Pharmacokinetic Variability Research Articles

A battery of tandem mass spectrometry assays with stable isotope-dilution for the quantification of 15 anti-tuberculosis drugs and two metabolites in patients with susceptible-, multidrug-resistant- and extensively drug-resistant tuberculosis

ObjectiveAnti-tuberculosis (antiTB) drugs are characterized by an important inter-interindividual pharmacokinetic variability poorly predictable from individual patients’ characteristics. Therapeutic drug monitoring (TDM) may therefore be beneficial for patients with Mycobacterium tuberculosis infection, especially for the management of multidrug/extensively drug resistant- (MDR/XDR)-TB. Our objective was to develop robust HPLC-MS/MS methods for plasma quantification of 15 antiTB drugs and 2 metabolites, namely rifampicin, isoniazid plus N-acetyl-isoniazid, pyrazinamide, ethambutol (the conventional quadritherapy for susceptible TB) as well as combination of agents against MDR/XDR-TB: bedaquiline, clofazimine, delamanid and its metabolite M1, levofloxacin, linezolid, moxifloxacin, pretomanid, rifabutin, rifapentine, sutezolid, and cycloserine. MethodsPlasma protein precipitation was used for all analytes except cycloserine, which was analyzed separately after derivatization with benzoyl chloride. AntiTB quadritherapy drugs (Pool1) were separated by Hydrophilic Interaction Liquid Chromatography (column Xbridge BEH Amide, 2.1 × 150 mm, 2.5 μm, Waters®) while MDR/XDR-TB agents (Pool 2) and cycloserine (as benzoyl derivative) were analyzed by reverse phase chromatography on a column XSelect HSS T3, 2.1 × 75 mm, 3.5 µm (Waters®). All runs last <7 min. Quantification was performed by selected reaction monitoring electrospray tandem mass spectrometry, using stable isotopically labelled internal standards. ResultsThe method covers the clinically relevant plasma levels and was extensively validated based on FDA recommendations, with intra- and inter-assay precision (CV) < 15% over the validated ranges. Application of the method is illustrated by examples of TDM for two patients treated for drug-susceptible- and MDR-TB. ConclusionSuch convenient extraction methods and the use of stable isotope-labelled drugs as internal standards provide an accurate and precise quantification of plasma concentrations of all major clinically-used antiTB drugs regimens and is optimally suited for clinically efficient TDM against tuberculosis.

Red blood cell membrane functionalized biomimetic nanoparticles for systemic lupus erythematosus treatment

Cyclosporin A (CsA) is a powerful immunosuppressant often used to treat Systemic lupus erythematosus (SLE). However, current CsA formulations have poor bioavailability and high pharmacokinetic variability, which have greatly affected its further application in clinical. Nanomaterials can enhance the effect of free drugs but can not avoid clearance by the mononuclear phagocytic system (MPS). In this work, inspired by cell membrane biomimetic nanotechnology, we designed red blood cell membrane-coated and Cyclosporin A (CsA)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs (CsA-RNPs) to treat SLE. The resultant CsA-RNPs possess the typical core-shell structures, narrow size distribution and negative surface charge. At the same time, CsA-RNPs have powerful drug loading and sustained release ability. Besides, benefiting from the decoration of cell membrane, the CsA-RNPs show excellent biocompatibility. Furthermore, CsA-RNPs had a 2.63-fold higher half-life (t1/2) and 4.87-fold area under curve (AUC0–∞) than free CsA, exhibiting outstanding performance in SLE treatment of MRL/lpr mice. These properties indicate the potential value of biomimetic cell membrane-coated PLGA NPs as a promising strategy for CsA delivery and clinical SLE therapy.

Liposomal amphotericin B exposure in critically ill patients: a prospective pharmacokinetic study.

Liposomal amphotericin B (L-AmB) is a broad-spectrum antifungal drug. Little is known about its pharmacokinetics (PK) in critically ill patients. The aim of this study was to document the PK of L-AmB in this population. It was also explored if covariates may be identified that influence its exposure. All adult, critically ill patients (at the intensive care unit or hematology ward) treated with L-AmB between October 2016 and January 2020 were eligible for this study. The administered dose was left at the discretion of the treating clinician. Plasma samples were collected at predose and 1, 2, 4, 8, 12, 16, 20 and 24h postdose at an early (day 2-3) and/or later (≥ day 6) treatment day. Additionally, daily trough concentrations were collected until day 14. Of 33 included patients, 31 were evaluable; their median [IQR] age and body weight was 59 [54-64] years and 68 [59-77] kg, respectively. L-AmB was administered at doses between 2.7mg/kg and 12.3mg/kg, with a median [IQR] trough concentration of 3.1 [2.0-4.7] mg/l. The overall median area under the 24 h concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were 169.0 [117.0-253.0] mg h/l and 23.2 [16.9-33.7] mg/l, respectively. A considerable intra- and interpatient PK variability for Cmax and AUC0-24 was observed but no explaining variables, except the administered dose, could be identified. The PK of L-AmB in critically ill patients was documented. A considerable variability in exposure was observed between and within patients; however, it was not associated with a multitude of patient-related characteristics.

