| 1. |
- Abrantes, João A., et al.
(författare)
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Elucidation of Factor VIII Activity Pharmacokinetics : A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa
- 2017
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 102:6, s. 977-988
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.
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| 2. |
- Alfirevic, A., et al.
(författare)
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Phenotype Standardization for Statin-Induced Myotoxicity
- 2014
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 96:4, s. 470-476
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Forskningsöversikt (refereegranskat)abstract
- Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
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| 3. |
- Amidon, K. S., et al.
(författare)
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Bioequivalence of Oral Products and the Biopharmaceutics Classification System : Science, Regulation, and Public Policy
- 2011
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 90:3, s. 467-470
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Tidskriftsartikel (refereegranskat)abstract
- The demonstration of bioequivalence (BE) is an essential requirement for ensuring that patients receive a product that performs as indicated by the label. The BE standard for a particular product is set by its innovator, and this standard must subsequently be matched by generic drug products. The Biopharmaceutics Classification System (BCS) sets a scientific basis for an improved BE standard for immediate-release solid oral dosage forms. In this paper, we discuss BE and the BCS, as well as the issues that are currently relevant to BE as a pharmaceutical product standard.
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| 4. |
- Avery, P. J., et al.
(författare)
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A Proposal for an Individualized Pharmacogenetics-Based Warfarin Initiation Dose Regimen for Patients Commencing Anticoagulation Therapy
- 2011
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 90:5, s. 701-706
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)(days 4-7)>4.0 (n = 63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction = 4.2 mg), whereas in those with mean INR(days 4-7) < 2.0 (n = 145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.
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| 5. |
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| 6. |
- Batty, J. A., et al.
(författare)
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An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT-HF Substudy
- 2014
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Ingår i: Clinical Pharmacology & Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 95:3, s. 321-330
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Tidskriftsartikel (refereegranskat)abstract
- To explore the pharmacogenetic effects of the cytochrome P450 (CYP) 2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional * 4 allele (1846G> A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6* 4 allele (EM: * 1* 1, 60.4%; IM: * 1* 4, 35.8%; and PM: * 4* 4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6* 4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.
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| 7. |
- Baverel, Paul G., et al.
(författare)
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Dose-Exposure-Response Relationship of the Investigational Anti-Interleukin-13 Monoclonal Antibody Tralokinumab in Patients With Severe, Uncontrolled Asthma
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 103:5, s. 826-835
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G(4) monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV1)) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV1 response relationship in patients with asthma. Near-maximal FEV1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.
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| 8. |
- Bergstrand, Martin, et al.
(författare)
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Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release, and pharmacokinetics
- 2009
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 86:1, s. 77-83
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MMM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MMM studies.
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| 9. |
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| 10. |
- Bertilsson, L
(författare)
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CYP2D6, serotonin, and suicide--a relationship?
- 2010
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Ingår i: Clinical pharmacology and therapeutics. - : Springer Science and Business Media LLC. - 1532-6535 .- 0009-9236. ; 88:3, s. 304-305
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Tidskriftsartikel (refereegranskat)
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| 11. |
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| 12. |
- Bhatt, Deepak Kumar, et al.
(författare)
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Age- and Genotype-Dependent Variability in the Protein Abundance and Activity of Six Major Uridine Diphosphate-Glucuronosyltransferases in Human Liver
- 2019
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 105:1, s. 131-141
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The American Society for Clinical Pharmacology and Therapeutics. The ontogeny of hepatic uridine diphosphate-glucuronosyltransferases (UGTs) was investigated by determining their protein abundance in human liver microsomes isolated from 136 pediatric (0-18 years) and 35 adult (age >18 years) donors using liquid chromatography / tandem mass spectrometry (LC-MS/MS) proteomics. Microsomal protein abundances of UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 increased by ∼8, 55, 35, 33, 8, and 3-fold from neonates to adults, respectively. The estimated age at which 50% of the adult protein abundance is observed for these UGT isoforms was between 2.6-10.3 years. Measured in vitro activity was generally consistent with the protein data. UGT1A1 protein abundance was associated with multiple single nucleotide polymorphisms exhibiting noticeable ontogeny-genotype interplay. UGT2B15 rs1902023 (*2) was associated with decreased protein activity without any change in protein abundance. Taken together, these data are invaluable to facilitate the prediction of drug disposition in children using physiologically based pharmacokinetic modeling as demonstrated here for zidovudine and morphine.
