Introduction: Alirocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin 9 (PCSK9), reduces low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemia. We aimed to develop a population pharmacokinetics (PopPK) model to characterize the pharmacokinetics of alirocumab in Japanese patients. We compared the pharmacokinetic and pharmacodynamic data from Japanese and non-Japanese studies in the ODYSSEY programme.

Methods: A PopPK non-linear mixed-effects model was developed from five clinical studies, including 296 healthy volunteers and patients, 54 from non-Japanese phase Ⅰ trials and 242 from three Japanese studies. Exposures in Japanese patients were computed using individual pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of alirocumab were investigated through inter-study ethnic comparisons in high cardiovascular risk patients (n＝758; including 186［24.5%］Japanese) receiving alirocumab 50, 75, or 150 mg every 2 wks.

Results: Body weight and free PCSK9 concentrations were the only covariates affecting the pharmacokinetics of alirocumab in Japanese patients, and were included in the final PopPK model. A 23％ (alirocumab 50 mg) to 60％ (alirocumab 150 mg) higher steady-state exposure was observed in Japanese versus non-Japanese patients; no difference between populations was observed when exposure was normalized for body weight. Consistent with the slightly higher exposure with alirocumab 50 mg, a slightly higher reduction of free PCSK9 was reported, resulting in a greater LDL-C reduction in Japanese patients. No clinically meaningful differences in LDL-C reduction were observed between Japanese and non-Japanese populations at a dose that fully saturated PCSK9 (150 mg).

Conclusions: No ethnic differences were identified in the pharmacokinetics and pharmacodynamics of alirocumab.

Trial Registration: ClinicalTrials.gov identifiers: NCT01623115, NCT01812707, NCT01448317, NCT01074372, NCT01026597, NCT01644188, NCT01288443, NCT02107898,NCT01812707

Background: This study aims to systematize quality assurance and document management support to ensure the smooth implementation of investigator-initiated clinical trials (IITs).

Methods: A sample survey was performed to investigate whether and how signed original informed consent (IC) documents for IITs were stored at Kanazawa University Hospital. Based on the findings, initiatives were implemented utilizing an electronic medical record (EMR) system: 1) The latest versions of IC forms were issued directly from the EMRs for version control. Forms were printed with a 2D barcode to facilitate their re-entry into subjects' medical records. 2) A new management protocol was introduced in the clinical trial support office to ensure consistent uploading processes for signed IC documents and the archiving of paper records. 3) Patients were registered to trials individually using their EMRs, enabling investigators to access their consent and progress statuses in one place. After implementing these initiatives, the storage of signed original IC documents was re-assessed.

Results: The EMR system presented a simpler IC document management compared to the conventional approach. The updated post-consent document handling procedure improved and consolidated signed original IC document archiving. In addition to the separate registration of trial subjects, investigators responsible for the trial were explicitly identified in the EMR system in the event of uncertainty in other departments. This approach allows for easy confirmation of subjectsʼ consent status when preparing and administering trial drugs.

Conclusions: Our approach of consolidated document and trial process management can improve the reliability of clinical research.

Draft guidelines on population pharmacokinetics/pharmacodynamic analysis suggest that population pharmacokinetics (PPK) analysis would be a highly useful method for evaluating ethnic difference and appropriate dosages for individual patients. The results of such analyses are beginning to be included in package inserts and interview forms, but the validity of those data has not yet been evaluated. In the present study, we investigated and discussed the issue of whether PPK analysis can detect factors that are deduced from the pharmacokinetic characteristics of drugs or detected by clinical pharmacokinetic (CPK) studies.

Among 112 drugs that had been newly approved in Japan in 2016, we excluded blood products, vaccines, radiopharmaceuticals, in vivo diagnostic agents, high-molecular-weight drugs and drugs for which blood concentrations had not been determined. Clinical pharmacokinetic parameters (bioavailability, urinary excretion rate of unchanged drug, systemic clearance, volume of distribution, unbound fraction in plasma, and blood-to-plasma ratio) were extracted from the package insert, interview form, and review report and summary technical documentation. The results obtained from PPK and CPK analyses were compared based on the pharmacokinetic characteristics of each drug.

Twenty drugs were eligible for comparison, and PPK analysis was performed on all of them. Among 15 drugs in which CPK studies detected changes in blood concentrations in patients with liver or kidney dysfunction, significant covariates were detected by PPK analysis in only 6 drugs.

In order to increase the detection power of covariates by PPK analysis in patients with liver or kidney dysfunction, a proper study design should be developed based on information about expected factors related to the variability of blood drug concentrations, particularly the blood unbound drug concentrations, using pharmacokinetic data from healthy volunteers. When providing data from PPK analysis, it is necessary to clearly define the background and indicate the limitations.