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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.
Open this publication in new window or tab >>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 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0211981Article in journal (Refereed) 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.

National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-379038 (URN)10.1371/journal.pone.0211981 (DOI)000459330800014 ()30789941 (PubMedID)
Funder
Swedish Foundation for Strategic Research
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Netterberg, I., Li, C.-C., Molinero, L., Budha, N., Sukumaran, S., Stroh, M., . . . Friberg, L. (2019). A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients. Clinical Pharmacology and Therapeutics, 105(2), 486-495
Open this publication in new window or tab >>A PK/PD Analysis of Circulating Biomarkers and Their Relationship to Tumor Response in Atezolizumab-Treated non-small Cell Lung Cancer Patients
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2019 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 105, no 2, p. 486-495Article in journal (Refereed) Published
Abstract [en]

To assess circulating biomarkers as predictors of antitumor response to atezolizumab (anti-programmed death-ligand 1 (PD-L1), Tecentriq) serum pharmacokinetic (PK) and 95 plasma biomarkers were analyzed in 88 patients with relapsed/refractory non-small cell lung cancer (NSCLC) receiving atezolizumab i.v. q3w (10-20 mg/kg) in the PCD4989g phase I clinical trial. Following exploratory analyses, two plasma biomarkers were chosen for further study and correlation with change in tumor size (the sum of the longest diameter) was assessed in a pharmacokinetic/pharmacodynamic (PK/PD) tumor modeling framework. When longitudinal kinetics of biomarkers and tumor size were modeled, tumor shrinkage was found to significantly correlate with area under the curve (AUC), baseline factors (metastatic sites, liver metastases, and smoking status), and relative change in interleukin (IL)-18 level from baseline at day 21 (RCFBIL-18,d21). Although AUC was a major predictor of tumor shrinkage, the effect was estimated to dissipate with an average half-life of 80 days, whereas RCFBIL-18,d21 seemed relevant to the duration of the response.

Place, publisher, year, edition, pages
WILEY, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-377669 (URN)10.1002/cpt.1198 (DOI)000457465200034 ()30058723 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-08-09Bibliographically approved
Toxopeus, E. L. A., de Man, F. M., Krak, N., Biermann, K., Nieuweboer, A. J. M., Friberg, L. E., . . . Mathijssen, R. H. J. (2019). Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer. Cancers, 11(2), Article ID 173.
Open this publication in new window or tab >>Association between Paclitaxel Clearance and Tumor Response in Patients with Esophageal Cancer
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 2, article id 173Article in journal (Refereed) Published
Abstract [en]

Inter-individual variability in paclitaxel pharmacokinetics may play a role in the response to chemotherapy. Therefore, we studied the association between paclitaxel clearance and treatment response in patients with esophageal cancer. All patients who received paclitaxel (plus carboplatin) treatment for esophageal cancer between 2007 and 2013 were included. The treatment was given as neoadjuvant chemoradiotherapy (nCRT), induction chemotherapy (iCT), or palliative chemotherapy (pCT). The treatment response was assessed by the tumor regression grade (TRG) or by the RECIST1.1 criteria, respectively. The unbound paclitaxel clearance (CL) was estimated with NONMEM. The log-transformed clearance was related to response with ANOVA and independent sample t-tests. A total of 166 patients were included, of whom 113 received nCRT, 23 iCT and 30 pCT. In patients receiving nCRT, paclitaxel clearance was not associated with tumor regression grade (p-value = 0.25), nor with pathologically complete response (geometric mean 561.6 L/h) and residual disease (geometric mean 566.1 L/h, p-value = 0.90). In patients who underwent iCT or pCT, also no association between paclitaxel clearance and RECIST outcome was identified (iCT: p-value = 0.08 and pCT: p-value = 0.81, respectively). In conclusion, systemic paclitaxel exposure was not associated with response to common paclitaxel-based treatment regimens for esophageal cancer. Future studies should focus on tumor exposure in relation to systemic exposure and treatment outcome.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
paclitaxel, esophageal cancer, treatment response, pharmacokinetics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-380502 (URN)10.3390/cancers11020173 (DOI)000460747200047 ()30717316 (PubMedID)
Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-04-23Bibliographically approved
Hermann, R., Litwin, J. S., Friberg, L. E., Dangond, F. & Munafo, A. (2019). Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis. British Journal of Clinical Pharmacology, 85(7), 1484-1494
Open this publication in new window or tab >>Effects of cladribine tablets on heart rate, atrio-ventricular conduction and cardiac repolarization in patients with relapsing multiple sclerosis
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2019 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, no 7, p. 1484-1494Article in journal (Refereed) Published
Abstract [en]

