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Population pharmaco...
Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose
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- Zhao, Chenyan (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Uppsala University, Sweden
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- Chirkova, Anna (författare)
- Juvabis AG, CH-8001 Zurich, Switzerland.
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- Rosenborg, Staffan (författare)
- Karolinska Institutet,Karolinska Institutet, Sweden; Karolinska University Hospital, Sweden
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- Palma Villar, Rodrigo (författare)
- RISE,Kemiska processer och läkemedel
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- Lindberg, Johan (författare)
- RISE,Kemiska processer och läkemedel
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- Hobbie, Sven N. (författare)
- RISE Res Inst Sweden, Dept Chem & Pharmaceut Safety, Lund, Sweden.,University of Zurich, Switzerland
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- Friberg, Lena (författare)
- Uppsala universitet,Institutionen för farmaci,Uppsala University, Sweden
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(creator_code:org_t)
- 2022-07-18
- 2022
- Engelska.
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 77:10, s. 2718-2728
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- Background Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. Objectives To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. Methods The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. Results A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. Conclusions The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily.
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)
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