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Germovsek, E., Hansson, A., Kjellsson, M. C., Perez Ruixo, J. J., Westin, A., Soons, P. A., . . . Karlsson, M. (2020). Relating Nicotine Plasma Concentration to Momentary Craving Across Four Nicotine Replacement Therapy Formulations. Clinical Pharmacology and Therapeutics, 107(1), 238-245
Öppna denna publikation i ny flik eller fönster >>Relating Nicotine Plasma Concentration to Momentary Craving Across Four Nicotine Replacement Therapy Formulations
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2020 (Engelska)Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 107, nr 1, s. 238-245Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
WILEY, 2020
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-408092 (URN)10.1002/cpt.1595 (DOI)000512979000045 ()31355455 (PubMedID)
Tillgänglig från: 2020-04-04 Skapad: 2020-04-04 Senast uppdaterad: 2020-04-04Bibliografiskt granskad
Duthaler, U., Leisegang, R., Karlsson, M., Krähenbühl, S. & Hammann, F. (2020). The effect of food on the pharmacokinetics of oral ivermectin. Journal of Antimicrobial Chemotherapy, 75(2), 438-440
Öppna denna publikation i ny flik eller fönster >>The effect of food on the pharmacokinetics of oral ivermectin
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2020 (Engelska)Ingår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, nr 2, s. 438-440Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Ivermectin is an older anthelminthic agent that is being studied more intensely given its potential for mass drug administration against scabies, malaria and other neglected tropical diseases. Its pharmacokinetics (PK) remain poorly characterized. Furthermore, the majority of PK trials are performed under fasted-state dosing conditions, and the effect of food is therefore not well known. To better plan and design field trials with ivermectin, a model that can account for both conditions would be valuable.

Objectives: To develop a PK model and characterize the food effect with single oral doses of ivermectin.

Patients and methods: We performed a population-based PK analysis of data pooled from two previous trials of a single dose of 12mg ivermectin, one with dosing after a high-fat breakfast (n=12) and one with fasted-state dosing (n=3).

Results: The final model described concentration-time profiles after fed and fasted dosing accurately, and estimated the food effect associated with relative bioavailability to 1.18 (95% CI 1.10-1.67).

Conclusions: In this analysis, the effect of a high-fat breakfast compared with a fasted-state administration of a single oral dose of 12mg ivermectin was minimal.

Ort, förlag, år, upplaga, sidor
OXFORD UNIV PRESS, 2020
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-407631 (URN)10.1093/jac/dkz466 (DOI)000515116900023 ()31691813 (PubMedID)
Tillgänglig från: 2020-03-31 Skapad: 2020-03-31 Senast uppdaterad: 2020-03-31Bibliografiskt granskad
Wellhagen, G. J., Kjellsson, M. C. & Karlsson, M. O. (2019). A Bounded Integer Model for Rating and Composite Scale Data. AAPS Journal, 21(4), Article ID 74.
Öppna denna publikation i ny flik eller fönster >>A Bounded Integer Model for Rating and Composite Scale Data
2019 (Engelska)Ingår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 21, nr 4, artikel-id 74Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Rating and composite scales are commonly used to assess treatment efficacy. The two main strategies for modelling such endpoints are to treat them as a continuous or an ordered categorical variable (CV or OC). Both strategies have disadvantages, including making assumptions that violate the integer nature of the data (CV) and requiring many parameters for scales with many response categories (OC). We present a method, called the bounded integer (BI) model, which utilises the probit function with fixed cut-offs to estimate the probability of a certain score through a latent variable. This method was successfully implemented to describe six data sets from four different therapeutic areas: Parkinson's disease, Alzheimer's disease, schizophrenia, and neuropathic pain. Five scales were investigated, ranging from 11 to 181 categories. The fit (likelihood) was better for the BI model than for corresponding OC or CV models (ΔAIC range 11-1555) in all cases but one (ΔAIC -63), while the number of parameters was the same or lower. Markovian elements were successfully implemented within the method. The performance in external validation, assessed through cross-validation, was also in favour of the new model (ΔOFV range 22-1694) except in one case (ΔOFV -70). A residual for diagnostic purposes is discussed. This study shows that the BI model respects the integer nature of data and is parsimonious in terms of number of estimated parameters.

