., et al.
(författare)
-
Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial
- 2016
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 55:9, s. 1079-1090
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations.Methods: Model development was performed using NONMEMA (R) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CLCR), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance.Results: A two-compartment model with first-order elimination and first-order absorption after an absorption lag-time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CLCR. Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance.Conclusion: Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (aecurrency sign60 kg), moderate renal impairment (CLCR aecurrency sign50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.
|
|
| 37. |
- Kuypers, Dirk R., et al.
(författare)
-
Mycophenolic Acid Exposure after Administration of Mycophenolate Mofetil in the Presence and Absence of Ciclosporin in Renal Transplant Recipients
- 2009
-
Ingår i: Clinical Pharmacokinetics. - 0312-5963. ; 48:5, s. 329-341
-
Tidskriftsartikel (refereegranskat)abstract
- Background and objective: The pharmacokinetics of mycophenolic acid (MPA) are complex, with large interindividual variability over time. There are also well documented interactions with ciclosporin, and assessment of MPA exposure is therefore necessary when reducing or stopping ciclosporin therapy. Here we report on the pharmacokinetic and pharmacodynamic behaviour of MPA in renal transplant patients on standard dose, reduced dose and no ciclosporin. Study design: The CAESAR study, a prospective 12-month study in primary renal allograft recipients, was designed to determine whether mycophenolate mofetil-based regimens containing either low-dose ciclosporin or low-dose ciclosporin withdrawn by 6 months could minimize nephrotoxicity and improve renal function without an increase in acute rejection compared with a mycophenolate mofetil-based regimen containing standard-dose ciclosporin. Patients and methods: A subset of patients from the CAESAR study contributed to this pharmacokinetic analysis of MPA exposure. Blood samples were taken over one dosing interval on day 7 and at months 3, 7 and 12 post-transplantation. The sampling timepoints were predose, 20, 40 and 75 minutes and 2, 3, 4, 6, 9 and 12 hours after mycophenolate mofetil dosing. Assessments included plasma concentrations of MPA and mycophenolic acid glucuronide (MPAG) and ciclosporin trough concentrations. The area under the plasma concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) for MPA was the primary pharmacokinetic parameter, and the AUC12 for MPAG was the secondary parameter. Results: In total, 536 de novo renal allograft recipients were randomized in the CAESAR study. Of these, 114 patients were entered into the pharmacokinetic substudy and 110 patients contributed to the pharmacokinetic analysis. There was a rapid rise in MPA concentrations (median time to peak concentration 0.72-1.25 hours). At day 7 and month 3, the MPA AUC12 values were similar in the ciclosporin withdrawal and low-dose ciclosporin groups (patients with the same ciclosporin target concentrations to month 6), while at 7 and 12 months, the values in the ciclosporin withdrawal group were higher than in the low-dose group (19.9% and 30.2% higher, respectively). MPA AUC12 values in the standard-dose ciclosporin group were lower than in the other groups at all timepoints and increased over time. At all timepoints, the MPA peak plasma concentration was similar in all groups, and the MPAG concentrations rose more slowly than MPA concentrations. The ratio of the AUC from 6 to 12 hours/AUC(12) suggests that an increasing AUC in the ciclosporin withdrawal group is due to an increase in the enterohepatic recirculation. Conclusion: These findings are consistent with the hypothesis that ciclosporin inhibits the biliary secretion and/or hepatic extraction of MPAG, leading to a reduced rate of enterohepatic recirculation of MPA. Several concurrent mechanisms, such as ciclosporin-induced changes in renal tubular MPAG excretion and enhanced elimination of free MPA through competitive albumin binding with MPAG, can also contribute to the altered MPAG pharmacokinetics observed in the presence and absence of ciclosporin.
|
|
| 38. |
|
|
| 39. |
- Kvist, EE, et al.
(författare)
-
Quantitative pharmacogenetics of nortriptyline - A novel approach
- 2001
-
Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 40:11, s. 869-877
-
Forskningsöversikt (refereegranskat)abstract
- Objective: To quantitatively model nortriptyline clearance as a function of the cytochrome P450 (CYP) 2D6 genotype and to estimate the contribution of genotype to the interindividual variability in steady-state plasma concentration and metabolic clearance. Design: Modelling study using data from two previously published studies. Participants: 20 healthy volunteers receiving single oral doses of nortriptyline and 20 patients with depression on steady-state oral treatment. Methods: A total of 275 nortriptyline plasma concentrations were analysed by standard nonlinear regression and nonlinear mixed effect models. The pharmacokinetic model was a 1-compartment model with first order absorption and elimination. All participants had previously been genotyped with respect to the CYP2D6 polymorphism. Results: A model in which the intrinsic clearance is a linear function of the number of functional CYP2D6 genes and hepatic blood flow is fixed to 60 L/h gave the closest fit of the pharmacokinetic model to the data. Stable estimates were obtained for population pharmacokinetic parameters and interindividual variances. Assuming 100% absorption, the model allows systemic clearance and bioavailability to be estimated. Bioavailability was found to vary between 0.17 and 0.71, depending on the genotype. Using the frequency distribution of CYP2D6 genotype with the above results we estimate that, in compliant Swedish individuals on nortriptyline monotherapy, the number of functional CYP2D6 genes could explain 21% of the total interindividual variance in oral clearance of nortriptyline and 34% of that in steady-state plasma concentrations. Conclusion: Nonlinear mixed-effects modelling can be used to quantify the influence of the number of functional CYP2D6 genes on the metabolic clearance and plasma concentration of drugs metabolised by this enzyme. Gene dose has a significant impact on drug pharmacokinetics and prior knowledge of it may aid in predicting plasma concentration of the drug and thus tailoring patient-specific dosage regimens.
|
|
| 40. |
- Kvitne, Kine Eide, et al.
(författare)
-
Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals
- 2024
-
Ingår i: Clinical Pharmacokinetics. - : Springer. - 0312-5963 .- 1179-1926. ; 63:1, s. 109-120
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Objective: Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals.Methods: This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery.Results: The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 +/- 2.3% and 11 +/- 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 mu g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 mu g h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 +/- 0.33 hours at week 3 to 0.77 +/- 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 mu g h/L [-0.94, 3.2]) or the diet group (0.94 mu g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 +/- 7%, diet: 3 +/- 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 mu g h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/mu g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals.Conclusions: Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.
|
|
