Clinical Pharmacokinetics最新文献

Background and objective: Treatment of rifampicin-resistant tuberculosis (RR-TB) often includes fluoroquinolones, but data on long-term exposure during and after pregnancy are limited. We examined the pharmacokinetics and safety of levofloxacin in an observational cohort of pregnant and postpartum women receiving treatment for RR-TB.

Methods: Participants were enrolled in their second or third trimester and underwent intensive pharmacokinetic sampling to quantify levofloxacin plasma concentrations at 20-26 weeks' and 30-38 weeks' gestation and at 2-8 weeks postpartum. The levofloxacin plasma concentration target was 7 µg/mL. Pharmacokinetic parameters over 12 and 24 h were described using non-compartmental analysis and within-participant comparison during pregnancy versus postpartum. Adverse events were extracted from medical records. Infants were enrolled in utero and followed on study for 4-6 months after birth.

Results: A total of 11 pregnant women, with a median age of 31 years, received RR-TB treatment including levofloxacin; 6 (55%) were living with HIV. In the second trimester, third trimester, and postpartum, median maximum plasma drug concentration values were 10.3, 10.6, and 10.6 µg/mL, and area under the concentration time curve over 12 h (AUC_0-12) were 69.0, 77.6, and 80.2 µg·h/mL, respectively. Compared with postpartum, median AUCs were lower and clearance was higher in the second but not the third trimester. Eight (72%) women and seven (64%) infants experienced severe or life-threatening adverse events or outcomes that were unlikely to be related to levofloxacin.

Conclusions: Levofloxacin AUC_0-12 was lower in the second trimester than the third trimester of pregnancy and the postpartum period, but exposures overall were within target ranges. Further research is warranted to explore the clinical significance of these findings.

Background and objective: Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated to treat patients with myelofibrosis (MF).

Methods: Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50 mg in a phase 1 study in participants with mild (N = 6), moderate (N = 6), or severe (N = 1) hepatic impairment and matched participants with normal hepatic function (N = 7). All participants in this study were enrolled per Child-Pugh classification, with demographics matched per age, weight, and race.

Results: Navitoclax maximum plasma concentration (C_max), area under the plasma concentration-time curve for time zero to infinity (AUC_0-∞), and terminal elimination half-life (t_1/2) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C_max and AUC_0-∞ values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function. Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea (N = 1) and diarrhea (N = 1).

Conclusions: In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.

Objectives: The volume kinetics of a commercially available colloid fluid, Gelofusine, have not been studied previously.

Methods: Intravenous Gelofusine 10 mL/kg was infused over 30 min in 15 patients undergoing vascular surgery. Of the 15 patients, 14 were classified as American Society of Anesthesiologists (ASA) class III status. The distribution and elimination of the infused volume was calculated with mixed-model kinetics based on 280 measurements of the hemoglobin-derived plasma dilution (19 per patient) collected over 180 min.

Results: The expanded central fluid space volume (V_c, the plasma) amounted to 2.16 L (95% confidence interval [CI] 1.06-2.35) at baseline. The maximum volume expansion of V_c was 706 mL (95% CI 599-812) after infusing Gelofusine 800 mL. Elimination occurred with a half-life of 115 min (95% CI 110-124). Noradrenaline was infused in eight of the 15 patients, leading to a dose-dependent reduction in elimination half-life. For example, an infusion rate of 3 µg/min decreased the half-life to 60 min (- 48%). Distribution of the infused volume to the extravascular space was small (15%), and redistribution to the plasma was accelerated by noradrenaline. Mean arterial pressure and urinary creatinine were not statistically significant covariates, and the model was not strengthened by considering the urine output. Infusion protocols aiming to achieve steady state plasma volume expansion during surgery can begin with a fast infusion over 20 min, then decreasing the rate by 80%.

Conclusion: The kinetics of Gelofusine was predictable in patients of American Society of Anesthesiologists class III status undergoing vascular surgery, with the fluid expanding the vascular space and the half-life shortened by noradrenaline.

Trial registration: Retrospectively registered with ClinicalTrials.gov NCT06474052, June 24, 2024.

Introduction: Sepsis affects approximately 8% of pediatric intensive care unit (PICU) admissions in high-income countries. Ceftriaxone, a broad-spectrum beta-lactam antibiotic, is widely used for treating severe infections and bacterial meningitis in children. Despite its frequent use, limited studies address the population pharmacokinetic (popPK) of ceftriaxone in pediatrics. External validation of popPK models is essential to confirm their suitability for individualized dosing in PICU patients, enabling selection of the model best suited to this population.

Methods: This study used data from the EXPAT Kids study, a prospective pharmacokinetics /pharmacodynamics (PK/PD) study. The included popPK models were implemented in NONMEM, with diagnostic goodness-of-fit and visual predictive check analyses performed to assess model accuracy. Predictive performance was evaluated using the relative prediction error, relative root mean square error, and mean (absolute) percentage error.

Results: The predictive performance of the evaluated models varied widely. The included models showed only modest performance and generally seemed to overpredict ceftriaxone concentrations. Unbound ceftriaxone popPK models did not perform adequately. None of the models met all the predefined thresholds for accuracy and precision.

Conclusions: Our external dataset comprised high ceftriaxone trough concentrations, indicating re-evaluation of current ceftriaxone dosing regimens to minimize the risk of overdosing and prevent toxicity. Future research should focus on the fine dosing balance for ceftriaxone, especially in patients with meningitis, by considering adequate exposure while preventing high trough concentrations. Model-informed precision dosing may enhance the use of the optimal individual dosage for critically ill children. However, our findings highlight the importance of externally evaluating ceftriaxone popPK models in the PICU population.

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.

Background and objective: Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment.

Methods: The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM.

Results: Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function.

Conclusions: No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.