Spotlight on the March 2017 Compass

This issue, Yusuke Tanigawara and Ryuji Kato, open with a detailed guide of useful information for the Congress in Kyoto.

Debbie Marriot, Vice-Chair of the Anti-Infective Drugs Committee, compiled reports from presenters at a recent meeting in Sydney concerning Vancomycin TDM, held under IATDMCT auspice. Together they serve as a great snapshot of the state of current practice and the diverse challenges we still face. Concerning measurement, between method variation occurs between assays from different and even the same manufacturer: isotope dilution Mass Spectrometry is proposed for unambiguous traceability. We are reminded that alternative fluids for sampling remain ‘off-label’ and lab staff are encouraged to participate in local discussion of results in this context.

Vancomycin use in several special populations are covered. In children and neonates, dose recommendations vary. A trough range of 7-10mg/L has been proposed to correlate better to the 24h AUC/MIC target of 400 mcg*h/L, and AUC based dose adaptation might be the optimal method for target attainment. Obese patients require dosing based on Ideal Body Weight and fixed dose regimens may result in underdosing: TDM has a role in achieving adequate exposure. Alongside pharmacokinetic alterations common in the elderly, including reduced renal function and use of concomitant drugs that may affect it, we are reminded of the possibility for pharmacodynamic alterations with increased age, such as immunosenescence.

The remaining presentations concern TDM and dose adaptation in practice. While consensus recommendations suggest trough levels 10-15 or 15-20 mg/L, depending on indication, as surrogates for the AUC based target, approximately a third of patients achieve this with lower troughs and thus risk nephrotoxicity. Michael Neely, Chair of the Anti-Infective Drugs Committee, was the international guest. We have covered some of the various occasions Michael has represented the Association in different countries, promoting the clinical application of pharmacometrics. Michael presented data using the BestDose software to apply either Multiple Model dosing or a novel algorithm that additionally individualizes sampling times (MMOpt). While this experienced clinical group likely dosed to target AUC in the control arm (in which the software results were not used to guide clinical decisions), in the intervention arms there were fewer trough levels >20mg/L and nephrotoxic events. There were substantially fewer samples in the MMOpt arm. DoseMe is an Australian software, and several of the clinician presenters mention its use at their centres. The company founder covered the processes to attain registration as a medical device and challenges involving compliance with regulatory bodies and international standards. Although there are advantages to AUC based dose adaptation, one speaker highlighted that it is ‘not a panacea’ and several speakers highlight challenges implementing TDM and adherence to local guidelines at a hospital level.

Kamisha Johnson-Davis, on behalf of the Clinical Toxicology/Drugs of Abuse Committee, writes about the medicinal and recreational use of Cannabis, covering history of use and legal status, pharmacodynamics, pharmacokinetics and botany, especially determinations of active principals between strains, which vary widely across countries and production facilities. This is clearly a hot topic, mentioned in recent blog posts (February and March). Young Scientists, Lilian Richter and Lea Wagman, attended the International Microsomes and Drug Oxidation Symposium, celebrated for the 21st time since its origins in 1968. Though a relatively small event, several of the founding scientists are pioneers in the field of drug metabolism, and have made important contributions from analytics to pharmacogenetics. Representing the Standards of Practice committee, Manuela Neuman presents an overview of adverse drug reactions and the importance of pharmacovigilance, highlighting the work of her group in developing assays to predict and diagnose idiosyncratic Type B reactions, specifically Drug Induced Liver Disease (DILI). Though very rare, Type B reactions have at times led to withdrawal of novel drugs from the market. Manuela and colleagues use a lymphocyte toxicity assay, serum and tissue cytokine and chemokine levels and histological assessment of the organ involved to determine Type B reactions as a standard of care at their center.

It was a real pleasure to read about the Gala event held to celebrate the retirement of Hans Mauer as director of the Department of Experimental and Clinical Toxicology, Homburg, Saar), a laboratory whose work is recognised world-wide. Hans is succeeded by Young Scientist Committee Chair, Markus Meyer. Professor Mauer took his final bow as director with a presentation titled ‘Witch Ointments and Love Potions’, covering works by Goethe, Handel, Shakespeare, Donizetti and others in which the stars were concoctions from the solanacee plants: Atropa belladonna (deadly nightshade), Hyoscyamus niger (henbane or stinking nightshade), and Solanum dulcamara (bittersweet nightshade). The juicy details are in the Compass.