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| 13. |
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| 14. |
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| 15. |
- Brinkman, D. J., et al.
(författare)
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Essential Competencies in Prescribing: A First European Cross-Sectional Study Among 895 Final-Year Medical Students
- 2017
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY-BLACKWELL. - 0009-9236 .- 1532-6535. ; 101:2, s. 281-289
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Tidskriftsartikel (refereegranskat)abstract
- European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed.
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| 16. |
- Cars, Thomas, et al.
(författare)
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Effectiveness of Drugs in Routine Care : A Model for Sequential Monitoring of New Medicines Using Dronedarone as Example
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 103:3, s. 493-501
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Tidskriftsartikel (refereegranskat)abstract
- Although there is no doubt about the scientific value of randomized controlled clinical trials, they are usually conducted in selected populations different fromthose treated in clinical practice. Therefore, it is important to optimize real-time post-marketing evaluation of the effectiveness, safety, and cost of new drugs. Using electronic health records and administrative health databases froma well-defined region with universal access to healthcare, we have built a framework for real-time sequential monitoring of the effectiveness of newly marketed drugs in routine care. We chose the antiarrhythmic agent dronedarone as the study drug and flecainide as the comparator drug for illustration of the model. We demonstrate that this model produces consistent results with increasing precision over time as data accumulates in the clinical systems. We believe that use of this model at the introduction of new drugs can provide complementary evidence, especially in settings of adaptive licensing of new drugs.
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| 17. |
- Caster, Ola, et al.
(författare)
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Logistic regression in signal detection : Another Piece Added to the Puzzle
- 2013
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 94:3, s. 312-312
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- To the Editor: In their article, “Performance of Pharmacovigilance Signal-Detection Algorithms for the FDA Adverse Event Reporting System,” Harpaz et al.1 report an evaluation of signal-detection algorithms for spontaneous reports in the US Food and Drug Administration Adverse Event Reporting System against a benchmark constructed by the Observational Medical Outcomes Partnership.
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| 18. |
- Chu, X., et al.
(författare)
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Intracellular Drug Concentrations and Transporters : Measurement, Modeling, and Implications for the Liver
- 2013
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 94:1, s. 126-141
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Forskningsöversikt (refereegranskat)abstract
- Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.
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| 19. |
- Cooper-DeHoff, Rhonda M., et al.
(författare)
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The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and Statin-Associated Musculoskeletal Symptoms
- 2022
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 111:5, s. 1007-1021
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Tidskriftsartikel (refereegranskat)abstract
- Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin-associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long-term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP-C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin-induced myopathy.
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| 20. |
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| 21. |
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| 22. |
- Cullberg, M., et al.
(författare)
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Pharmacokinetics of ximelagatran and relationship to clinical response in acute deep vein thrombosis
- 2005
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Ingår i: Clin Pharmacol Ther. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 77:4, s. 279-90
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis. METHODS: A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models. RESULTS: The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P < 10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat. CONCLUSIONS: The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.
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| 23. |
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| 24. |
- Damoiseaux, David, et al.
(författare)
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Presence of Five Chemotherapeutic Drugs in Breast Milk as a Guide for the Safe Use of Chemotherapy During Breastfeeding : Results From a Case Series.
