| 1. |
- Ma, Guangli, et al.
(författare)
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Comparison of the agonist-antagonist interaction model and the pool model for the effect of remoxipride on prolactin
- 2010
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 70:6, s. 815-824
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Tidskriftsartikel (refereegranskat)abstract
- AIMS The tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist-antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short-term prolactin response, from which the original pool model was built. METHODS The remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM. RESULTS According to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well. CONCLUSIONS According to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio-rhythm of prolactin time-course and the tolerance development across different populations, drugs, treatment schedules and time.
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| 2. |
- Bender, Brendan C, et al.
(författare)
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Population pharmacokinetic pharmacodynamic modelling in oncology : a tool for predicting clinical response
- 2015
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 79:1, s. 56-71
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Forskningsöversikt (refereegranskat)abstract
- In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic-pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.
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| 3. |
- Hamberg, Anna-Karin, et al.
(författare)
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Characterising variability in warfarin dose requirements in children using modelling and simulation
- 2013
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 78:1, s. 158-169
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation.METHODS: Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimise a published adult pharmacometric warfarin model for use in children.RESULTS: Genotype effects in children were found to be comparable to what has been reported for adults, with CYP2C9 explaining up to a 4-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a 2-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a 3-fold difference in dose for a 4-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children.CONCLUSIONS: The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting warfarin dose variability in children. With this new knowledge more individualised dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.
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| 4. |
- Hermann, Robert, et al.
(författare)
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Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis
- 2019
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Ingår i: British Journal of Clinical Pharmacology. - : WILEY. - 0306-5251 .- 1365-2125. ; 85:7, s. 1484-1494
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Tidskriftsartikel (refereegranskat)abstract
- Aims Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune-mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing-remitting multiple sclerosis (RRMS). Methods CLARITY was a 96-week, double-blind, placebo-controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post-dose ECGs. ECG data were collected 15 minutes pre-dose and between 0.5 and 3 hours post-dose at pre-study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. Results For cladribine tablets 3.5 mg/kg, the maximum change in placebo-adjusted post-dose QTcF vs. visit-baseline (BL) was -0.42 ms (90% CI: -3.61-4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: -0.08-6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post-dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53-11.44) and 8.74 ms (90% CI: 3.18-14.31), respectively. No significant changes were observed in T-wave morphology in either treatment group. Conclusions Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization.
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| 5. |
- Netterberg, Ida, et al.
(författare)
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The risk of febrile neutropenia in breast cancer patients following adjuvant chemotherapy is predicted by the time course of interleukin-6 and C-reactive protein by modelling.
- 2018
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 84:3, s. 490-500
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Early identification of patients with febrile neutropenia (FN) is desirable for initiation of preventive treatment, such as with antibiotics. In this study, the time courses of two inflammation biomarkers, interleukin (IL)-6 and C-reactive protein (CRP), following adjuvant chemotherapy of breast cancer, were characterized. The potential to predict development of FN by IL-6 and CRP, and other model-derived and clinical variables, was explored.METHODS: The IL-6 and CRP time courses in cycles 1 and 4 of breast cancer treatment were described by turnover models where the probability for an elevated production following initiation of chemotherapy was estimated. Parametric time-to-event models were developed to describe FN occurrence to assess: (i) predictors available before chemotherapy is initiated; (ii) predictors available before FN occurs; and (iii) predictors available when FN occurs.RESULTS: The IL-6 and CRP time courses were successfully characterized with peak IL-6 typically occurring 2 days prior to CRP peak. Of all evaluated variables the CRP time course was most closely associated with the occurrence of FN. Since the CRP peak typically occurred at the time of FN diagnosis it will, however, have limited value for identifying the need for preventive treatment. The time course of IL-6 was the predictor that could best forecast FN events. Of the variables available at baseline, age was the best, although in comparison a relatively weak, predictor.CONCLUSIONS: The developed models add quantitative knowledge about IL-6 and CRP and their relationship to the development of FN. The study suggests that IL-6 may have potential as a clinical predictor of FN if monitored during myelosuppressive chemotherapy.
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| 6. |
- Zecchin, Chiara, et al.
(författare)
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Models for change in tumour size, appearance of new lesions and survival probability in patients with advanced epithelial ovarian cancer
- 2016
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 82:3, s. 717-727
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Tidskriftsartikel (refereegranskat)abstract
- AimsThe aims of this study were (i) to develop a modelling framework linking change in tumour size during treatment to survival probability in metastatic ovarian cancer; and (ii) to model the appearance of new lesions and investigate their relationship with survival and disease characteristics. MethodsData from a randomized Phase III clinical trial comparing carboplatin monotherapy to gemcitabine plus carboplatin combotherapy in 336 patients with metastatic ovarian cancer were used. A population model describing change in tumour size based on drug treatment information was established and its relationship with time to appearance of new lesions and survival were investigated with time to event models. ResultsThe tumour size profiles were well characterized as evaluated by visual predictive checks. Metastasis in the liver at enrolment and change in tumour size up to week 12 were predictors of time to appearance of new lesions. Survival was predicted based on the patient tumour size and ECOG performance status at enrolment and on appearance of new lesions during treatment and change in tumour size up to week 12. Tumour size and survival data from a separate study were adequately predicted. ConclusionsThe proposed models simulate tumour dynamics following treatment and provide a link to the probability of developing new lesions as well as to survival. The models have potential to be used for optimizing the design of late phase clinical trials in metastatic ovarian cancer based on early phase clinical study results and simulation.
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