Clinical Pharmacokinetics最新文献

Background and objective: Teicoplanin is a glycopeptide antibiotic used to treat severe Gram-positive infections. This systematic review provides a comprehensive overview of the current knowledge on the pharmacokinetics of teicoplanin across the entire population, with the aim to identify gaps in the existing literature, prioritise pharmacokinetic research, and support optimal dosing strategies.

Methods: A systematic literature search of the MEDLINE, Embase, Web of Science, and Scopus databases was conducted. Articles published until 1 October 2024 were identified as eligible when they included a pharmacokinetic analysis of teicoplanin. Relevant pharmacokinetic data were extracted from all included articles. Allometric scaling was carried out for reported values of clearance (CL) and volume of distribution (Vd) to an individual of 70 kg. Articles were categorised into eight subgroups. A qualitative assessment of the included studies was conducted using the clinical pharmacokinetic statement checklist.

Results: In total, 85 articles were included in this review. Pharmacokinetic data for 186 healthy volunteers, 130 neonates, 788 children, 1434 adult patients, 48 older adults (≥ 65 years), 674 critically ill patients, 33 patients with impaired renal function, and 159 patients with extracorporeal elimination techniques were extracted for a total of 3452 subjects. Unbound concentrations were assessed in 7.1% of the articles. The Vd_scaled ranged from 1.5 to 583 L/70 kg. The CL_scaled ranged from 0.0073 to 6.38 L/h/70 kg. Covariates on drug disposition were identified in 55.3% of studies, 65.6% of which identified a relationship between renal function and CL. Target attainment was described in 42.4% of articles. Dosing recommendations were provided in 61.2% of all studies. Studies had an average quality score of 69.9% ± standard deviation 15.7.

Conclusion: Individual dosing strategies based on renal function need to be developed, particularly in patients with immature or impaired renal function, using state-of-the art pharmacokinetic/pharmacodynamic modelling approaches. Since teicoplanin is highly plasma protein bound and it is suggested that total concentrations cannot be easily translated to unbound concentrations, future research should also include the measurement of unbound concentrations for pharmacokinetic and target attainment evaluation.

Trial registration: Prospectively registered in PROSPERO.

Trial registration number: CRD42023483334. Registration date: 03/12/2023.

Aim: The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of single escalating oral doses of DDCI-01 (a novel, highly selective, long-acting phosphodiesterase type 5 inhibitor) administered via capsules to healthy volunteers.

Methods: This randomized, double-blind, placebo-controlled, single ascending dosing, Phase Ia clinical study involved 52 healthy volunteers who were randomized (3:1 ratio) to receive a single oral dose of DDCI-01 (1.25, 2.5, 5, 10, 20, 40, or 60 mg) or a placebo. Adverse events and pharmacokinetic parameters were evaluated after 14 days post-administration.

Results: Within the studied dose range, DDCI-01 was safe and tolerable. Mild adverse events incidence was > 10% in all 39 volunteers receiving DDCI-01: myalgia (eight cases, 20.51%) and spontaneous penile erection (four cases, 10.26%). Drug exposure (C_max, AUC_0-t, and AUC_0-inf) increased with increasing dosage; however, no linear correlation was observed between drug exposure and dosage. The drug exposure increase was less than the expected dose-proportional increase. Terminal half-life of DDCI-01 ranged between 35.5 and 40.6 hours, whereas the values of apparent clearance (CL/F) and apparent volume (V_z/F) were in the range of 1.1-3.0 L/h and 59-175 L, respectively. Both CL/F and V_z/F increased with increasing doses of DDCI-01.

Conclusions: DDCI-01 demonstrated favorable safety and pharmacokinetic profiles within the dose range. The findings of this first-in-human study support further research for the indications of DDCI-01, such as pulmonary arterial hypertension and erectile dysfunction.

Registration: Chinese Center for Drug Evaluation (CDE) registry number CTR20201564. The date of registration: August 3, 2020.