Nyckelord
Bounded integer model, Categorical data, Composite scale, Nonlinear mixed-effects modelling, Probit regression, Rating scale
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-388766 (URN)10.1208/s12248-019-0343-9 (DOI)000470776700002 ()31172350 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2018-03317
Tillgänglig från: 2019-08-12 Skapad: 2019-08-12 Senast uppdaterad: 2019-08-12Bibliografiskt granskad
Thorsted, A., Bouchene, S., Tano, E., Castegren, M., Lipcsey, M., Sjölin, J., . . . Nielsen, E. I. (2019). A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6. PLoS ONE, 14(2), Article ID e0211981.
Öppna denna publikation i ny flik eller fönster >>A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6
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2019 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 2, artikel-id e0211981Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

Nationell ämneskategori
Fysiologi
Identifikatorer
urn:nbn:se:uu:diva-379038 (URN)10.1371/journal.pone.0211981 (DOI)000459330800014 ()30789941 (PubMedID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF)
Tillgänglig från: 2019-03-11 Skapad: 2019-03-11 Senast uppdaterad: 2019-03-11Bibliografiskt granskad
Germovsek, E., Ambery, C., Yang, S., Beerahee, M., Karlsson, M. O. & Plan, E. L. (2019). A Novel Method for Analysing Frequent Observations from Questionnaires in Order to Model Patient-Reported Outcomes: Application to EXACT (R) Daily Diary Data from COPD Patients. AAPS Journal, 21(4), Article ID UNSP 60.
Öppna denna publikation i ny flik eller fönster >>A Novel Method for Analysing Frequent Observations from Questionnaires in Order to Model Patient-Reported Outcomes: Application to EXACT (R) Daily Diary Data from COPD Patients
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2019 (Engelska)Ingår i: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 21, nr 4, artikel-id UNSP 60Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease with approximately 174 million cases worldwide. Electronic questionnaires are increasingly used for collecting patient-reported-outcome (PRO) data about disease symptoms. Our aim was to leverage PRO data, collected to record COPD disease symptoms, in a general modelling framework to enable interpretation of PRO observations in relation to disease progression and potential to predict exacerbations. The data were collected daily over a year, in a prospective, observational study. The e-questionnaire, the EXAcerbations of COPD Tool (EXACT (R)) included 14 items (i.e. questions) with 4 or 5 ordered categorical response options. An item response theory (IRT) model was used to relate the responses from each item to the underlying latent variable (which we refer to as disease severity), and on each item level, Markov models (MM) with 4 or 5 categories were applied to describe the dependence between consecutive observations. Minimal continuous time MMs were used and parameterised using ordinary differential equations. One hundred twenty-seven COPD patients were included (median age 67years, 54% male, 39% current smokers), providing approximately 40,000 observations per EXACT (R) item. The final model suggested that, with time, patients more often reported the same scores as the previous day, i.e. the scores were more stable. The modelled COPD disease severity change over time varied markedly between subjects, but was small in the typical individual. This is the first IRT model with Markovian properties; our analysis proved them necessary for predicting symptom-defined exacerbations.