Promising Nanocarriers to Enhance Solubility and Bioavailability of Cannabidiol for a Plethora of Therapeutic Opportunities.

In recent years, the interest in cannabidiol (CBD) has increased because of the lack of psychoactive properties. However, CBD has low solubility and bioavailability, variable pharmacokinetics profiles, poor stability, and a pronounced presystemic metabolism. CBD nanoformulations include nanosuspensions, polymeric micelles and nanoparticles, hybrid nanoparticles jelled in cross-linked chitosan, and numerous nanosized lipid formulations, including nanostructured lipid carriers, vesicles, SNEEDS, nanoemulsions, and microemulsions. Nanoformulations have resulted in high CBD solubility, encapsulation efficiency, and stability, and sustained CBD release. Some studies assessed the increased Cmax and AUC and decreased Tmax. A rational evaluation of the studies reported in this review evidences how some of them are very preliminary and should be completed before performing clinical trials. Almost all the developed nanoparticles have simple architectures, are well-known and safe nanocarriers, or are even simple nanosuspensions. In addition, the conventional routes of administration are generally investigated. As a consequence, many of these studies are almost ready for forthcoming clinical translations. Some of the developed nanosystems are very promising for a plethora of therapeutic opportunities because of the versatility in terms of the release, the crossing of physiological barriers, and the number of possible routes of administration.

Pharmacokinetics, blood and urine profile effects, and injection site histopathology following three daily injections of subcutaneous high concentration buprenorphine in New Zealand white rabbits (Oryctolagus cuniculus)

Buprenorphine is a common analgesic administered to rabbits and high concentration formulations can reduce handling stress without sacrificing pain relief. The objective of this study was to evaluate the pharmacokinetics of high concentration buprenorphine and its metabolites following multiple subcutaneous doses in the rabbit. Laboratory variables (complete blood cell count , biochemistry profile, urinalysis) were compared for drug effects and injection sites were evaluated via histopathology. High concentration buprenorphine (HCB) was administered subcutaneously (0.24 mg/kg) to six, 17-week-old, intact female, New Zealand white rabbits ( Oryctolagus cuniculus ) for three doses, 24 hours apart. Two control animals received an equal volume of saline. Blood samples were collected at -72, 0, 0.33, 0.66, 1.5, 3, 6, 12, 24, 48, 72, 96, 120, and 144 hours. Buprenorphine and its metabolites were measured via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). Blood and urine profiles were collected prior to and following HCB administration and compared within and between groups. Injection sites and major organ systems were evaluated grossly and microscopically for drug effects. High concentration buprenorphine administered once every 24 hours for three doses had a variable accumulation index of 1.68 (1.24–2.29), reflecting variability in terminal half-life. Subsequently, the metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide had accumulation indices of 1.79 (1.25–2.77) and 1.84 (1.43–2.88), respectively. No significant laboratory changes were attributed to multiple dose drug administration. Local subcutaneous vasculitis and panniculitis were reported in rabbits receiving HCB. Ante-mortem examination did not find clinical disease, however 6 of 8 rabbits, including controls, had multifocal inflammatory changes in the liver and lungs on histopathology. Subcutaneous high concentration buprenorphine in rabbits has substantial pharmacokinetic variability and accumulation of both the parent drug and metabolites occurs with multiple dosing regimens. Subclinical illness may have impacted these findings and is a notable study limitation. Local inflammation in subcutaneous fat at injection sites was noted in rabbits administered HCB. High concentration buprenorphine has a quick onset of action when administered subcutaneously in the rabbit, but individual variability is notable. Subclinical inflammatory illness may prolong buprenorphine metabolism and clearance and should be considered in determining dosing regimens in rabbits, especially if disease is present or suspected. Inflammation at HCB injection sites is a drug sequela; monitoring injection sites is recommended.

Pharmacokinetics of immediate and sustained-release formulations of paroxetine: Population pharmacokinetic approach to guide paroxetine personalized therapy in chinese psychotic patients.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine’s pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine’s PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population’s apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients.

Tacrolimus Concentration Is Effectively Predicted Using Combined Clinical and Genetic Factors in the Perioperative Period of Kidney Transplantation and Associated with Acute Rejection.

