My passion lies in utilizing mathematical techniques to uncover insights hidden within data and models. Currently, I use mathematical models to inform the clinical development of compounds for cardiovascular, renal, or metabolic diseases. However, my enthusiasm extends beyond discovering new solutions to problems. It also involves inspiring and empowering others to find their passions and see the beauty and elegance of mathematics.
In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-l... more In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [ 14 C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
The underrepresentation of pregnant individuals in clinical trials and drug development programs ... more The underrepresentation of pregnant individuals in clinical trials and drug development programs causes a lack of safety and efficacy data for this population and poses a significant public health challenge. This article outlines various stakeholder efforts that aim to address this disparity. It emphasizes the largely untapped potential of model-informed drug development (MIDD) tools and underscores the importance of early engagement between pharmaceutical companies and regulatory agencies during drug development.
Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitati... more Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analy-HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? Mechanistically built PD models can be used for biomarker identification and improved precision dosing in drugs with small therapeutic windows, such as warfarin.
Background: Comprehensive knowledge about pharmacologically relevant processes is comprised in la... more Background: Comprehensive knowledge about pharmacologically relevant processes is comprised in large-scale systems biology models. While these models thus contain important biological information, their complexity renders them unsuitable for parameter estimation, e.g. when analysing clinical data. It[for full text, please go to the a.m. URL]
Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an an... more Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S-constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N-acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. Methods: A non-linear mixed-effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration-time data from 3416 samples in 219 participants from four phase 1-2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). Results: The final model described the AZD8233 plasma concentration-time profile from four phase 1-2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two-compartment model with first-order absorption. The supra-proportional increase in maximum plasma concentration (C max) across the observed dose range was described by non-linear Michaelis-Menten elimination (maximum elimination rate, 9.9 mg/h [12% relative standard error]; concentration yielding half-maximal elimination rate, 4.8 mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233. Conclusions: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher C max observed in the Asian population relative to non-Asians.
Background: AZD8233 is a chemically modified 16-mer antisense oligonucleotide linked to N-acetyl ... more Background: AZD8233 is a chemically modified 16-mer antisense oligonucleotide linked to N-acetyl galactosamine (GalNAc) for efficient targeting of PCSK9 mRNA in hepatocytes to prevent the synthesis of PCSK9. We are reporting preliminary data from the first in human study. The aim with the study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of AZD8233 in subjects with LDL-C ≥100 mg/dL. Methods: This was a randomized, single-blind, placebo-controlled; single ascending dose study (NCT03593785) of AZD8233 administered subcutaneously (SC) to 56 subjects enrolled in 7 cohorts (6 on active and 2 on placebo in each cohort). Doses studied ranged from 4 to 120 mg. Serial blood samples were collected to assess PK, PCSK9 and LDL-C profiles after administration of AZD8233. PK parameters were calculated using non-compartmental methods. Results: After SC administration, AZD8233 was generally well tolerated, no clinically relevant safety and tolerability findings were observed and no serious adverse events were reported. Peak plasma concentrations were achieved within 1 to 3 hours after dosing. After peaking, plasma concentrations declined biphasically with a terminal half-life of 2 to 3 weeks. A dose dependent decrease in plasma levels of PCSK9 and LDL-C was observed. The largest mean percent reductions from baseline were &amp;amp;gt;90 % for PCSK9 and 70% for LDL-C. PCSK9 and LDL-C levels slowly returned to baseline or close to baseline levels over the 16 weeks post dose follow up period. Conclusions: The safety, PK and PD support further evaluation of AZD8233 in multiple ascending dose studies. The PD data indicate that a high level of PCSK9 and LDL-C reduction can be maintained over a dose interval of once monthly or less frequent at a dose below 100mg.
CPT: pharmacometrics & systems pharmacology, Oct 1, 2022
Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, target... more Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first‐in‐human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de‐risk a phase IIb study. The focus of the case‐study is on the cross‐functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.
