Population pharmacokinetics of free and liposome-encapsulated mitoxantrone in patients with relapsed/refractory lymphoma or small cell lung cancer.

OBJECTIVE: This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone. METHODS: A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters. RESULTS: The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (Cmax) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC. CONCLUSION: The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.

Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis.

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

Development and Evaluation of a Quantitative Systems Pharmacology Model for Mechanism Interpretation and Efficacy Prediction of Atezolizumab in Combination with Carboplatin and Nab-Paclitaxel in Patients with Non-Small-Cell Lung Cancer.

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy.

Reaching the cyclosporine a level target slowly in four weeks correlates with better prognosis for Chinese patients after allogeneic haematopoietic cell transplantation.

OBJECTIVES: This study investigated the impact of early cyclosporin A (CsA) initiation (day -5) on the risk of acute graft versus host disease (aGvHD) after allogeneic haematopoietic cell transplantation (allo-HSCT). METHODS: Sixty-seven leukaemia patients who underwent allo-HSCT were investigated. The correlation between the CsA level in the first four weeks and the following indices was examined: GvHD, cumulative incidence (CI) of GvHD, CI of relapse at month 18, and non-relapse mortality (NRM) at month 18. RESULTS: A significant association between aGvHD and CsA level in the fourth week after allo-HSCT was observed, with the incidence of aGvHD in the fourth week in the lower level group being higher than that in the higher level group (p = 0.044). The CI of aGvHD was 30.1% and 9.8% at day +90 and 42.3% and 17.1% at day +180 in the lower level and higher level groups, respectively. CONCLUSION: For Chinese patients, early introduction and reaching the target CsA concentration within four weeks after allo-HSCT have a positive effect on preventing GvHD, especially in the fourth week after HSCT. Compared to the Western population, the target CsA concentration is lower and the time required to reach the target (within 4 weeks) is longer in the Chinese population (274.75 ng/mL).

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study.

Background: Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. Methods: First, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC-MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. Results: The LC-MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Conclusion: Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies.

Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer.

PURPOSE: The objective of this study was to investigate the pharmacokinetic characteristics of pegylated liposomal doxorubicin (PLD) in Chinese female patients with advanced breast cancer by constructing population pharmacokinetic (popPK) models of liposome-encapsulated and free doxorubicin. Additionally, the relationship between pharmacokinetic parameters and drug-related adverse events (AEs) was explored through toxicity correlation analysis. METHODS: A total of 20 patients with advanced breast cancer were selected from a PLD bioequivalence study. All patients received a single intravenous dose of 50 mg/m2 PLD. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A popPK model was simultaneously built to characterize the pharmacokinetic profiles of liposome-encapsulated and free doxorubicin by non-linear mixed effects model (NONMEM). PLD-related toxicities were graded according to the common terminology criteria for adverse events (CTCAE) v5.0. The Spearman correlation analysis was conducted to explore the relationship between pharmacokinetic parameters and drug-related AEs of both liposome-encapsulated doxorubicin and free doxorubicin. RESULTS: The concentration-time profiles of both liposome-encapsulated doxorubicin and free doxorubicin were well described by a one-compartment model. The most common AEs to PLD were nausea, vomiting, neutropenia, leukopenia, and stomatitis, most of which were grade I-II. The toxicity correlation analysis results indicated that stomatitis was related to the Cmax of liposome-encapsulated doxorubicin (P < 0.05). No other AEs were found to be correlated with the pharmacokinetic parameters of either free or liposome-encapsulated doxorubicin. CONCLUSION: A one-compartment model adequately described the popPK characteristics of both liposome-encapsulated and free doxorubicin in Chinese female patients with advanced breast cancer. Most AEs to PLD were mild. Additionally, the occurrence of mucositis may be positively correlated with the Cmax of liposome-encapsulated doxorubicin.

Population Pharmacokinetics of Anlotinib, a Multiple Receptor Tyrosine Kinase Inhibitor, in Chinese Patients With Malignant Tumors.

The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single-dose phase and 12 mg once daily in the multiple-dose phase. A population pharmacokinetic model was established using nonlinear mixed-effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness-of-fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1-compartment model with first-order absorption and first-order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them.

Modified microvessel density based on perfusion distance: a preferable NSCLC prognostic factor.

Background: Despite the vital role of blood perfusion in tumor progression, the prognostic value of typical blood perfusion markers, such as microvessel density (MVD) or microvessel area (MVA), in patients with non-small cell lung cancer (NSCLC) is still unclear. This study established a modified MVD (mMVD) measurement based on perfusion distance and determined its prognostic value in patients with NSCLC. Methods: A total of 100 patients with NSCLC were enrolled in this retrospective study. The intratumor microvessels of NSCLC patients were visualized using immunohistochemical staining for CD31. The blood perfusion distance was evaluated as the distance from each vessel to its nearest cancer cell (Dmvcc), and the cutoff value for prognosis was determined. Apart from the total MVD (tMVD), microvessels near cancer cells within the cutoff-Dmvcc were counted as mMVD. Predictive values for mortality and recurrence were evaluated and compared. Results: The Dmvcc ranged from 1.6 to 269.8 µm (median, 13.1 µm). The mMVD (range: 2-70; median 23) was counted from tMVD according to the cutoff-Dmvcc (~20 µm). Compared with tMVD, a larger fraction of mMVD (80% vs. 2.9%) played a significant role in overall survival, with an improved area under the receiver operating characteristic (ROC) curve (AUC) (0.74 vs. 0.56). A high mMVD was an independent positive indicator of overall survival (OS) and progression-free survival (PFS). In contrast, tMVD was only related to PFS at the optimal cutoff. Conclusions: Perfusion-distance-based mMVD is a promising prognostic factor for NSCLC patients with superior sensitivity, specificity, and clinical applicability compared to tMVD. This study provides novel insights into the prognostic role of tumor vessel perfusion in patients with NSCLC.

Efficacy of caspofungin combined with clindamycin for Pneumocystis jirovecii pneumonia in a systemic lupus erythematosus patient: A case report and literature review.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection with a difficult diagnosis, rapid progression, high mortality rate and poor prognosis. The primary treatment and prevention of PCP is trimethoprim/sulfamethoxazole (TMP/SMZ). However, there are many cases of intolerance or resistance to the drug, so the convenient and effective alternatives are deficient. CASE PRESENTATION: A 66-year-old woman who took an immunosuppressive agent for a long time was diagnosed with PCP. Poor compliance of treatment was found out after monitoring TMP/SMZ plasma concentrations in this patient. She stopped taking the drug herself because of nausea. As a result of intolerance to TMP/SMZ, caspofungin combined with clindamycin were chosen to continue anti-PCP treatment in this patient. She finally improved and discharged from hospital. CONCLUSION: The new combination of caspofungin and clindamycin may be beneficial for patients with PCP who have failed treatment or are intolerant of TMP/SMZ. In addition, the trend of ß-glucan levels can be a predictor of therapeutic efficacy in PCP.