- 2022
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 112:2, s. 404-410
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about infant's safety of chemotherapy during breastfeeding where evidence is limited to a few case reports. This lack of knowledge has led to a general tendency to advise against breastfeeding during cytotoxic therapy despite the overwhelming benefits that breastfeeding offers to both the mothers and their children. In this case series, the presence of five chemotherapies in breast milk was determined. The aim was to obtain insight into the presence of these drugs in breast milk to inform and help clinicians in making informed decisions for women who want to breastfeed. Three patients collected 24-hour samples of breast milk every day for 1, 2, or 3 weeks after chemotherapy, 210 in total. After determination of drug concentrations, the infant daily dose, relative daily infant dose (RID%) and cumulative RID were calculated. Cumulative RIDs in patients varied from 10% to values lower than 1%. Rich data allowed us to design a table which gives predictions on the amount of days that breast milk has to be discarded to reach cumulative RIDs below 5, 1, and 0.1% for each compound. For cyclophosphamide, paclitaxel, and carboplatin, cumulative RIDs below 1 or 0.1% are reached if breast milk is discarded for 1-3 days after administration. This might suggest that breastfeeding in between cycles is an option. However, other pharmacological parameters should also be taken into consideration. For doxorubicin, also the levels of the active metabolite doxorubicinol need quantification. Similarly, breastfeeding during treatment with cisplatin might give substantial exposure and we advise caution.
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| 25. |
- Danese, E., et al.
(författare)
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Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis
- 2012
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 1532-6535 .- 0009-9236. ; 92:6, s. 746-756
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Forskningsöversikt (refereegranskat)abstract
- A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I-2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
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| 26. |
- Darpo, B, et al.
(författare)
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Design of the "Thorough QT Study"
- 2008
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Ingår i: Clinical pharmacology and therapeutics. - : Springer Science and Business Media LLC. - 1532-6535 .- 0009-9236. ; 83:4, s. 528-529
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 27. |
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| 28. |
- de Jong, F. A., et al.
(författare)
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Irinotecan-induced diarrhea : functional significance of the polymorphic ABCC2 transporter protein
- 2007
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 81:1, s. 42-49
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Tidskriftsartikel (refereegranskat)abstract
- Interindividual pharmacokinetic variability of the anticancer agent irinotecan is high. Life-threatening diarrhea is observed in up to 25% of patients receiving irinotecan and has been related with irinotecan pharmacokinetics and UGT1A1 genotype status. Here, we explore the association of ABCC2 (MRP2) polymorphisms and haplotypes with irinotecan disposition and diarrhea. A cohort of 167 Caucasian cancer patients who were previously assessed for irinotecan pharmacokinetics (90-min infusion given every 21 days), toxicity, and UGT1A1*28 genotype were genotyped for polymorphisms in ABCC2 using Pyrosequencing. Fifteen ABCC2 haplotypes were identified in the studied patients. The haplotype ABCC2*2 was associated with lower irinotecan clearance (28.3 versus 31.6 l/h; P=0.020). In patients who did not carry a UGT1A1*28 allele, a significant reduction of severe diarrhea was noted in patients with the ABCC2*2 haplotype (10 versus 44%; odds ratio, 0.15; 95% confidence interval, 0.04–0.61; P=0.005). This effect was not observed in patients with at least one UGT1A1*28 allele (32 versus 20%; odds ratio, 1.87; 95% confidence interval, 0.49–7.05; P=0.354). This study suggests that the presence of the ABCC2*2 haplotype is associated with less irinotecan-related diarrhea, maybe as a consequence of reduced hepatobiliary secretion of irinotecan. As the association was seen in patients not genetically predisposed at risk for diarrhea due to UGT1A1*28, confirmatory studies of the relationships of ABCC2 genotypes and irinotecan disposition and toxicity are warranted.
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| 29. |
- de Lange, E. C. M., et al.
(författare)
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Translational Aspects of Blood-Brain Barrier Transport and Central Nervous System Effects of Drugs : From Discovery to Patients
- 2015
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 97:4, s. 380-394
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Tidskriftsartikel (refereegranskat)abstract
- The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment.
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| 30. |
- de Lange, Elizabeth C. M., et al.
(författare)
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Understanding the Blood-Brain Barrier and Beyond : Challenges and Opportunities for Novel CNS Therapeutics
- 2022
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 111:4, s. 758-773
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Tidskriftsartikel (refereegranskat)abstract
- This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood-brain barrier (BBB) transport and intra-CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle-based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.