Disease progression in non‐alcoholic steatohepatitis (NASH) is highly heterogenous and remains po... more Disease progression in non‐alcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end‐stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical non‐alcoholic fatty liver disease (NAFLD) cohort with serial biopsies over three decades. We evaluated covariate effects on all model parameters and performed clinical trials simulations to predict fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibro...
Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, target... more Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first‐in‐human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de‐risk a phase IIb study. The focus of the case‐study is on the cross‐functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.
Background: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathop... more Background: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. Methods: Patients 7-28 days after myocardial infarction (±ST elevation), with &lt;50% left anterior descending coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4-and 12-week cohorts. Change in urine leukotriene E 4 (uLTE 4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. Results: Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE 4 levels of &gt;80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths.
AimsAZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide ... more AimsAZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration‐QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute.MethodsSubcutaneous single doses ranging from 4 to 120 mg were evaluated in 73 adult healthy male subjects. Time‐matched 12‐lead digital ECG and plasma concentrations (n = 15) were measured at baseline and up to 48 hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (ΔQTc) was a dependent variable and time‐matched AZD8233 concentration was an independent variable.ResultsThe high clinical exposure scenario was defined as 1.7‐fold the expected Cmax following an assumed therapeutic dose of 60 mg, which corresponds to AZD8233 plasma concentration of 1.39 μg/mL. Estimated placebo‐corrected and ba...
In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-l... more In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5-lipoxygenase-activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [ 14 C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half-life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug-related exposure (DRE), while a direct N-glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
The underrepresentation of pregnant individuals in clinical trials and drug development programs ... more The underrepresentation of pregnant individuals in clinical trials and drug development programs causes a lack of safety and efficacy data for this population and poses a significant public health challenge. This article outlines various stakeholder efforts that aim to address this disparity. It emphasizes the largely untapped potential of model-informed drug development (MIDD) tools and underscores the importance of early engagement between pharmaceutical companies and regulatory agencies during drug development.
Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitati... more Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analy-HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? Mechanistically built PD models can be used for biomarker identification and improved precision dosing in drugs with small therapeutic windows, such as warfarin.
Background: Comprehensive knowledge about pharmacologically relevant processes is comprised in la... more Background: Comprehensive knowledge about pharmacologically relevant processes is comprised in large-scale systems biology models. While these models thus contain important biological information, their complexity renders them unsuitable for parameter estimation, e.g. when analysing clinical data. It[for full text, please go to the a.m. URL]
Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an an... more Aims: The aim of this study was to characterize the population pharmacokinetics of AZD8233, an antisense oligonucleotide (ASO) that targets the PCSK9 transcript to reduce hepatocyte PCSK9 protein production and plasma levels. AZD8233 utilizes generation 2.5 S-constrained ethyl motif (cET) chemistry and is conjugated to a triantennary N-acetylgalactosamine (GalNAc3) ligand for targeted hepatocyte uptake. Methods: A non-linear mixed-effect modelling approach utilizing NONMEM software was applied to AZD8233 concentration-time data from 3416 samples in 219 participants from four phase 1-2 studies, one in healthy volunteers (NCT03593785) and three in patients with dyslipidaemia (NCT04155645, NCT04641299 and NCT04823611). Results: The final model described the AZD8233 plasma concentration-time profile from four phase 1-2 studies in healthy volunteers or participants with dyslipidaemia, covering a dose range of 4 to 120 mg. The pharmacokinetics of AZD8233 were adequately described by a two-compartment model with first-order absorption. The supra-proportional increase in maximum plasma concentration (C max) across the observed dose range was described by non-linear Michaelis-Menten elimination (maximum elimination rate, 9.9 mg/h [12% relative standard error]; concentration yielding half-maximal elimination rate, 4.8 mg/L [18% relative standard error]). Body weight, sex, estimated glomerular filtration rate and disease status (healthy participant vs. patient with dyslipidaemia) were identified as factors affecting exposure to AZD8233. Conclusions: Covariate analysis showed body weight to be the main factor affecting exposure to AZD8233, which largely explained the higher C max observed in the Asian population relative to non-Asians.