Precision dosing of classical cytotoxic drugs in oncology remains underdeveloped, especially in treating non-small cell lung cancer (NSCLC). Despite advancements in targeted therapy and immunotherapy, classical cytotoxic agents continue to play a critical role in NSCLC treatment. However, the current body surface area (BSA)-based dosing of these agents fails to adequately address interindividual variability in pharmacokinetics. By better considering patient characteristics, treatment outcomes can be improved, reducing risks of under-exposure and over-exposure. This narrative review explores opportunities for precision dosing for key cytotoxic agents used in NSCLC treatment: cisplatin, carboplatin, pemetrexed, docetaxel, (nab-)paclitaxel, gemcitabine, and vinorelbine. A comprehensive review of regulatory reports and an extensive literature search were conducted to evaluate current dosing practices, pharmacokinetics, pharmacodynamics, and exposure-response relationships. Our findings highlight promising developments in precision dosing, although the number of directly implementable strategies remains limited. The most compelling evidence supports using the biomarker cystatin C for more precise carboplatin dosing and adopting weekly dosing schedules for docetaxel, paclitaxel, and nab-paclitaxel. Additionally, we recommend direct implementation of therapeutic drug monitoring (TDM)-guided dosing for paclitaxel. This review stresses the urgent need to reassess conventional dosing paradigms for classical cytotoxic agents to better align with the principles of the precision dosing framework. Our recommendations show the potential of precision dosing to improve NSCLC treatment, addressing gaps in the current dosing of classical cytotoxic drugs. Given the large NSCLC patient population, optimising the dosing of these agents could significantly improve treatment outcomes and reduce toxicity for many patients.

Aims: The primary objective of this study was to determine whether concomitant therapy with ticagrelor and rosuvastatin affects rosuvastatin plasma concentrations in patients receiving rosuvastatin 40 mg/day after myocardial infarction.

Methods: We included 93 patients who had experienced a myocardial infarction and were receiving high-dose rosuvastatin 40 mg/day and a P2Y12 receptor antagonist, either ticagrelor, prasugrel or clopidogrel. We used liquid chromatography with tandem mass spectrometry to measure rosuvastatin plasma concentrations after liquid-liquid extraction.

Results: Rosuvastatin plasma concentrations (9.7 ng/mL) were approximately twice as high in patients receiving ticagrelor therapy as in those receiving prasugrel (5.1 ng/mL, p < 0.001) or clopidogrel (5.0 ng/mL, p = 0.009), and ticagrelor was an independent factor influencing rosuvastatin concentrations. In addition, creatinine levels were associated with increased rosuvastatin concentrations (p = 0.039).

Conclusion: Our results suggest an important pharmacokinetic interaction between ticagrelor and rosuvastatin, leading to approximately two-fold higher rosuvastatin plasma concentrations in those receiving concomitant ticagrelor than in those receiving prasugrel or clopidogrel. The association is significant and independent of other potential factors influencing rosuvastatin levels, indicating its potential clinical relevance.

Introduction: Pharmacokinetics (PKs) of drugs are often altered in the intensive care unit (ICU). Opioids are often used in the ICU, particularly as continuous infusions, and their characteristics lead them to undergo PK alterations. We conducted a systematic review to assess the PK of opioid infusions in the ICU.

Methods: Embase, MEDLINE, PubMed, CINAHL, and Evidence-Based Medicine Reviews (EBMR) were searched from inception to March 2024. Studies were included if they evaluated PKs of opioid infusions in adult patients in the ICU. Two reviewers independently selected and extracted data.

Results: Out of the 1040 records screened, 17 studies were included. Five studies were conducted on fentanyl, seven on morphine, one on hydromorphone, two on remifentanil, two on alfentanil, and one on sufentanil. Most studies where observational studies or case series. The mean age was 56 years old. Duration of the infusion varied between 3 h and 20 days. PKs of fentanyl, sufentanil, and hydromorphone were significantly impaired, whereas the PKs of morphine, alfentanil, and remifentanil were impaired to a lesser degree. The PK parameter that was most affected by critical illness was the half-life (T½).

Conclusions: To counter these PK alterations, new therapeutic avenues must be further explored in the ICU to individualize opioid infusions.

Background and objective: This study aimed to develop a population pharmacokinetic model for cefepime in critically ill pediatric and young adult patients to inform dosing recommendations and to evaluate the model's predictive performance for model-informed precision dosing.

Methods: Patients in the pediatric intensive care unit receiving cefepime were prospectively enrolled for clinical data collection and opportunistic plasma sampling for cefepime concentrations. Nonlinear mixed effects modeling was conducted using NONMEM. Allometric body weight scaling was included as a covariate with fixed exponents. Monte Carlo simulations determined optimal initial dosing regimens against susceptible pathogens. The model's predictions were evaluated with an external dataset.

