Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide Therapeutic Drug Monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document.

Characterization of the alcohol biomarker phosphatidylethanol in donor whole blood and apheresis red blood cells: Implications for transfusion recipients.

Introduction: Phosphatidylethanol (PEth) is a long-term marker of alcohol consumption used frequently in clinical scenarios such as liver transplant evaluation. Recent cases have demonstrated that packed red blood cell (pRBC) transfusion creates the potential for artificial elevation or decrease of observed PEth concentrations in recipients. Very little is known about the prevalence or stability of PEth in pRBCs.

Laboratorian Interpretation of Drug Testing Results in Pain Management: Lessons From College of American Pathologists Proficiency Testing.

Context.—: Accurate interpretation of drug test results is key to appropriate patient care in numerous settings, including pain management. Despite recommendations that providers should consult laboratory professionals for guidance when necessary, literature demonstrating laboratorian expertise in drug test interpretation is lacking.

Analysis of Hypoglycemic Drugs by Liquid Chromatography-Tandem Mass Spectrometry.

A rapid and simple method to measure oral hypoglycemic agents is essential in the evaluation of a patient with spontaneous hypoglycemia. As a result, a robust high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the qualitative detection of first-generation sulfonylureas (e.g.

Artificial elevation of phosphatidylethanol due to red blood cell transfusion.

Introduction: Phosphatidylethanol (PEth) is a marker of alcohol consumption used in clinical and forensic settings. PEth positivity in individuals expected to abstain from alcohol can have serious consequences. PEth is located on erythrocytes, thus packed red blood cell (pRBC) transfusion is a potential cause of false-positive results.

Development of an LC-MS/MS assay with automated sample preparation for phosphatidylethanol (PEth)- Not your typical clinical marker.

Phosphatidylethanol (PEth) is a group of phospholipids formed exclusively in the presence of ethanol on the erythrocyte membrane, making it a direct biomarker for long-term ethanol consumption for which a clinical reference interval has been established. Here, we describe an assay for quantitation for two most abundant PEth homologues, PEth 16:0/18:1 and PEth 16:0/18:2, from human whole blood, and present challenges overcome throughout the development process. Since PEth is localized within erythrocyte membranes, a reliable sample preparation technique is an important aspect of PEth analysis.

Determination of the Duplicated Allele Using Real-Time PCR Signal: An Alternative Approach.

duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with differing activity scores are detected. We evaluated whether visual inspection of plots from real-time-PCR-based targeted genotyping with copy number variation (CNV) detection could reliably determine the duplicated allele.

Drug testing in support of the diagnosis of neonatal abstinence syndrome: The current situation.

Illicit drug use during pregnancy is a concern worldwide, with many international studies describing attempted strategies to mitigate this problem. Drug misuse during pregnancy is associated with significant maternal as well as perinatal complications, which include a high incidence of stillbirths, fetal distress, neonatal abstinence syndrome (NAS) and increased neonatal mortality. Unfortunately, the identification of a drug-exposed mother or neonate is challenging.

Therapeutic Drug Monitoring and Dosage Adjustments of Immunosuppressive Drugs When Combined With Nirmatrelvir/Ritonavir in Patients With COVID-19.

Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component.

Endogenous and iatrogenic sources of variability in response to opioid therapy in Post-Surgical and injured orthopedic patients.

Background: Hydrocodone is the most prescribed opioid in the US. The objective was to evaluate associations between genetic, intrinsic, and extrinsic patient factors, plasma hydrocodone and metabolites, common side effects, and pain scores in a cohort of orthopedic surgery patients.

Methods: Data for each patient was collected by review of the electronic hospital record (EHR), and patient interview.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome.

Assessment of mass spectrometry-based pain management testing in clinical laboratories across North America.

Background: Urine drug testing (UDT) is a useful tool in monitoring compliance to prescribed medication and can also help identify behaviors of drug misuse, abuse, and diversion. Mass spectrometry (MS)-based screening is recommended as the first-line of UDT for pain management patients; however, this testing comes with an inherent lack of standardization in methodologies and various analytical challenges. The objective of this study was to assess the current state of UDT for pain management in a cross-section of clinical laboratories in North America.

Quantification of Serum Sulfamethoxazole and Trimethoprim by Ultra-fast Solid-Phase Extraction-Tandem Mass Spectrometry.

Background: The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is used to treat a number of bacterial infections. TMP/SMX concentrations in serum are conventionally monitored using high-performance liquid chromatography (HPLC) or liquid chromatography tandem mass spectrometry. These methods require laborious manual extraction techniques and relatively long sample analysis times, necessitating the development of a simple, high-throughput method.

