Coming dissertations at Uppsala university
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Pharmacometric tools to support translational drug development
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524851
The use of model-informed drug development has been shown to save significant costs and improve decision making early in the drug development process. The work in this PhD thesis aimed to employ pharmacometric tools to support translational drug development from the preclinical to the late clinical stages.
Pharmacometric modeling was used to characterize the treatment-shortening potential of different anti tuberculosis regimens. The results provided additional evidence in favor of the treatment-shortening capacity of the BPaMZ regimen over BPaL and standard of care, HRZE.
Pharmacokinetic-pharmacodynamic (PKPD) modeling was used to enable the evaluation of the exposure-response of a new anti-tubercular drug, MPL-447, in C3HeB/FeJ mice, thought to be of a translational value in tuberculosis drug development. Model-based evaluation revealed a significant impact of necrotic lesion development in mice on both bacterial growth and sensitivity to treatment with MPL-447, highlighting the significance of accounting for the heterogenous lesion profile in the C3HeB/FeJ mouse model when evaluating drug efficacy.
Pharmacokinetic (PK) modeling was employed to perform interspecies PK scaling of the CB 4332 protein using information from three preclinical species. This approach accounted for the impact of immunogenicity and species-related differences in elimination. Simulations predicted the protein plasma concentrations in humans after different dosing regimens and suggested that a 7 mg/kg dose would be required to reach the target at steady-state.
Using combined biomarker data, PKPD modeling was employed to simultaneously analyze two tuberculosis efficacy biomarkers. The final biomarker model facilitated the prediction of the relationship between the two biomarkers over time. With this modeling framework, missing biomarker data can be predicted using information from the other biomarker.
Several model-based approaches were also explored to evaluate pediatric study power in rare diseases. These approaches were performed analyzing pediatric data alone or combined with the adult data. While Bayesian priors performed well when analyzing pediatric data alone, less technical modeling approaches proved sufficient when pediatric and adult data were combined.
In conclusion, the research presented in this thesis has addressed various challenges encountered in translational drug development. The work has contributed to the evaluation of new anti-tubercular drugs and regimens, the assessment of newly proposed animal models, and optimizing the utilization of biomarker information. Furthermore, this thesis has provided insights into the selection of First-in-Human dose for a protein, showcasing the applicability of model-based approaches in this critical decision-making process. The research has contributed to improving analysis approaches for pediatrics in rare diseases.
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Gaze Following in Infancy : Mechanisms and Developmental Context
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524912
Few things are as fundamental to humans as the ability to share attention. It allows us to coordinate our actions with, and assimilate knowledge from, the actions of others with remarkable efficiency and accuracy. This ability emerges in infancy and sets the stage for all subsequent social development. In this thesis, I explore how infants align visual attention with others toward external objects, a skill known as gaze following. The included studies investigate this phenomenon at different levels, ranging from processes within the infant (Study I) to the impact of infants’ immediate emotional context at a micro-scale (Study II) and cultural variation at a macro scale (Study III).
Previous work has suggested different mechanistic explanations for emerging gaze following, ranging from perceptual cueing to reinforcement learning, to social motivation. Study I aimed to conduct a critical test comparing the perceptual cueing perspective with the social-first perspective. The results indicate that infants initially use both cues, but rely more on social information towards the end of the first year.
The theories of gaze following emergence can be framed in a broader discussion regarding the developmental base (experience-dependent or experience-expectant). It has been suggested that infants’ environment influences the early development of gaze following. However, some theoretical perspectives hold an experience-expectant perspective that infants are predisposed to align visual attention with others, suggesting that gaze following should be relatively robust early in life. In Study II, we found that infants’ gaze following was impacted by attachment quality and maternal Postpartum depression (PPD) at 6 and 10 months, respectively, aligning with an experience-dependent view of development.
Study III extends this work to test the universality of Study II and gaze following as a valid measure of attention sharing. We found that across different cultural contexts (Bhutanese and Swedish), infants follow gaze to a similar degree. However, the impact of infants’ social and emotional environment observed in Study II was not found in Bhutan. We discuss the possibility that cultures relying more on interdependent values possess inherent protective factors that mitigate the negative effects of PPD on the infant.
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The role of imaging in follow-up and prognosis of patients radically operated for melanoma
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-525153
Cutaneous malignant melanoma (CMM) is the cancer type in Sweden with the most rapidly increasing incidence. This thesis investigated if whole-body imaging improves the follow-up scheme post-surgery in high-risk CMM patients and explored the long-term outcomes for early-stage melanoma patients compared to the general population.
We launched the nationwide randomized phase III study: “Trial to assess the Role of Imaging after radical surgery of CMM stage IIB-C and III (TRIM study, NCT 03116412)” with allocation to physical examinations for three years according to Swedish national guidelines +/- five scheduled whole-body imaging procedures. Primary endpoint is overall survival (OS) at five years. Secondary endpoints include Health-Related Quality of Life (HRQoL) outcomes.
In paper I, the TRIM study protocol and the recruitment status were described and evaluated. Based on enrollment of more than 550 patients at 19 centra, we found the study protocol feasible and identified some obstacles for optimal inclusion rate.
In paper II, we evaluated HRQoL and anxiety/depression in > 200 patients in the TRIM study who responded to the Hospital Anxiety and Depression (HAD) scale and the EORTC Quality of Life Questionnaire (QLQ)-C30 at baseline and after one year. No statistically significant differences were found between the study arms. Levels of anxiety and depression symptoms were generally low.
The Malignant Melanoma Database Sweden (MMBaSe) was created by record linkages between the Swedish Melanoma Register and several population-based registers. The MMBaSe includes 67 000 individuals diagnosed with CMM or melanoma in situ (MIS) between 1996 and 2018 and matched, randomly selected, melanoma-free comparators representing the general population.
Overall survival and mortality risks were assessed in two cohort studies in patients with MIS (paper III) and thin CMM (≤ 1 mm) (paper IV) in comparison to their matched comparators. Mortality risks were adjusted for socioeconomic status (SES) and comorbidities. We found several statistically significant differences. Individuals diagnosed with melanoma had higher SES and a lower comorbidity burden. While melanoma patients were at higher risk of dying from CMM, they had lower risks of dying from several other diseases.
In paper III we found a better OS and a lower risk of death in MIS patients, findings that remained after adjustments.
In paper IV, patients with thin CMM had a similar OS as the general population. In individuals with stage T1a disease (< 0.8 mm), the OS at 5 years was slightly better than in comparators.