Safety of drug use in patients with a primary mitochondrial disease: An international Delphi-based consensus

Clinical guidance is often sought when prescribing drugs for patients with primary mitochondrial disease. Theoretical considerations concerning drug safety in patients with mitochondrial disease may lead to unnecessary withholding of a drug in a situation of clinical need. The aim of this study was to develop consensus on safe medication use in patients with a primary mitochondrial disease. A panel of 16 experts in mitochondrial medicine, pharmacology, and basic science from six different countries was established. A modified Delphi technique was used to allow the panellists to consider draft recommendations anonymously in two Delphi rounds with predetermined levels of agreement. This process was supported by a review of the available literature and a consensus conference that included the panellists and representatives of patient advocacy groups. A high level of consensus was reached regarding the safety of all 46 reviewed drugs, with the knowledge that the risk of adverse events is influenced both by individual patient risk factors and choice of drug or drug class. This paper details the consensus guidelines of an expert panel and provides an important update of previously established guidelines in safe medication use in patients with primary mitochondrial disease. Specific drugs, drug groups, and clinical or genetic conditions are described separately as they require special attention. It is important to emphasise that consensus-based information is useful to provide guidance, but that decisions related to drug prescribing should always be tailored to the specific needs and risks of each individual patient. We aim to present what is current knowledge and plan to update this regularly both to include new drugs and to review those currently included

DEVELOPMENT OF A PEDIATRIC BRAIN PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL IN CHILDREN WITH AND WITHOUT MENINGITIS.

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Pharmacokinetics and dosimetry of cobalt-55 and cobalt-57

The isotopes Co-55 and Co-57 have been evaluated for PET and SPECT imaging in several clinical brain studies. For clinical application of cobalt, it is important to know the delivered radiation dose. The biodistribution of Co-55 in both rat and humans after intravenous (bolus)-administration was studied. Based on pharmacokinetic data, radiation dose calculations according to the MIRD system are presented, By combining present measurements with literature data on (CoCl2)-Co-60, the radiation dose delivered by (CoCl2)-Co-56 (T-1/2 78.8 days) and (CoCl2)-Co-57 (T-1/2 = 270 days) could be assessed. Methods: Whole-body Co-PET was performed in two healthy volunteers and one rat after intravenous injection of 37 and 3.7 MBq (1 resp, 0.1 mCl) Co-55, respectively. Blood samples were withdrawn during 300 min in humans. In seven rats the Co-55-biodistribution was determined by postmortem analysis. The residence time of the liver (critical organ) was determined in rats and humans. Blood partition-data of Co-55 were assessed resulting in basic pharmacokinetic data in humans. Based on these kinetic data, radiation dose was calculated using the MIRD protocol. Results: In both the humans and the rat, the liver and bladder retained the highest fractions of Co-55 (about 50% resp. 40% of the administered dose), The liver residence time in humans was 8.6 hr. The free fraction Co-55 in the human plasma was at maximum 12%. The total-body mean transit time was 152 min. The volume of the central compartment = 2.8 liter and the steady-state distribution volume = 48 liter. Conclusion: From these results, according to the WHO recommendations for class II studies, 22.2 MBq (0.6 mCi) Co-55 and 14.8 MBq (0.4 mCi) Co-57 (excluding any radionuclide contamination) can be used