Abstract Propofol is a commonly used intravenous anesthetic. Although the kidney plays a minor role in elimination, pharmacokinetics (PK) and pharmacodynamics (PD) have been found to be significantly affected in patients with chronic kidney disease (CKD). The study was a prospective, single‐centre study in CKD patients undergoing surgery under general anaesthesia. A total of 9–10 blood samples were collected from each of 38 patients at prespecified sampling time points for propofol quantification. Time to loss of consciousness and time to eye opening were recorded, along with the bispectral index (BIS), as PD endpoints. The concentration time profile (287 samples) and BIS data from 35 patients were included in model development. Creatinine clearance was identified as an important covariate affecting the PK model. Stage 3 and 4 patients achieved higher plasma concentrations at the same induction and maintenance propofol doses and tended to have lower BIS. The propofol C max was higher in stage 4 patients than in stages 1 or 2. The average concentration at LOC was significantly higher in stage 4 (6.61 ± 6.28 µg/mL) as compared to stages 1 (2.06 ± 1.69 µg/mL) or stage 2 (1.64 ± 1.77 µg/mL). Average time to eye opening was also higher in stages 3 and 4 (12.9 ± 4.7 and 9.5 ± 3.1 min, respectively) as compared to stages 1 and 2 (7 ± 3.2 and 7.9 ± 2.4 min, respectively). The moderate‐severe renal impairment status decreases the requirement of the induction dose of propofol to achieve surgical anesthesia compared to those with normal creatinine clearance. Prolonged clearance also leads to prolonged emergence from anesthesia.
Abstract Oseltamivir (OSE) is widely prescribed for pregnant women with influenza; however, its optimal dosing strategy remains undefined in cases involving carboxylesterase 1 ( CES1 ) gene polymorphism and hepatic cirrhosis. This study aimed to explore OSE dosing regimens for pregnant patients with comorbid CES1 polymorphism and hepatic cirrhosis. A mechanistic physiologically based pharmacokinetic (PBPK) model of OSE was first built and verified in healthy populations, then extrapolated to adult patients with CES1 polymorphism, hepatic cirrhosis, and pregnant patients. The PBPK model successfully predicted and verified the PKs of OSE and its active metabolite oseltamivir carboxylate (OSC) in both non‐pregnant and pregnant women. Simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (C max ) values ranged from 0.5 to 2.0, with the average folding error and absolute average folding error for all concentration–time data points reaching 0.89 and 1.38, respectively. Importantly, for pregnant patients, OSE administration is recommended to be tailored by CES1 genotype, cirrhosis severity, and pregnancy trimester, to achieve post‐dosing AUC levels comparable to those of the non‐pregnant reference population. This integrated pregnancy PBPK model enables us to comprehensively and extensively explore the PK characteristics of OSE and OSC in pregnant women under complex scenarios, thereby providing valuable guidance for clinical applications and precise management of influenza during pregnancy.
Abstract Clinical pharmacokinetic drug–drug interaction (PK‐DDI) studies are frequently required in drug development when metabolizing enzymes and transporters determine pharmacokinetics. Drugs can be victims, perpetrators, or victims and perpetrators, of PK‐DDIs, so the clinical consequences of these interactions, particularly the risks of severe adverse effects and therapeutic failures leading to poor clinical outcomes, must be well understood prior to regulatory filings. In this Commentary, background information on PK‐DDIs is summarized to the point in drug development where the decision is made to conduct a human study. Practical considerations for the design and conduct of clinical PK‐DDI studies are then addressed sequentially, including guidance about study populations, the selection of probe drugs, their doses and durations, suitable study designs, the contentious issues with inclusion and exclusion criteria, which endpoints are the most important, and samples sizes and power estimates. Guidance on how results should be reported is given, including clinical study reports and scientific literature. Although intended primarily for the pharmaceutical industry, the key points apply across all sectors of drug development and are best considered together with regulatory guidelines on drug interaction studies.
Abstract Dolutegravir is central to antiretroviral therapy in pregnancy, although conventional pharmacokinetic measures cannot fully explain variability in maternal cardiometabolic outcomes or fetal exposure. This narrative review proposes an integrated omics framework linking pharmacogenomics, transcriptomics, proteomics, and metabolomics with longitudinal pharmacokinetics and clinical phenotyping. Using dolutegravir as a case study, we examine genetic determinants of drug disposition, gestational changes in molecular pathways, and emerging evidence implicating adipose dysfunction, mitochondrial metabolism, lipid remodeling, and insulin resistance. We distinguish established pharmacokinetic findings from mechanistic hypotheses requiring pregnancy‐specific validation. Proposed studies combine serial maternal sampling, targeted placental and adipose investigations, and offspring follow‐up, while accounting for HIV, antiretroviral backbone, gestational physiology, and environmental confounding. Prespecified analyses, analytical validation, and independent replication are essential to avoid overinterpretation. Integrated omics should complement, not replace, pharmacometrics, ultimately identifying reproducible mechanisms and clinically useful biomarkers to inform individualized monitoring and treatment strategies while preserving dolutegravir's proven virologic benefits.