Aims Cladribine tablets have shown significant efficacy for the treatment of relapsing multiple sclerosis, a chronic and debilitating immune-mediated disorder. This study was conducted to examine acute and/or cumulative effects of cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dose over 2 years) on heart rate, AV conduction and cardiac repolarization in patients with relapsing-remitting multiple sclerosis (RRMS). Methods CLARITY was a 96-week, double-blind, placebo-controlled, multicentre trial which evaluated the safety and efficacy of cladribine tablets 3.5 and 5.25 mg/kg body weight in patients with RRMS. A total of 135 patients were included in the ECG substudy, providing a total of 1534 post-dose ECGs. ECG data were collected 15 minutes pre-dose and between 0.5 and 3 hours post-dose at pre-study evaluation, study Day 1 and Weeks 5, 9, 13, 48 and 52. Results For cladribine tablets 3.5 mg/kg, the maximum change in placebo-adjusted post-dose QTcF vs. visit-baseline (BL) was -0.42 ms (90% CI: -3.61-4.44) at Week 1 (acute effects), and 3.20 ms (90% CI: -0.08-6.33) for cladribine tablets 5.25 mg/kg. The greatest observed differences in post-dose QTcF vs. study BL occurred at Week 48 for both the 3.5 and 5.25 mg/kg doses of cladribine tablets with 5.99 ms (90% CI: 0.53-11.44) and 8.74 ms (90% CI: 3.18-14.31), respectively. No significant changes were observed in T-wave morphology in either treatment group. Conclusions Cladribine tablets 3.5 mg/kg (approved dose in Europe/other regions) did not confer clinically meaningful effects on heart rate, AV conduction and ventricular repolarization.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
cardiac safety, cladribine, modelling, multiple sclerosis, QT, QTc interval
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-390805 (URN)10.1111/bcp.13919 (DOI)000473090600015 ()30883839 (PubMedID)
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Sou, T., Kukavica-Ibrulj, I., Soukarieh, F., Halliday, N., Levesque, R. C., Williams, P., . . . Bergström, C. A. S. (2019). Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection. Journal of Pharmaceutical Sciences, 108(1), 630-640
Open this publication in new window or tab >>Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
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2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 1, p. 630-640Article in journal (Refereed) Published
Abstract [en]

Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.

Keywords
pulmonary drug delivery, pharmacometrics, PK/PD modeling, preclinical pharmacokinetics, absorption, solubility, metabolic clearance, distribution, disposition, simulations
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-377374 (URN)10.1016/j.xphs.2018.09.017 (DOI)000456898100066 ()30257195 (PubMedID)
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Maarbjerg, S. F., Thorsted, A., Kristoffersson, A., Friberg, L. E., Nielsen, E. I., Wang, M., . . . Schroder, H. (2019). Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?. Pediatric Blood & Cancer, 66(6), Article ID e27654.
Open this publication in new window or tab >>Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?
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2019 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 66, no 6, article id e27654Article in journal (Refereed) Published
Abstract [en]

Background

Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens.

Procedure

This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4x MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range.

Results

A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4x MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC <= 8 mg/L.

Conclusions

Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.

Keywords
cancer, febrile neutropenia, pediatric, pharmacokinetics, piperacillin, target attainment
National Category
Pediatrics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-383501 (URN)10.1002/pbc.27654 (DOI)000465150800066 ()30740885 (PubMedID)
Available from: 2019-05-17 Created: 2019-05-17 Last updated: 2019-05-17Bibliographically approved
Schindler, E., Friberg, L., Lum, B. L., Wang, B., Quartino, A., Li, C., . . . Karlsson, M. O. (2018). A pharmacometric analysis of patient-reported outcomes in breast cancer patients through item response theory. Paper presented at The American Conference on Pharmacometrics 2015 (ACoP6), October 3 to 8, 2015, Virginia, USA. Pharmaceutical research, 35(6), Article ID 122.
Open this publication in new window or tab >>A pharmacometric analysis of patient-reported outcomes in breast cancer patients through item response theory
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2018 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 6, article id 122Article in journal (Refereed) Published
Abstract [en]

Purpose

An item response theory (IRT) pharmacometric framework is presented to characterize Functional Assessment of Cancer Therapy-Breast (FACT-B) data in locally-advanced or metastatic breast cancer patients treated with ado-trastuzumab emtansine (T-DM1) or capecitabine-plus-lapatinib.

Methods

In the IRT model, four latent well-being variables, based on FACT-B general subscales, were used to describe the physical, social/family, emotional and functional well-being. Each breast cancer subscale item was reassigned to one of the other subscales. Longitudinal changes in FACT-B responses and covariate effects were investigated.

