The place of analytical chemistry in clinical pharmacology

TMS-007, also known as JX10, is an anti-inflammatory pro-fibrinolytic drug, an SMTP family triprenyl phenol (Figure 1). I read with great interest the article by Moritoyo et al1 who have reported in this journal the first randomized, placebo-controlled, double blind, dose-escalation in-human study on healthy male Japanese subjects.1 Niizuma et al2 have reported a similar study on Japanese patients with acute ischaemic stroke. In both studies from the same group,1, 2 TMS-007 (JX10) was administered as a single intravenous infusion at pharmacologically relevant doses. Moritoyo et al1 reported that TMS-007 was generally well tolerated and caused no serious adverse reactions apart from one episode of mild epistaxis. The authors assessed pharmacokinetic parameters using serial plasma samples collected before (time 0) and 5, 15, 31, 60, 120, 240, 540 and 1440 min after the initiation of the drug infusion. The TMS-007 levels in the plasma samples were determined by using a ‘fully validated high-performance liquid chromatography-tandem mass spectrometry method’ (LC-MS/MS).1 The lower limit of quantification (LLOQ) and the upper limit of quantification (ULOQ) were reported to be 0.01 μg/mL (12 nmol/L) and 20 μg/mL (23 μmol/L) TMS-007 (molecular weight, 869.11), respectively. The precision values (coefficient of variation [CV]) amounted to 8.7% at LLOQ and to 2.3% at ULOQ. The TMS-007 concentrations measured in the study samples ranged between 0 and 60 μg/mL (69 μmol/L). The Cmax and AUC0–24 h values increased almost linearly with increasing dose of the drug. To the best of my knowledge, the article by Moritoyo et al1 described the application of an LC-MS/MS method to measure TMS-007 concentrations in plasma of healthy humans for the first time. As a chemist analyst and clinical pharmacologist, I would like to have learned more details on the analytical performance of the LC-MS/MS method applied by Moritoyo et al1 beyond precision (CV) and sensitivity (LLOQ). I would be interested to know methodological details, such as use of a stable-isotope labelled drug serving as internal standard at proper concentrations, and main instrumental conditions, such as the ionization technique (ESI?) and mode (positive, negative or both) and the mass transition(s) used in quantitative analyses. The authors have neither provided such information in their article nor did they refer to previous reports describing the LC-MS/MS method used in the study. By using the search term ‘TMS-007’ in PubMed (https://pubmed.ncbi.nlm.nih.gov/; assessed on 1/3/2026), I found two articles of the same group by K. Hasumi published in 20231 and 2024.2 It is notable that in quantitative LC-MS/MS, matrix effects are common and may cause considerable ion suppression/enhancement as demonstrated first for finasteride3 and then for many other drugs.4 Use of stable-isotope internal standards results in accurate concentrations because they outweigh matrix effects. In another clinical journal, Niizuma et al2 have reported mean JX10 (TMS-007) plasma concentrations of 10, 30 and 50 μg/mL at intravenous doses of 1, 3 and 6 mg/kg, respectively, without any reference to the applied analytical method. The modern LC-MS/MS technology has the capability of delivering accurate concentrations of drugs such as TMS-007 in human plasma samples in wide nanomolar-to-micromolar ranges. Yet, it is neither trivial nor advisable to treat analytical chemistry as a ‘pure routine’ in clinical analysis, even when mass spectrometry–based methods such as LC-MS/MS are used.5 It is necessary to describe the analytical methods in clinical journals that have been applied in the reported studies in sufficient detail. Proven means are adherence to the guidelines of scientific journals for authors and reviewers.6, 7 Regrettably, organizations such as the FDA8 do not address this vital issue in their guidelines, presumably because this is generally considered as self-evident. Analytical chemistry is vital for clinical journals. Nevertheless, this important discipline is addressed quite differently. Journals generally provide authors with the opportunity to report additional online-hosted supporting (supplementary) information related to their current article. In the author guidelines, the British Journal of Clinical Pharmacology provides the information that ‘Supporting information is information that is not essential to the article, but provides greater depth and background’. Such statements are too general and may be even misleading. Clinical journals should request to describe essential parts of the analytical methods applied in their clinical studies, either in the main article or in the Supporting Information. It is obvious that only validated quantitative analytical methods should be used in clinical studies. In their articles, authors should clearly state whether their methods have been previously reported. Ideally, analytical methods are validated and published in advance, preferably in peer-reviewed chemical analysis oriented journals. This does not hinder, as claimed by some clinicians, but rather promotes and ensures good scientific practice.5-7 Partial or full description of unpublished analytical methods as supporting information is not meaningful, except the journals invite experts to peer-review this part of the paper as well. I would like to mention two clinical pharmacological papers, which appeared recently in two clinical pharmacological journals and described in sufficient detail the LC-MS/MS methods used in the studies with proper reference to previously published methods.9, 10 Research data are not shared.