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Oral eflornithine t...
Oral eflornithine treatment of late-stage human African trypanosomiasis
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- Boberg, Mikael (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi,Institute of Neuroscience and Physiology, Department of Pharmacology
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(creator_code:org_t)
- ISBN 9789180099639
- 2022
- Engelska.
- Relaterad länk:
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https://gup.ub.gu.se...
Abstract
Ämnesord
Stäng
- Human African trypanosomiasis is a fatal disease unless treated. It is a parasitic vector borne disease endemic in sub-Saharan African countries. Eflornithine is a recommended treatment for gambiense human African trypanosomiasis (g-HAT) in the later disease stage when the parasites have infected the central nervous system. Eflornithine is currently dosed as a racemic mixture of D- and L-eflornithine via repeated intravenous infusions, which comes with several disadvantages. The work in this thesis aimed to assess the feasibility of an oral eflornithine treatment. A chiral liquid chromatography method was developed for separation and preparation of the D- and L-eflornithine enantiomers from the racemic mixture. The acquired enantiopure material was used to determine that L-eflornithine had higher antiparasitic in vitro potency compared to D-eflornithine. The in vitro findings were used with a mathematical modeling approach to predict survival in late-stage g-HAT patients treated with L-eflornithine using pharmacodynamic time-to-event modeling. The in vivo pharmacokinetics in the rat after oral or intravenous doses of enantiopure L-eflornithine was characterized using nonlinear mixed effects modeling and compared to the racemic mixture. Moreover, the distribution of D- and L-eflornithine to the third brain ventricle from the systemic circulation was examined using in vivo microdialysis. Clinical pharmacokinetics in plasma and cerebrospinal fluid for L-eflornithine was modeled using literature data. The pharmacokinetic model was used to predict drug exposure and estimate the probability of target attainment for oral L-eflornithine-based treatments against late-stage g-HAT. L-eflornithine administered as monotherapy dosed at 750 mg/kg/day four or twelve times daily could serve as efficacious regimens. In combination with nifurtimox, dose regimens of L-eflornithine at 375 mg/kg/day dosed two, four or twelve times daily could be efficacious. These results are based on in vitro and preclinical in vivo data as well as clinical data using a translational modeling and simulation approach. Future clinical pharmacokinetic studies are warranted to assess the feasibility of an oral L-eflornithine-based treatment and to establish optimal treatment strategies against late-stage g-HAT.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- Sleeping Sickness
- Neglected Tropical Diseases
- Enantiomers
- Nonlinear Mixed Effects Modeling
- Pharmacokinetics
- Pharmacodynamics
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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