Volumetric Microsampling of Capillary Blood Spot vs Whole Blood Sampling for Therapeutic Drug Monitoring of Tacrolimus and Cyclosporin A: Accuracy and Patient Satisfaction.

Background: Immunosuppressant therapeutic drug monitoring (TDM) usually requires outpatient travel to hospitals or phlebotomy sites for venous blood collection; however Mitra® Microsampling Device (MSD) sampling could allow self-collection and shipping of samples to a laboratory for analysis. This study examined the feasibility of using volumetric microsampling by MSD for TDM of tacrolimus (TaC) and cyclosporin A (CsA) in transplant patients, along with their feedback on the process.

Methods: MSD was used to collect TaC and CsA from venous (VB) or capillary (CB) blood.

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug-Drug Interactions.

Background: COVID-19 is a novel infectious disease caused by the severe acute respiratory distress (SARS)-coronavirus-2 (SARS-CoV-2). Several therapeutic options are currently emerging but none with universal consensus or proven efficacy. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 because of their immunosuppressed conditions due to chronic use of immunosuppressive drugs (ISDs).

The challenge that chlorine presented during the development of a benzodiazepine assay.

During the routine validation of a benzodiazepine method (performed on a Liquid Chromatography - Tandem Mass Spectrometer), it was noted that lorazepam, triazolam, and α-hydroxytriazolam showed a quadratic shift/bias in the calibration curve, particularly at high concentrations. The ultimate cause of this bias was determined to be due to the natural presence of chlorine (Cl) isotopes (Cl and Cl) in these benzodiazepines. The presence of the heavy (Cl) isoforms of Cl resulted in the analyte's mass being the same as the internal standard which, in turn, caused the internal standard to appear "falsely increased", thus skewing the calibration curve.

Lack of Influence by CYP3A4 and CYP3A5 Genotypes on Pain Relief by Hydrocodone in Postoperative Cesarean Section Pain Management.

Background: Genetic polymorphisms of cytochrome P450 are contributors to variability in individual response to drugs. Within the P450 family, CYP2D6 is responsible for metabolizing hydrocodone, a widely prescribed opioid for pain management. Alternatively, CYP3A4 and CYP3A5 can form norhydrocodone and dihydrocodeine.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report.

Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document.

Unidentified anion gap metabolic acidosis.

A 35-month-old female with nonketotic hyperglycinemia (NKH) presented to the Emergency department with severe hypoglycemia, fever, and several episodes of seizures. Due to worsening respiratory status, additional seizures and anion gap worsening metabolic acidosis the patient was transferred to the pediatric intensive care unit. The useful mnemonics for causes of high anion gap metabolic acidosis are the classic MUDPILES (representing Methanol, Uraemia, Diabetes, Paraldehyde, Iron (and Isoniazid), Lactate, Ethylene glycol, and Salicylate) and the more recently proposed GOLD MARK (Glycols [ethylene and propylene], Oxoproline, l-lactate, d-lactate, Methanol, Aspirin, Renal failure, and Ketoacidosis) as causes of the anion gap metabolic acidosis were all ruled out.

Simultaneous Determination of Tacrolimus and Cyclosporine A in Whole Blood by Ultrafast LC-MS/MS.

Numerous methods for the measurement of tacrolimus and cyclosporine A involving traditional liquid chromatography tandem mass spectrometry (LC-MS/MS) have previously been described. The majority of these methods use solid-phase extraction, liquid-liquid extraction, or protein precipitation extraction with instrument run times greater than 15 s per sample. Continued demands in clinical labs for greater efficiency and throughput have put increased stress on traditional technologies such as high-performance liquid chromatography-ultraviolet detection (HPLC-UV) and traditional LC-MS/MS.

Targeted Opioid Screening Assay for Pain Management Using High-Resolution Mass Spectrometry.

The use and adherence monitoring of opioids in pain management is recommended by numerous clinical practice guidelines. Many physicians use urine immunoassay screening tests, which suffer from a lack of sensitivity and specificity, to verify compliance to pain medications. However, several immunoassay tests are required to comprehensively detect the synthetic, semisynthetic, and natural opioids due to the limited cross-reactivity of each assay.

An Introduction to Drug Testing: The Expanding Role of Mass Spectrometry.

Measurement of drugs and their metabolites in biological fluids is the foundation of both therapeutic drug monitoring (TDM) and toxicology. The introduction of methods based on mass spectrometry (MS), coupled with gas or liquid chromatography, has revolutionized these areas. This chapter will introduce the reader to the application of MS to TDM and toxicology, the steps that should be considered during implementation and the processes that should be implemented to assure continued quality.