Results: Data from 510 samples across 100 patients were best fit with a two-compartment model with first-order elimination. Estimated glomerular filtration rate and cumulative percentage of fluid balance were identified as significant covariates on clearance and central volume of distribution, respectively. Internal validation showed no model misspecification. External validation confirmed that bias and precision for both population and individual predictions were within commonly accepted ranges. Monte Carlo simulations suggested that the usual dose of 50 mg/kg may require a 3-h infusion or a 6-h dosing interval to keep concentrations above the Pseudomonas aeruginosa minimum inhibitory concentration (≤ 8 mg/L) throughout the dosing interval for patients with normal or augmented renal clearance.

Conclusion: A cefepime population pharmacokinetic model for critically ill pediatric patients was successfully developed, accounting for patient renal function, fluid status, and body size, using real-world data. The model was internally and externally validated for use in optimal dosing simulations and model-informed precision dosing.

Background: Atrial fibrillation (AF) has multiple cardio-metabolic comorbidities, including obesity. The use of direct oral anticoagulants (DOACs) in patients with AF and obesity is still uncertain owing to the concern of possible ineffective DOAC plasma concentration. We evaluated the peak and trough plasma concentrations of DOACs in AF patients with different degrees of obesity.

Methods: Observational single-center study including patients with obesity and AF, between April 2022 and April 2024. Obesity was defined as body mass index (BMI) ≥ 30.0 kg/m². The 2-hour peak and trough DOAC plasma concentrations were assessed. Intake of DOAC was verified on site. Multivariable logistic regression analysis was used to assess the odds ratio (OR) and 95% confidence interval (95% CI) of factors associated with below-range trough concentration (BRTC) and below-range peak concentration (BRPC).

Results: In total, 160 patients (33.8% women) with a mean age of 73.2 ± 9.1 years were included. The median BMI was 32.3 kg/m². DOACs prescribed were apixaban (46.8%), rivaroxaban (21.8%), dabigatran (16.4%), and edoxaban (15.0%); 18.1% and 14.4% had BRTC and BRPC concentrations, respectively. Patients with BRTC were more frequently treated with edoxaban and dabigatran and had a higher BMI. On multivariable logistic regression analysis, dabigatran [hazard ratio (HR) 3.039, 95% CI 1.155-7.999, p = 0.024) and BMI ≥ II class (OR 2.625, 95% CI 1.087-6.335, p = 0.032] were associated with BRTC. Dabigatran (OR 4.296, 95% CI 1.523-12.120, p = 0.006) and apixaban (OR 0.277, 95% CI 0.096-0.802, p = 0.018) were directly and inversely associated with BRPC, respectively.

Conclusions: A nonnegligible proportion of patients with obesity and AF have below-range plasma concentrations of DOACs. Assessment of DOAC plasma concentration in obesity class ≥ II may be useful in these patients.

Background and objectives: This study investigates the pharmacokinetics (PK) of entrectinib and its metabolite M5 (CYP3A4 substrates) in patients with hepatic impairment (HI) and applies physiologically based pharmacokinetic (PBPK) modelling to understand the observed changes mechanistically.

Method: After a single oral administration of entrectinib at 100 mg, measured plasma concentrations for entrectinib and M5 in control subjects and HI patients were compared to predictions made with Simcyp^®. Model sensitivity analyses explored the possible reasons for mismatches to observed data. Reduced oral absorption due to lower bile salt (BS) levels in the intestinal lumen in hepatic impairment was examined.

Results: Physiologically based pharmacokinetic model simulations overestimated the 80% increase in entrectinib area under the plasma concentration curve between 0h to infinity (AUC_inf) observed in patients with severe HI, predicting a > 2-fold rise. Observed maximal plasma concentration (C_max) increased by 25% from controls to mild HI but decreased by 61% from mild to severe HI. Although the model predicted C_max within a 2-fold range, there was a trend to greater over-prediction with increasing HI severity. For M5, PBPK modelling did not capture the observed trends well. The C_max and AUC_inf were overestimated in HI patients and the trend to reduction of C_max with minimal change in AUC_inf with increasing severity of HI was not well captured. Decreasing Simcyp^® default luminal BS concentrations by 2-, 6-, and 8.7-fold for mild, moderate, and severe HI improved the predictions for both entrectinib and M5.

Conclusion: Physiologically based pharmacokinetic model simulations tended to overestimate the observed moderate changes in entrectinib exposures due to HI. For improved prediction of poorly soluble lipophilic drugs like entrectinib there is a need for PBPK models of HI to account for additional pathophysiological changes such as reduced intestinal BS levels.

Trial registration: NCT number: NCT04226833.