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| 31. |
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| 32. |
- Desta, Z, et al.
(författare)
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PharmVar GeneFocus: CYP2B6
- 2021
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Ingår i: Clinical pharmacology and therapeutics. - : Wiley. - 1532-6535 .- 0009-9236. ; 110:1, s. 82-97
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Tidskriftsartikel (refereegranskat)
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| 33. |
- Dong, Jin, et al.
(författare)
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Understanding Statin-Roxadustat Drug–Drug-Disease Interaction Using Physiologically-Based Pharmacokinetic Modeling
- 2023
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 114:4, s. 825-835
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Tidskriftsartikel (refereegranskat)abstract
- A different drug–drug interaction (DDI) scenario may exist in patients with chronic kidney disease (CKD) compared with healthy volunteers (HVs), depending on the interplay between drug–drug and disease (drug-drug-disease interaction (DDDI)). Physiologically-based pharmacokinetic (PBPK) modeling, in lieu of a clinical trial, is a promising tool for evaluating these complex DDDIs in patients. However, the prediction confidence of PBPK modeling in the severe CKD population is still low when nonrenal pathways are involved. More mechanistic virtual disease population and robust validation cases are needed. To this end, we aimed to: (i) understand the implications of severe CKD on statins (atorvastatin, simvastatin, and rosuvastatin) pharmacokinetics (PK) and DDI; and (ii) predict untested clinical scenarios of statin-roxadustat DDI risks in patients to guide suitable dose regimens. A novel virtual severe CKD population was developed incorporating the disease effect on both renal and nonrenal pathways. Drug and disease PBPK models underwent a four-way validation. The verified PBPK models successfully predicted the altered PKs in patients for substrates and inhibitors and recovered the observed statin-rifampicin DDIs in patients and the statin-roxadustat DDIs in HVs within 1.25- and 2-fold error. Further sensitivity analysis revealed that the severe CKD effect on statins PK is mainly mediated by hepatic BCRP for rosuvastatin and OATP1B1/3 for atorvastatin. The magnitude of statin-roxadustat DDI in patients with severe CKD was predicted to be similar to that in HVs. PBPK-guided suitable dose regimens were identified to minimize the risk of side effects or therapeutic failure of statins when co-administered with roxadustat.
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| 34. |
- Donker, Erik M., et al.
(författare)
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The European List of Key Medicines for Medical Education: A Modified Delphi Study
- 2024
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 115:3, s. 515-524
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Tidskriftsartikel (refereegranskat)abstract
- Rational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely accessible in Europe. For this, we used a modified Delphi study method consisting of three parts. In part one, we created an initial list based on a literature search. In part two, a group of 64 coordinators in CPT education, selected via the Network of Teachers in Pharmacotherapy of the European Association for Clinical Pharmacology and Therapeutics, evaluated the accessibility of each medicine in his or her country, and provided a diverse group of experts willing to participate in the Delphi part. In part three, 463 experts from 24 European countries were invited to participate in a 2-round Delphi study. In total, 187 experts (40%) from 24 countries completed both rounds and evaluated 416 medicines, 98 of which were included in the final list. The top three Anatomical Therapeutic Chemical code groups were (1) cardiovascular system (n = 23), (2) anti-infective (n = 21), and (3) musculoskeletal system (n = 11). This European List of Key Medicines for Medical Education could be a starting point for country-specific lists and could be used for the training and assessment of CPT.
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| 35. |
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| 36. |
- Fang, Lanyan, et al.
(författare)
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Model-Informed Drug Development and Review for Generic Products : Summary Of FDA Public Workshop
- 2018
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 104:1, s. 27-30
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Tidskriftsartikel (refereegranskat)abstract
- On October 2nd and 3rd, 2017, the US Food and Drug Administration (FDA) hosted a public workshop titled “Leveraging Quantitative Methods and Modeling to Modernize Generic Drug Development and Review.”1 This report summarizes Session 2 of the public workshop: “Model Informed Drug Development and Review for Generic Products.” The session focused on the application of quantitative methods and modeling in modernizing the generic drug development and review.