Nyckelord
EXACT questionnaire, IRT, Markov model, NONMEM, PRO
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-383495 (URN)10.1208/s12248-019-0319-9 (DOI)000466176800001 ()31028495 (PubMedID)
Tillgänglig från: 2019-05-17 Skapad: 2019-05-17 Senast uppdaterad: 2019-05-17Bibliografiskt granskad
Krause, A., Kloft, C., Huisinga, W., Karlsson, M., Pinheiro, J., Bies, R., . . . Musser, B. J. (2019). Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development. Pharmaceutical Statistics 17 (5):593-606, Sep/Oct 2018, DOI:10.1002/pst.1873 [Letter to the editor]. Pharmaceutical statistics, 18(3), 278-281
Öppna denna publikation i ny flik eller fönster >>Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development. Pharmaceutical Statistics 17 (5):593-606, Sep/Oct 2018, DOI:10.1002/pst.1873
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2019 (Engelska)Ingår i: Pharmaceutical statistics, ISSN 1539-1604, E-ISSN 1539-1612, Vol. 18, nr 3, s. 278-281Artikel i tidskrift, Letter (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2019
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-389924 (URN)10.1002/pst.1940 (DOI)000470930500001 ()30932340 (PubMedID)
Tillgänglig från: 2019-08-01 Skapad: 2019-08-01 Senast uppdaterad: 2019-08-01Bibliografiskt granskad
Arshad, U., Chasseloup, E., Nordgren, R. & Karlsson, M. O. (2019). Development of visual predictive checks accounting for multimodal parameter distributions in mixture models. Journal of Pharmacokinetics and Pharmacodynamics, 46(3), 241-250
Öppna denna publikation i ny flik eller fönster >>Development of visual predictive checks accounting for multimodal parameter distributions in mixture models
2019 (Engelska)Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 46, nr 3, s. 241-250Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Mixture model analysis provides the probability for an individual to belong to a subpopulation (IPmix) and the most likely subpopulation for an individual to belong to (MIXEST). Using simulated data examples, two implementation strategies were followed to split the data into subpopulations for the development of mixture model specific VPCs. The first strategy splits the observed and simulated data according to the MIXEST assignment. A shortcoming of the MIXEST-based allocation strategy was a biased allocation towards the dominating subpopulation. This shortcoming was avoided by splitting observed and simulated data according to the IPmix assignment. For illustration purpose, the approaches were also applied to an irinotecan mixture model demonstrating 36% lower clearance of irinotecan metabolite (SN-38) in individuals with UGT1A1 homo/heterozygote versus wild-type genotype. VPCs with segregated subpopulations were helpful in identifying model misspecifications which were not evident with standard VPCs. The new tool provides an enhanced power of evaluation of mixture models.

Ort, förlag, år, upplaga, sidor
SPRINGER/PLENUM PUBLISHERS, 2019
Nyckelord
Visual predictive checks, Mixture models, Multimodal parameter distributions, Pharmacokinetics, Pharmacodynamics
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-385960 (URN)10.1007/s10928-019-09632-9 (DOI)000468597100003 ()30968312 (PubMedID)
Tillgänglig från: 2019-06-19 Skapad: 2019-06-19 Senast uppdaterad: 2019-06-19Bibliografiskt granskad
Schalkwijk, S., ter Heine, R., Colbers, A., Capparelli, E., Best, B. M., Cressey, T. R., . . . Burger, D. M. (2019). Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling. Journal of Antimicrobial Chemotherapy, 74(5), 1348-1356
Öppna denna publikation i ny flik eller fönster >>Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling
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2019 (Engelska)Ingår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, nr 5, s. 1348-1356Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Darunavir 800mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available. Objectives: To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women. Patients and methods: A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC(0-tau) and C-trough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure. Results: Simulations predicted that total darunavir exposure (AUC(0-tau)) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC(0-tau) was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%). Conclusions: The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.

Ort, förlag, år, upplaga, sidor
OXFORD UNIV PRESS, 2019
Nationell ämneskategori
Infektionsmedicin
Identifikatorer
urn:nbn:se:uu:diva-393535 (URN)10.1093/jac/dky567 (DOI)000482043300029 ()30715324 (PubMedID)
Tillgänglig från: 2019-09-24 Skapad: 2019-09-24 Senast uppdaterad: 2019-09-24Bibliografiskt granskad
Abrantes, J. A., Jönsson, S., Karlsson, M. & Nielsen, E. I. (2019). Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data. British Journal of Clinical Pharmacology, 85(6), 1326-1336
Öppna denna publikation i ny flik eller fönster >>Handling interoccasion variability in model-based dose individualization using therapeutic drug monitoring data
2019 (Engelska)Ingår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, nr 6, s. 1326-1336Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

AIMS: This study aims to assess approaches to handle interoccasion variability (IOV) in a model-based therapeutic drug monitoring (TDM) context, using a population pharmacokinetic model of coagulation factor VIII as example.

