Expert Opinion on Drug Metabolism & Toxicology最新文献

Introduction: Bone and joint infections (BJIs) are a major health concern causing remarkable morbidity and mortality. However, which antimicrobial treatment could be the best according to specific clinical scenarios and/or to the pharmacokinetic/pharmacodynamic (PK/PD) features remains an unmet clinical need. This multidisciplinary opinion article aims to develop evidence-based algorithms for empirical and targeted antibiotic therapy of patients affected by BJIs.

Areas covered: A multidisciplinary team of four experts had several rounds of assessment for developing algorithms devoted to empirical and targeted antimicrobial therapy of BJIs. A literature search was performed on PubMed-MEDLINE (until April 2023) to provide evidence for supporting therapeutic choices. Four different clinical scenarios were structured according to specific infection types (i.e. vertebral osteomyelitis, prosthetic joint infections, infected non-unions and other chronic osteomyelitis, and infectious arthritis), need or not of surgical intervention or revision, isolation or not of clinically relevant bacterial pathogens from blood and/or tissue cultures, and PK/PD features of antibiotics.

Expert opinion: The proposed therapeutic algorithms were based on a multifaceted approach considering the peculiar features of each antibiotic (spectrum of activity, PK/PD properties, bone penetration rate, and anti-biofilm activity), and could be hopefully helpful in improving clinical outcome of BJIs.

Introduction: Type 2 diabetes and liver disease, mainly metabolic-associated fatty liver disease (MAFLD) and more rarely cirrhosis, coexist in many patients. This duality has direct implications for the physician when choosing glucose-lowering agents, with classical concerns but also recent new hopes.

Areas covered: This updated comprehensive review will consider the pharmacokinetics, the tolerance/safety profile, the benefit/risk balance in cirrhosis, the effects on MAFLD and the risk of hepatocellular carcinoma of old and new glucose-lowering compounds in patients with liver disease, with a special focus on glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors.

Expert opinion: We are currently facing a new paradigm in the management of patients with diabetes and liver disease. From previous reluctance when using antidiabetic agents (except insulin) in diabetic patients with hepatic impairment because of safety concerns, the commercialization of novel glucose-lowering agents has changed the scene. These agents, which have a good safety profile, are associated with weight loss and pleiotropic effects. They have proven their efficacy in improving MAFLD. However, more specific studies are still needed to prove their efficacy in preventing the progression to fibrosis/cirrhosis and confirm this new opportunity for the management of patients with diabetes and liver disease.

Introduction: Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations.

Areas covered: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented.

Expert opinion: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.

Introduction: Tacrolimus is a potent immunosuppressive drug with many side effects including nephrotoxicity and post-transplant diabetes mellitus. To limit its toxicity, therapeutic drug monitoring (TDM) is performed. However, tacrolimus' pharmacokinetics are highly variable within and between individuals, which complicates their clinical management. Despite TDM, many kidney transplant recipients will experience under- or overexposure to tacrolimus. Therefore, dosing algorithms have been developed to limit the time a patient is exposed to off-target concentrations.

Areas covered: Tacrolimus starting dose algorithms and models for follow-up doses developed and/or tested since 2015, encompassing both adult and pediatric populations. Literature was searched in different databases, i.e. Embase, PubMed, Web of Science, Cochrane Register, and Google Scholar, from inception to February 2023.

Expert opinion: Many algorithms have been developed, but few have been prospectively evaluated. These performed better than bodyweight-based starting doses, regarding the time a patient is exposed to off-target tacrolimus concentrations. No benefit in reduced tacrolimus toxicity has yet been observed. Most algorithms were developed from small datasets, contained only a few tacrolimus concentrations per person, and were not externally validated. Moreover, other matrices should be considered which might better correlate with tacrolimus toxicity than the whole-blood concentration, e.g. unbound plasma or intra-lymphocytic tacrolimus concentrations.

Background: DWP16001, a sodium-glucose cotransporter-2 inhibitor, has shown promise for improving blood glucose control and facilitating weight loss. Co-administration with phentermine could enhance these effects. So, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions of DWP16001 and phentermine.

Methods: We conducted a randomized, open-label, 3-treatment, 6-sequence, 3-period crossover study involving 24 healthy adults. Participants received either DWP16001 (2 mg), phentermine (37.5 mg), or a combination of both once daily for 7 days. Blood samples, urine samples, and body weights were collected to evaluate the PK and PD.

Results: The PK of the combination was found to be similar to that of the monotherapy. The geometric mean ratio (GMR) of C_max,ss, and AUC_tau,ss were 0.98 and 1.00, respectively, for DWP16001, and 1.01 and 0.94, respectively, for phentermine. Co-administration did not significantly affect the 24-hour urinary glucose excretion compared to DWP16001 monotherapy, and the GMR was 0.90. Participants tended to experience greater weight loss in the combination therapy group, and all demonstrated good tolerance.

Conclusions: Our findings indicate that there were no significant interactions during co-administration. These results suggest that the combination of DWP16001 and phentermine may be safe and effective for the treatment of obesity and diabetes.

Clinical trial registration: NCT05321732.

Introduction: Drugs available for the treatment of breast cancer are increasing, yielding improved oncological outcomes. The efficacy and safety of anticancer drugs significantly depend on pharmacokinetic profiles, which could be influenced by several factors, such as sex hormones.

Areas covered: This article discusses the potential hormone-related pharmacokinetic influences on novel breast cancer pharmacotherapies.

