The drug was approved in the EU and US. The dosage of 0.3 mg/kg was approved and listed on the label.
An investigational drug was in Phase 3 to treat a rare genetic disease disorder. The number of subjects participating in the Phase 3 study was limited. Phase 3 study demonstrated clinically significant efficacy and favorable safety. The client is preparing for an NDA. Although 0.3 mg/kg was used for all patients, it was unknown whether this dose could be justified in the NDA submission.
Clinical Pharmacology Consulting proposed an analysis plan. We divided patients into four quartiles based on pharmacokinetic (PK) exposures. The efficacy endpoint was analyzed for each quartile. We found that efficacy was comparable across the 4 PK-exposure quartiles, indicating that the PK exposures at 0.3 mg/kg reached the plateau of the dose-response curve. Likewise, the frequency of adverse events (AEs) did not increase with increasing PK exposure to the drug, indicating that the incidence of these AEs was independent of the PK concentrations of the three analytes. The analysis results were included in the CTD 2.7.2 summary of Clinical Pharmacology for NDA and other CTD modules.
We evaluated seven in vitro DDI studies and four human PK study reports. We identified CYP enzymes as potential perpetrators that affect the pharmacokinetics of the investigational drug. We also identified CYP enzymes that could be affected by the investigational drug. Further, we estimated the effect size based on physiologically based pharmacokinetic (PBPK) assessment based on area under the curve (AUC) ratios. We identified CYPs, UGTs, and transporters that are unlikely to cause potential DDIs with the investigational drug.
Clinical studies in healthy subjects confirmed the predicted DDIs from in vitro data. Results were used in the DDI section of the drug product label for NDA (New Drug Application).
During FIH trial conduct, we performed non-compartment (NCA) PK analyses for each dose cohort on an ongoing basis. We found that the predicted and observed PK concentrations were in good agreement. The proposed dose range is adequate for RP2D selection.
The client was developing a molecule for the potential treatment of cancer with multiple mutations. For a New Drug Application (IND), the client needed an investigational plan for a first-in-human study (FIH). However, the selection of starting dose and dose range in the FIH study was a challenge: choosing a narrow dose range might not identify a recommended phase-2 dose (RP2D), whereas selecting a wider dose range would be an expensive and time-consuming addition to the study objectives for the RP2D.
Clinical Pharmacology Consulting proposed to choose starting dose and dose range selection using Modeling & Simulation technique in addition to traditional method with toxicology studies. We conducted a population pharmacokinetic (PK) modeling study across various species for allometric scaling to humans. PK exposures at various dose levels and schedules were obtained by simulation. Second, pharmacodynamic (PD) modeling was conducted to generate in vivo tumor-growth inhibition data. Linking the PK and PD models, the doses with the probability of achieving target concentrations for tumor growth inhibition were predicted, and a dose range was proposed for the FIH study. Our protocol was approved for the FIH study.
Clinical Pharmacology Consulting was asked to evaluate the risk of QT prolongation for a small molecule. The small molecule drug was being developed for treatment of multiple different types of seizures at phase 3 stage. Usually, for a small molecule at phase 3 stage, a thorough QT/QTc study should be conducted to support NDA. Because a thorough QT/QTc study is expensive and time-consuming, the question was whether the study could be waived based on the available preclinical and clinical data.
To answer this question, Clinical Pharmacology Consulting proposed a strategy to address this question. Our overall assessment of the risk for QT prolongation included nonclinical data, the time course of QT prolongation, the magnitude of QT prolongation, categorical analyses of outliers, and certain adverse events (AEs) in patients that can signal potential proarrhythmic effects. A total of eight nonclinical studies, ten phase 1 and 2 clinical studies, and three individual and pooled concentration-QTc modeling analyses from multiple single ascending dose and multiple ascending dose studies were included. We authored a 140- page report for the results of the integrated analysis to support client’s application to waive a TQT study.
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