METHODS: We assessed five model-based TDM approaches: empirical Bayes estimates (EBEs) from a model including IOV, with individualized doses calculated based on individual parameters either (i) including or (ii) excluding variability related to IOV; and EBEs from a model excluding IOV by (iii) setting IOV to zero, (iv) summing variances of interindividual variability (IIV) and IOV into a single IIV term, or (v) re-estimating the model without IOV. The impact of varying IOV magnitudes (0-50%) and number of occasions/observations was explored. The approaches were compared with conventional weight-based dosing. Predictive performance was assessed with the prediction error (PE) percentiles.

RESULTS: When IOV was lower than IIV, the accuracy was good for all approaches (50th percentile of the PE [P50] <7.4%), but the precision varied substantially between IOV magnitudes (P97.5 61-528%). Approach (ii) was the most precise forecasting method across a wide range of scenarios, particularly in case of sparse sampling or high magnitudes of IOV. Weight-based dosing led to less precise predictions than the model-based TDM approaches in most scenarios.

CONCLUSIONS: Based on the studied scenarios and theoretical expectations, the best approach to handle IOV in model-based dose individualisation is to include IOV in the generation of the EBEs, but exclude the portion of unexplained variability related to IOV in the individual parameters used to calculate the future dose.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2019
Nyckelord
NONMEM, pharmacokinetics, population analysis, therapeutic drug monitoring
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-381215 (URN)10.1111/bcp.13901 (DOI)000468974200029 ()30767254 (PubMedID)
Tillgänglig från: 2019-04-05 Skapad: 2019-04-05 Senast uppdaterad: 2019-06-24Bibliografiskt granskad
Gottipati, G., Berges, A. C., Yang, S., Chen, C., Karlsson, M. & Plan, E. L. (2019). Item Response Model Adaptation for Analyzing Data from Different Versions of Parkinson's Disease Rating Scales. Pharmaceutical research, 36(9), Article ID 135.
Öppna denna publikation i ny flik eller fönster >>Item Response Model Adaptation for Analyzing Data from Different Versions of Parkinson's Disease Rating Scales
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2019 (Engelska)Ingår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 36, nr 9, artikel-id 135Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Purpose: The aim of this work was to allow combination of information from recent and historical trials in Parkinson's Disease (PD) by developing bridging methodology between two versions of the clinical endpoint.

Methods: A previously developed Item Response Model (IRM), that described longitudinal changes in Movement Disorder Society (MDS) sponsored revision of Unified Parkinson's Disease Rating Scale (UPDRS) [MDS-UPDRS] data from the De Novo PD cohort in Parkinson's Progression Markers Initiative, was first adapted to describe baseline UPDRS data from two clinical trials, one in subjects with early PD and another in subjects with advanced PD. Assuming similar IRM structure, items of the UPDRS version were mapped to those in the MDS-UPDRS version. Subsequently, the longitudinal changes in the placebo arm of the advanced PD study were characterized.

Results: The parameters reflecting differences in the shared items between endpoints were successfully estimated, and the model diagnostics indicated that mapping was better for early PD subjects (closer to De Novo cohort) than for advanced PD subjects. Disease progression for placebo in advanced PD patients was relatively shallow.

Conclusion: An IRM able to handle two variants of clinical PD endpoints was developed; it can improve the utilization of data from diverse sources and diverse disease populations.

Ort, förlag, år, upplaga, sidor
SPRINGER/PLENUM PUBLISHERS, 2019
Nyckelord
Data integration, disease progression, item response theory, movement disorder society (sponsored revision) - Unified parkinson's disease rating scale, parkinson's disease
Nationell ämneskategori
Neurologi
Identifikatorer
urn:nbn:se:uu:diva-390377 (URN)10.1007/s11095-019-2668-6 (DOI)000475976900001 ()31317279 (PubMedID)
Tillgänglig från: 2019-08-12 Skapad: 2019-08-12 Senast uppdaterad: 2019-08-12Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0003-1258-8297

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