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| 37. |
- Faraj, Alan, et al.
(författare)
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Subcutaneous Marzeptacog Alfa (Activated) for On‐Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors
- 2024
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 115:3, s. 498-505
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Tidskriftsartikel (refereegranskat)abstract
- Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in patients with hemophilia A/B and was studied in a phase III trial evaluating MarzAA compared with standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized four-point efficacy scale (poor, fair, good, and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure (poor/fair), and treatment success (good/excellent)). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (> 33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (≤ 3 hours) whereas at later timepoints (> 12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (P < 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.
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| 38. |
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| 39. |
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| 40. |
- Fowler, Christopher J
(författare)
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Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer : a critical examination of the preclinical literature
- 2015
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Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley-Blackwell. - 0009-9236 .- 1532-6535. ; 97:6, s. 587-596
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Tidskriftsartikel (refereegranskat)abstract
- An Internet search with search words "cannabis cures cancer" produce a wealth of sites claiming that cannabis has this effect. These sites are freely accessible to the general public and thus contribute to public opinion. But do delta9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) cure cancer? In the absence of clinical data other than a safety study and case reports, preclinical data should be evaluated in terms of its predictive value. Using a strict approach where only concentrations and/or models relevant to the clinical situation are considered, the current preclinical data do not yet provide robust evidence that systemically administered Δ9-THC will be useful for the curative treatment of cancer. There is more support for an intratumoral route of administration of higher doses of Δ9-THC. CBD produces effects in relevant concentrations and models, although more data are needed concerning its use in conjunction with other treatment strategies.
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| 41. |
- Friberg, L. E., et al.
(författare)
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An agonist-antagonist interaction model for prolactin release following risperidone and paliperidone treatment
- 2009
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 85:4, s. 409-417
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Tidskriftsartikel (refereegranskat)abstract
- A mechanistic pharmacokinetic/pharmacodynamic model is presented, characterizing the time course of prolactin in healthy as well as schizophrenic subjects following the administration of various doses and formulations of the antipsychotic drugs risperidone and paliperidone. Prolactin concentrations from nine studies (1,462 subjects) were analyzed in NONMEM. A competitive agonist-antagonist interaction model described the competition between these drugs and dopamine for the D(2) receptors that regulate prolactin release. Tolerance development was explained by a feedback loop with prolactin stimulating dopamine release, whereas models wherein tolerance is described in terms of depletion of a prolactin pool did not explain the data well. The diurnal prolactin rhythm was described by a two-period cosine function. Baseline prolactin was health-status dependent and higher in women than in men, although the drug-induced release was less than proportional to baseline. This quantitative mechanism-based model is the first to describe prolactin release in patients, and it confirms that paliperidone and risperidone have similar potencies for prolactin release.
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| 42. |
- Friberg, Lena E.
(författare)
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Pivotal Role of Translation in Anti-Infective Development
- 2021
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:4, s. 856-866
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Tidskriftsartikel (refereegranskat)abstract
- The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.
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| 43. |
- Friberg, Lena, et al.
(författare)
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Modeling and Simulation of the Time Course of Asenapine Exposure Response and Dropout Patterns in Acute Schizophrenia
- 2009
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 86:1, s. 84-91
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Tidskriftsartikel (refereegranskat)abstract
- Modeling and simulation were utilized to characterize the efficacy dose response of sublingual asenapine in patients with schizophrenia and to understand the outcomes of six placebo-controlled trials in which placebo responses and dropout rates varied. The time course of total Positive and Negative Syndrome Scale (PANSS) scores was characterized for placebo and asenapine treatments in a pharmacokinetic-pharmacodynamic model in which the asenapine effect was described by an E-max model, increasing linearly over the 6-week study period. A logistic regression model described the time course of dropouts, with previous PANSS value being the most important predictor. The last observation carried forward (LOCF) time courses were well described in simulations from the combined PANSS + dropout model. The observed trial outcomes were successfully predicted for all the placebo arms and the majority of the treatment arms. Although simulations indicated that the post hoc probability of success of the performed trials was low to moderate, these analyses demonstrated that 5 and 10 mg twice-daily (b.i.d.) doses of asenapine have similar efficacy.