Expert opinion: Recently approved drugs for the treatment of breast cancer belong to different classes, each with unique pharmacokinetic profile. The impact of hormones, such as estrogen and progesterone, may occur at different steps of drug metabolism. Key effects of sex hormones ha ve been reported on multidrug-resistant transporters and enzymes involved in the liver metabolism of drugs, such as cytochromes. Nevertheless, no data is currently available to establish hormone-related metabolic interactions that may account for variability in drug scheduling and selection. Whereas we recognize influences may occur, we do not assume hormones alone can yield clinically significant metabolic changes. Rather, we believe that hormonal influences should be considered along with other elements that may affect drugs metabolism, such as concomitant medications, age-related pharmacokinetic changes, and genetic polymorphisms, in order to deliver treatment personalization and ensure better tolerability and safety of anticancer treatments.

Introduction: Hyphenated mass spectrometry (MS) has evolved into a very powerful analytical technique of high sensitivity and specificity. It is used to analyze a very wide spectrum of analytes in classical and alternative matrices. The presented paper will provide an overview of the current state-of-the-art of hyphenated MS applications in clinical toxicology primarily based on review articles indexed in PubMed (1990 to April 2023).

Areas covered: A general overview of matrices, sample preparation, analytical systems, detection modes, and validation and quality control is given. Moreover, selected applications are discussed.

Expert opinion: A more widespread use of hyphenated MS techniques, especially in systematic toxicological analysis and drugs of abuse testing, would help overcome limitations of immunoassay-based screening strategies. This is currently hampered by high instrument cost, qualification requirements for personnel, and less favorable turnaround times, which could be overcome by more user-friendly, ideally fully automated MS instruments. This would help making hyphenated MS-based analysis available in more laboratories and expanding analysis to a large number of organic drugs, poisons, and/or metabolites. Even the most recent novel psychoactive substances (NPS) could be presumptively identified by high-resolution MS methods, their likely presence be communicated to treating physicians, and be confirmed later on.

Introduction: Despite significant advancements in immunosuppressive regimens and surgical techniques, the prevalence of adverse events related to immunosuppression remains a major challenge affecting the long-term survival rates of pancreas and kidney allografts.

Areas covered: This article presents a comprehensive review of the literature and knowledge (Jan/2012-Feb/2023) concerning glucose metabolism disorders and nephrotoxicity associated with tacrolimus and mammalian target of rapamycin inhibitors (mTORi). Novel signaling pathways potentially implicated in these adverse events are discussed. Furthermore, we extensively examine the findings from clinical trials evaluating the efficacy and safety of tacrolimus, mTORi, and steroid minimization.

Expert opinion: Tacrolimus-based regimens continue to be the standard treatment following pancreas transplants. However, prolonged use of tacrolimus and mTORi may lead to hyperglycemia and nephrotoxicity. Understanding and interpreting experimental data, particularly concerning novel signaling pathways beyond calcineurin-NFAT and mTOR pathways, can offer valuable insights for therapeutic interventions to mitigate hyperglycemia and nephrotoxicity. Additionally, critically analyzing clinical trial results can identify opportunities for personalized safety-based approaches to minimize side effects. It is imperative to conduct randomized-controlled studies to assess the impact of mTORi use and steroid-free protocols on pancreatic allograft survival. Such studies will aid in tailoring treatment strategies for improved transplant outcomes.

Background: Trastuzumab is a humanized anti-HER2 monoclonal antibody used in the treatment of breast cancer. This study compared the pharmacokinetics (PK), immunogenicity and safety of trastuzumab (Roche Pharma AG) and its biosimilar (Chia Tai Tianqing Pharmaceutical Group Co. Ltd) in healthy Chinese subjects.

Research design and methods: A randomized, parallel, double-blind, single-dose study was conducted. Healthy male subjects were randomized to receive trastuzumab (n = 43) or its biosimilar (n = 43) intravenously at a dose of 4 mg. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay (ELISA), and PK parameters were statistically analyzed. Safety and immunogenicity were also evaluated.

Results: The geometric mean ratios (GMRs) of AUC_0-t, C_max and AUC_0-∞ for trastuzumab and its biosimilar were 92.3%, 100.77% and 92.2%, respectively. The 90% CIs were all within 80%-125%, meeting the bioequivalence standards. No serious adverse events or immunogenicity were reported, and all the adverse events reported were mild and similar between the two treatment groups.

Conclusions: Trastuzumab was well tolerated, showed a similar safety profile to its biosimilar, and demonstrated PK equivalence.

Clinical trial registration: This trial was registered at the [anonymized].

Introduction: The management of patients with BRAF-mutated advanced melanoma who are undergoing targeted therapy with MEK inhibitors can be complicated by the co-administration of multiple medications, which can give rise to drug-drug interactions of clinical significance.

Covered areas: Our review presents a comprehensive analysis of the pharmacokinetic and pharmacodynamic interactions of the three approved for advanced melanoma MEK inhibitor drugs - binimetinib, cobimetinib, and trametinib. MEDLINE (PubMed) was utilized for the literature search, comprising clinical studies, observational studies, and preclinical research. The review discusses the impact of these interactions on efficacy and safety of the treatments and differentiates between interactions supported by pharmacokinetic or pharmacodynamic mechanisms, those encountered in clinical practice, and those observed in preclinical studies.

Expert opinion: Physicians should be aware about potential benefits, but also increased toxicity caused by drug interactions between MEK inhibitors and other drugs in the management of patients with metastatic melanoma.