Background: AZD8233 is a chemically modified 16-mer antisense oligonucleotide linked to N-acetyl ... more Background: AZD8233 is a chemically modified 16-mer antisense oligonucleotide linked to N-acetyl galactosamine (GalNAc) for efficient targeting of PCSK9 mRNA in hepatocytes to prevent the synthesis of PCSK9. We are reporting preliminary data from the first in human study. The aim with the study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of AZD8233 in subjects with LDL-C ≥100 mg/dL. Methods: This was a randomized, single-blind, placebo-controlled; single ascending dose study (NCT03593785) of AZD8233 administered subcutaneously (SC) to 56 subjects enrolled in 7 cohorts (6 on active and 2 on placebo in each cohort). Doses studied ranged from 4 to 120 mg. Serial blood samples were collected to assess PK, PCSK9 and LDL-C profiles after administration of AZD8233. PK parameters were calculated using non-compartmental methods. Results: After SC administration, AZD8233 was generally well tolerated, no clinically relevant safety and tolerability findings were observed and no serious adverse events were reported. Peak plasma concentrations were achieved within 1 to 3 hours after dosing. After peaking, plasma concentrations declined biphasically with a terminal half-life of 2 to 3 weeks. A dose dependent decrease in plasma levels of PCSK9 and LDL-C was observed. The largest mean percent reductions from baseline were &amp;amp;gt;90 % for PCSK9 and 70% for LDL-C. PCSK9 and LDL-C levels slowly returned to baseline or close to baseline levels over the 16 weeks post dose follow up period. Conclusions: The safety, PK and PD support further evaluation of AZD8233 in multiple ascending dose studies. The PD data indicate that a high level of PCSK9 and LDL-C reduction can be maintained over a dose interval of once monthly or less frequent at a dose below 100mg.
CPT: pharmacometrics & systems pharmacology, Oct 1, 2022
Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, target... more Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first‐in‐human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de‐risk a phase IIb study. The focus of the case‐study is on the cross‐functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.
Disease progression in non‐alcoholic steatohepatitis (NASH) is highly heterogenous and remains po... more Disease progression in non‐alcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end‐stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical non‐alcoholic fatty liver disease (NAFLD) cohort with serial biopsies over three decades. We evaluated covariate effects on all model parameters and performed clinical trials simulations to predict fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibro...
Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, target... more Here, we show model‐informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first‐in‐human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de‐risk a phase IIb study. The focus of the case‐study is on the cross‐functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.
Background: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathop... more Background: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. Methods: Patients 7-28 days after myocardial infarction (±ST elevation), with &lt;50% left anterior descending coronary artery stenosis and Thrombolysis in Myocardial Infarction flow grade ≥ 2 after percutaneous coronary intervention, were randomized 2:1:2 to once-daily AZD5718 200 mg or 50 mg, or placebo, in 4-and 12-week cohorts. Change in urine leukotriene E 4 (uLTE 4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. Results: Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE 4 levels of &gt;80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths.
AimsAZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide ... more AimsAZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration‐QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute.MethodsSubcutaneous single doses ranging from 4 to 120 mg were evaluated in 73 adult healthy male subjects. Time‐matched 12‐lead digital ECG and plasma concentrations (n = 15) were measured at baseline and up to 48 hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (ΔQTc) was a dependent variable and time‐matched AZD8233 concentration was an independent variable.ResultsThe high clinical exposure scenario was defined as 1.7‐fold the expected Cmax following an assumed therapeutic dose of 60 mg, which corresponds to AZD8233 plasma concentration of 1.39 μg/mL. Estimated placebo‐corrected and ba...
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Papers by Jane Knöchel