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| 44. |
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| 45. |
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| 46. |
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| 47. |
- Germovsek, Eva, et al.
(författare)
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A Time-to-Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations
- 2021
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:2, s. 416-423
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Tidskriftsartikel (refereegranskat)abstract
- Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch. Smokers motivated to quit were included in the NRT or placebo arms. Integrated craving (i.e., craving over a period of time) was assessed with 4-category, 5-category, or 100-mm visual analogue scale. The bounded integer model was used to assess latent craving from all scales. A time-to-event model linked predicted integrated craving to the hazard of smoking relapse. Available data included 9,323 adult subjects, observed for 3 weeks up to 2 years. At the study end, 9% (11% for NRT and 5% for placebo), on average, remained abstinent according to the protocol definition. A Gompertz-Makeham hazard best described the data, with a hazard of smoking relapse decreasing over time. Latent integrated craving was positively related to the hazard of smoking relapse, through a sigmoidal maximum effect function. For the same craving, being on NRT was found to reduce the hazard of relapse by an additional 30% compared with placebo. This work confirmed that low craving is associated with a high probability of remaining smoking abstinent and that NRT, in addition to reducing craving, increases the probability of remaining smoking abstinent.
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| 48. |
- Germovsek, Eva, et al.
(författare)
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Relating Nicotine Plasma Concentration to Momentary Craving Across Four Nicotine Replacement Therapy Formulations
- 2020
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 107:1, s. 238-245
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Tidskriftsartikel (refereegranskat)abstract
- Tobacco use is a major health concern. To assist smoking cessation, nicotine replacement therapy (NRT) is used to reduce nicotine craving. We quantitatively described the relationship between nicotine pharmacokinetics (PKs) from NRTs and momentary craving, linking two different pharmacodynamic (PD) scales for measuring craving. The dataset comprised retrospective data from 17 clinical studies and included 1,077 adult smokers with 39,802 craving observations from four formulations: lozenge, gum, mouth spray, and patch. A PK/PD model was developed that linked individual predicted nicotine concentrations with the categorical and visual analogue PD scales through a joint bounded integer model. A maximum effect model, accounting for acute tolerance development, successfully related nicotine concentrations to momentary craving. Results showed that all formulations were similarly effective in reducing craving, albeit with a fourfold lower potency for the patch. Women were found to have a higher maximal effect of nicotine to reduce craving, compared with men.
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| 49. |
- Giacomini, K. M., et al.
(författare)
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New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook from the International Transporter Consortium
- 2022
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Ingår i: Clinical Pharmacology & Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 112:3, s. 540-561
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Tidskriftsartikel (refereegranskat)abstract
- Enabled by a plethora of new technologies, research in membrane transporters has exploded in the past decade. The goal of this state-of-the-art article is to describe recent advances in research on membrane transporters that are particularly relevant to drug discovery and development. This review covers advances in basic, translational, and clinical research that has led to an increased understanding of membrane transporters at all levels. At the basic level, we describe the available crystal structures of membrane transporters in both the solute carrier (SLC) and ATP binding cassette superfamilies, which has been enabled by the development of cryogenic electron microscopy methods. Next, we describe new research on lysosomal and mitochondrial transporters as well as recently deorphaned transporters in the SLC superfamily. The translational section includes a summary of proteomic research, which has led to a quantitative understanding of transporter levels in various cell types and tissues and new methods to modulate transporter function, such as allosteric modulators and targeted protein degraders of transporters. The section ends with a review of the effect of the gut microbiome on modulation of transporter function followed by a presentation of 3D cell cultures, which may enable in vivo predictions of transporter function. In the clinical section, we describe new genomic and pharmacogenomic research, highlighting important polymorphisms in transporters that are clinically relevant to many drugs. Finally, we describe new clinical tools, which are becoming increasingly available to enable precision medicine, with the application of tissue-derived small extracellular vesicles and real-world biomarkers.
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| 50. |
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