Background Tacrolimus has unpredictable pharmacokinetic (PK) characteristics, which are partially attributed to CYP3A5 polymorphism. The potential effects of clinical factors in the postoperative period of transplantation on tacrolimus PK and those of early tacrolimus PK variability on clinical outcomes are yet to be clarified. Methods We examined the genetic and clinical factors affecting early tacrolimus PK variability in 256 kidney transplant recipients. The relationships among tacrolimus exposure, graft function delay (DGF), and acute rejection (AR) were further explored. Findings. The CYP3A5 genotype were strongly associated with tacrolimus concentration/dose ratio (C0/D). Additionally, ABCB1 (rs1045642 and rs2032582) and ABCC2 (rs3740066) were found to have potential independent effects on early tacrolimus C0/D in multivariate analysis. Red blood counts and albumin level were the most significant clinical factors associated with tacrolimus C0/D. Wuzhi capsule also exerted an effect on tacrolimus PK. A model combined with pharmacogenetic and clinical factors explained 43.4% tacrolimus PK variability compared with 16.3% on the basis of CYP3A5 genotype only. Notably, increasing tacrolimus concentrations in the early postoperative stage were associated with AR, but not DGF. Conclusions Combined analysis of genotype and specific clinical factors is important for the formulation of precise tacrolimus dose regimens in the early stage after kidney transplantation.

Right dose, right now: bedside, real-time, data-driven, and personalised antibiotic dosing in critically ill patients with sepsis or septic shock—a two-centre randomised clinical trial

BackgroundAdequate antibiotic dosing may improve outcomes in critically ill patients but is challenging due to altered and variable pharmacokinetics. To address this challenge, AutoKinetics was developed, a decision support system for bedside, real-time, data-driven and personalised antibiotic dosing. This study evaluates the feasibility, safety and efficacy of its clinical implementation.MethodsIn this two-centre randomised clinical trial, critically ill patients with sepsis or septic shock were randomised to AutoKinetics dosing or standard dosing for four antibiotics: vancomycin, ciprofloxacin, meropenem, and ceftriaxone. Adult patients with a confirmed or suspected infection and either lactate > 2 mmol/L or vasopressor requirement were eligible for inclusion. The primary outcome was pharmacokinetic target attainment in the first 24 h after randomisation. Clinical endpoints included mortality, ICU length of stay and incidence of acute kidney injury.ResultsAfter inclusion of 252 patients, the study was stopped early due to the COVID-19 pandemic. In the ciprofloxacin intervention group, the primary outcome was obtained in 69% compared to 3% in the control group (OR 62.5, CI 11.4–1173.78, p < 0.001). Furthermore, target attainment was faster (26 h, CI 18–42 h, p < 0.001) and better (65% increase, CI 49–84%, p < 0.001). For the other antibiotics, AutoKinetics dosing did not improve target attainment. Clinical endpoints were not significantly different. Importantly, higher dosing did not lead to increased mortality or renal failure.ConclusionsIn critically ill patients, personalised dosing was feasible, safe and significantly improved target attainment for ciprofloxacin.Trial registration: The trial was prospectively registered at Netherlands Trial Register (NTR), NL6501/NTR6689 on 25 August 2017 and at the European Clinical Trials Database (EudraCT), 2017-002478-37 on 6 November 2017.

242.7: Influence of CYP3A5 Polymorphisms on Tacrolimus Dosing in Renal Transplant Recipients

Introduction: Tacrolimus is a commonly used immunosuppressant after kidney transplantation it has narrow theraupetic range and demonstrates wide interindividual variability in pharmacokinetics leading to potential under immunosuppression or tacrolimus toxicity genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailibility between individuals. Aim of the study: Ti evaluate pharmacogenomic effect of CYP3A5 gene polymorphisms on tacrolimus dosing in renal transplant recipients. Materials and Methods: Present study we investigated pharmacogenomics associations of common CYP3A5 polymorphisms with requirements of tacrolimus in renal transplant patients: □INCLUSION CRITERIA - 50 patients on tacrolimus based triple immunosuppression were genotyped for cyp3A5 polymorphism most allels- *1/*1,*1/*3,*3/*3 alleles. □EXCLUSION CRITERIA- those patients on CYP inducers or inhibitors were excluded demographic data, weight based tacrolimus doses, serum tacrolimus level at 1 month, 3 months 1 year and present tacrolimus trough level were collected. Data was statistically analysed. Results: Mean age of the recipients was 33.41+/-10.2,72% were males mean tacrolimus level at 1 month was 8ng/ml (7-10ng/ml) at 1 month post transplant cyp *1/*1 was 5.75+_0.95,tac level in cyp3a5 *1/*3 was 9.52∔_1.42,CYP3A5*3/*3 -10.26+_1.02 with significant P VALUE <0.01 among patients with high tac level 36% were poor metabolisers,50% intermediate metabolizers,none of the extensive metabolisers had higher tacrolimus level. At>3 months of transplantation tac level in cyp3a5 *1/*1 was 5.75∔0.95, cyp3a5 *1/*3 was 6.33∓1.17, cyp3a5 *3/*3 was 6.78∔-0.8 with significant P value < 0.01. 56% developed tac toxicity - 84%(*3/*3) poor metabolisers, 14.3% in intermediate *1/*3 metabolisers.125 developed rejections in first three months of transplant,90.755 were extensive metabolisers Discussion: Tacrolimus toxicity as well as rejection due to sub theraupetic levels influence graft outcomes. bioavailibility of tacrolimus varies widely due to gene polymorphisms of CYP3A5 gene. CYP3A5*1/*1 had lower tac level in blood resulting higher rates of rejection requiring 1.5 to 2 times higher dose compared to poor metabolisersand intermediate metabolizers. Poor metabolizers *3/*3 had tacrolimus related toxicity at similar dose adjusted tac levels, indicating lower dose for maintanence (0.06mg/kg). Conclusion: Genotyped based dosing may improve achievement of theraupetic drug concentrations with reduced drug related complications in the era of personalised medicine.

