| 21. |
- Hennig, Stefanie, et al.
(författare)
-
Population Pharmacokinetics of Tobramycin in Patients With and Without Cystic Fibrosis
- 2013
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 52:4, s. 289-301
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives While several studies have examined the pharmacokinetics of tobramycin in patients with cystic fibrosis (CF), there is no consensus on whether they differ in patients with and without CF. The objectives of this study were to identify covariates which explain pharmacokinetic variability and to examine whether having the disease CF in itself alters these relationships and drug dose requirements. Methods To investigate this issue, a population pharmacokinetic meta-analysis of data from eight centres was undertaken. NONMEM (R) 7.2 was used to analyse the data, which comprised 4,514 concentration-time measurements from 465 adults and children with CF and 1,095 concentration-time measurements from 267 adults and children without CF. Results Tobramycin disposition was well described by a two-compartment model with first-order elimination. Patient age, fat-free mass, serum creatinine concentration and sex were identified as significant covariates in the final model. Fat-free mass was superior to total bodyweight as a descriptor of clearance, volume of distribution of the central and peripheral compartments and inter-compartmental clearance. CF as an independent disease-specific factor had no significant influence on the pharmacokinetics of tobramycin at any stage during covariate model building. An optimal dose of 11 mg/kg every 24 h was defined for CF patients using a utility function approach. Conclusion The pharmacokinetics of tobramycin do not differ significantly in CF patients compared with patients without CF when subject age, fat-free mass, sex and renal function are taken into consideration. Variations in tobramycin dosing between CF and non-CF patients should therefore reflect target concentrations or exposures based on differences in expected pathogen sensitivity and not the presence of CF.
|
|
| 22. |
- Hermann, Robert, et al.
(författare)
-
The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis
- 2019
-
Ingår i: Clinical Pharmacokinetics. - : ADIS INT LTD. - 0312-5963 .- 1179-1926. ; 58:3, s. 283-297
-
Forskningsöversikt (refereegranskat)abstract
- Cladribine Tablets (MAVENCLAD (R)) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (T-max) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median T-max 1.5 h, range 1-3 h), and maximum concentration (C-max) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT)1, concentrative nucleoside transporter (CNT)3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk.
|
|
| 23. |
- Hovd, M., et al.
(författare)
-
Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance
- 2023
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 62:5, s. 725-735
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionRosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity.MethodsPatients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day).ResultsA total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant.ConclusionsNeither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.
|
|
| 24. |
- Janssen, Julie M, et al.
(författare)
-
A Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic Model of Bortezomib in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.
- 2020
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 59:2, s. 207-216
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia.METHODS: Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m2 twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model.RESULTS: The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664-0.728) after administration.CONCLUSION: The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib.
|
|
| 25. |
- Janssen, Julie M, et al.
(författare)
-
Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer : A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP).
- 2021
-
Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 60:6, s. 775-784
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy.OBJECTIVE: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women.METHODS: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates.RESULTS: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients.CONCLUSION: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy.
|
|
| 26. |
- Janssen, J. M., et al.
(författare)
-
Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs
- 2023
-
Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 62:8, s. 1157-1167
-
Tidskriftsartikel (refereegranskat)abstract
- Background and Objective As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data.Methods Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients.Results The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes.Conclusion By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.
|
|
| 27. |
- Joerger, Markus, et al.
(författare)
-
Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : a study by the EORTC-PAMM-NDDG
- 2007
-
Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 46:12, s. 1051-1068
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. Patients and methods: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. Results: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 mu mol . h/L [95% CI 889, 1001] vs 602 mu mol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. Conclusions: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group
|
|
| 28. |
|
|
| 29. |
- Jones, AW, et al.
(författare)
-
Magnitude and time-course of arterio-venous differences in blood-alcohol concentration in healthy men
- 2004
-
Ingår i: Clinical Pharmacokinetics. - 0312-5963. ; 43:15, s. 1157-1166
-
Forskningsöversikt (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 (C-max) 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):, (t(max)) was the same (35 minutes). The AV whereas median time to reach C-max difference was greatest at 10 minutes after the end of drinking (mean 0.20 g/L [range 0.09-0.40 g/J), decreasing as the absorption of alcohol continued. At a C 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 n-minutes post-admistration the mean was -0.051 g/L (range -0.025 to -0.078 g/L). The slope of the post-absorptive phase g/L/h (SD 0.0167) for arterial blood compared with 0.109 g/L/h (k(0)) was 0.116 (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.
|
|
| 30. |
- 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.
|
|
