Clinical pharmacokinetic-pharmacodynamic relationships between drug exposure and the QT/QTc interval: Protocol for a systematic review and quantitative synthesis

Drug-induced QT/QTc prolongation is a central component of cardiac safety assessment. Concentration-QT/QTc modelling uses measured or model-predicted systemic drug exposure to estimate the magnitude and uncertainty of effects on ventricular repolarisation and can support regulatory decision-making in early clinical development. However, the evidence is dispersed across dedicated thorough QT studies, early-phase studies, population pharmacokinetic-pharmacodynamic analyses, and secondary pooled analyses, with substantial variation in exposure metrics, electrocardiographic acquisition, heart-rate correction, model structure, assessment of active metabolites and delayed effects, and reporting of uncertainty. This protocol describes a systematic review of quantitative human concentration-QT/QTc evidence. PubMed/MEDLINE, Embase, Scopus, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar will be searched from inception without date or language restrictions. Original human studies will be eligible when drug or metabolite concentrations are measured or estimated from a pharmacokinetic model informed by study data and are quantitatively related to QT or QTc outcomes. Two reviewers will independently screen records, extract data, and assess methodological limitations. The primary estimands will be the concentration-QT/QTc drug-effect parameter and the predicted placebo-adjusted change from baseline in QTc at a clinically relevant exposure. Random-effects meta-analysis will be undertaken only within the same active moiety when analyte, endpoint, correction method, model estimand, and exposure scenario are sufficiently comparable; otherwise, structured synthesis without meta-analysis will be performed. Risk of bias will be assessed using design-appropriate tools where applicable, supplemented by a prespecified concentration-QT/QTc methodological framework. Certainty will be evaluated for coherent drug-specific bodies of evidence. This review will provide a transparent map of clinical concentration-QT/QTc methods and estimates and identify priorities for future cardiac safety studies. PROSPERO registration: CRD420261469142.