Results

The IRT model could describe both item-level and subscale-level FACT-B data. Non-Asian patients showed better baseline social/family and functional well-being than Asian patients. Moreover, patients with Eastern Cooperative Oncology Group performance status of 0 had better baseline physical and functional well-being. Well-being was described as initially increasing or decreasing before reaching a steady-state, which varied substantially between patients and subscales. T-DM1 exposure was not related to any of the latent variables. Physical well-being worsening was identified in capecitabine-plus-lapatinib-treated patients, whereas T-DM1-treated patients typically stayed stable.

Conclusion

The developed framework provides a thorough description of FACT-B longitudinal data. It acknowledges the multi-dimensional nature of the questionnaire and allows covariate and exposure effects to be evaluated on responses.

Keywords
ado-trastuzumab emtansine, capecitabine, kadcyla, lapatinib, nonlinear mixed effects, NONMEM, T-DM1
National Category
Cancer and Oncology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-280823 (URN)10.1007/s11095-018-2403-8 (DOI)000430933700012 ()29675616 (PubMedID)
Conference
The American Conference on Pharmacometrics 2015 (ACoP6), October 3 to 8, 2015, Virginia, USA
Available from: 2016-03-29 Created: 2016-03-15 Last updated: 2019-06-27Bibliographically approved
Bouchene, S., Marchand, S., Couet, W., Friberg, L. E., Gobin, P., Lamarche, I., . . . Karlsson, M. O. (2018). A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat. Basic & Clinical Pharmacology & Toxicology, 123(4), 407-422
Open this publication in new window or tab >>A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat
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2018 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 4, p. 407-422Article in journal (Refereed) Published
Abstract [en]

Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.

National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-366956 (URN)10.1111/bcpt.13026 (DOI)000444538100004 ()29665289 (PubMedID)
Funder
Swedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme, Health-F3-2011-278348
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-11-27Bibliographically approved
Paul, M., Daikos, G. L., Durante-Mangoni, E., Yahav, D., Carmeli, Y., Benattar, Y. D., . . . Leibovici, L. (2018). Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet. Infectious diseases (Print), 18(4), 391-400
Open this publication in new window or tab >>Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial
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2018 (English)In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 18, no 4, p. 391-400Article in journal (Refereed) Published
Abstract [en]

Background: Colistin-carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria.

Methods: A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 45 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual.

Findings: Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference -5.7%, 95% CI -13.9 to 2.4; risk ratio [RR] 0.93, 95% CI 0.83-1.03). Results were similar among patients with A baumannii infections (RR 0.97, 95% CI 0.87-1.09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury).

Interpretation: Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2018
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-353117 (URN)10.1016/S1473-3099(18)30099-9 (DOI)000428231600034 ()29456043 (PubMedID)
Available from: 2018-06-11 Created: 2018-06-11 Last updated: 2018-06-11Bibliographically approved
Pierrillas, P. B., Fouliard, S., Chenel, M., Hooker, A., Friberg, L. & Karlsson, M. (2018). Model-Based Adaptive Optimal Design (MBAOD) Improves Combination Dose Finding Designs: an Example in Oncology. AAPS Journal, 20(2), Article ID UNSP 39.
Open this publication in new window or tab >>Model-Based Adaptive Optimal Design (MBAOD) Improves Combination Dose Finding Designs: an Example in Oncology
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2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 2, article id UNSP 39Article in journal (Refereed) Published
Abstract [en]

Design of phase 1 combination therapy trials is complex compared to single therapy trials. In this work, model-based adaptive optimal design (MBAOD) was exemplified and evaluated for a combination of paclitaxel and a hypothetical new compound in a phase 1 study to determine the best dosing regimen for a phase 2 trial. Neutropenia was assumed as the main toxicity and the dose optimization process targeted a 33% probability of grade 4 neutropenia and maximal efficacy (based on preclinical studies) by changing the dose amount of both drugs and the dosing schedule for the new drug. Different starting conditions (e.g., initial dose), search paths (e.g., maximal change in dose intensity per step), and stopping criteria (e.g., "3 + 3 rule") were explored. The MBAOD approach was successfully implemented allowing the possibility of flexible designs with the modification of doses and dosing schedule throughout the trial. The 3 + 3 rule was shown to be highly conservative (selection of a dosing regimen with at least 90% of the possible maximal efficacy in less than 21% of the cases) but also safer (selection of a toxic design in less than 2% of the cases). Without the 3 + 3 rule, better performance was observed (>67% of selected designs were associated with at least 90% of possible maximal efficacy) while the proportion of DLTs per trial was similar. Overall, MBAOD is a promising tool in the context of dose finding studies of combination treatments and was showed to be flexible enough to be associated with requirements imposed by clinical protocols.

Keywords
combination therapy, dose escalation, MBAOD, oncology, recommended dosing regimen
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-386312 (URN)10.1208/s12248-018-0206-9 (DOI)000427539900002 ()29516207 (PubMedID)
Available from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2979-679X

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