Viability of Nanostructured Lipid Carrier System in Overcoming the Barriers Associated with Chemotherapeutic Delivery

Background: Delivery of anti-cancer agents is challenging due to some inherent problems associated with them like instability, low solubility, non-specificity, variable pharmacokinetics, narrow therapeutic window, multi-drug resistance development, and other physiological barrier related to tumor cells. In recent years, Nanostructured lipid carrier (NLC) has gained considerable importance in improving anti-cancer agents' therapeutic efficacy. Objective: The present review furnishes a comprehensive account of various barriers encountered in delivering the anti-cancer agent, the suitability of NLC to deliver anti-cancer agent, the techniques employed for the fabrication of NLC, its structure, along with its characterization. The main emphasis has given a break worth to overcome barriers in delivering chemotherapeutic through NLC so far; a number of qualitative literature have been included in this review. Further, the study describes the stability issue associated with the long-term storage of NLC. Conclusion: The NLCs systems offer a great potential to target various anti-cancer agents suffering from low solubility, non-specificity, and severe adverse effects. The NLC system's development can overcome barriers encountered in delivering anti-cancer agents and improve its efficacy in various melanoma types.

449TiP Evaluation of regorafenib treatment PERSOnalization based on therapeutic drug monitoring in patients with metastatic colorectal cancer (mCRC): RePERSO study

In randomized clinical trials, regorafenib (REG) has demonstrated a benefit in overall survival (OS) in mCRC patients, but limiting toxicities make treatment discontinuation frequent. Managing the high inter-patient variability of REG pharmacokinetics (PK) should help prevent toxicity and prolong the anti-tumor effect. In the prospective TEXCAN study, a sum of plasma concentrations of REG and its two main active metabolites M2 and M5 (Csum) at Day15 of Cycle 1 within 2.5 - 5.5 mg/L was associated with an improved OS (1).

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

33317 Study of nemolizumab pharmacokinetics, safety, and efficacy in adolescents with atopic dermatitis

Background: Atopic dermatitis (AD) is common in children, including moderate to severe disease (MTS). Nemolizumab, an interleukin 31 receptor-α (IL31RA) inhibitor, has safety and efficacy in adults with AD. The objective of this study was to evaluate nemolizumab in adolescents. Methods: Open-label 16-week study of nemolizumab in patients aged 12-17 years with MTS AD and associated pruritus with baseline average daily itch-NRS intensity of at least 4. Nemolizumab was administered subcutaneously as a loading dose of 60 mg at baseline, followed by 30 mg every 4 weeks until week 12 with background topical corticosteroid or calcineurin inhibitor treatment. Standard pharmacokinetic (PK), efficacy, and safety assessments performed. Results: 20 patients participated (8M/12F), with a mean age of 14.8 ± 1/6 years. Baseline (BL) mean Eczema Area and Severity Index (EASI) score was 25.2 ± 7.22. Concentrations peaked 1-2 weeks after loading dose, and steady state occurred by week 4. Nemolizumab PK showed linear elimination, a first order absorption, and a mean half-life of 16.7 ± 4.12 days. In population PK analysis, exposures in adolescents were comparable to adults. The main source of PK variability was body weight. There were marked improvements in key AD signs/symptoms (mean EASI decreased 66.5%, itch NRS decreased 43.2%, sleep NRS decreased 53.5%). Adverse events were experienced by 33.3% of subjects (n = 6) and were primarily mild or moderate in severity. Conclusion: Nemolizumab’s PK, safety and efficacy profile was consistent in adolescents and adults patients with MtS AD.

Evaluating the usefulness of the estimated glomerular filtration rate for determination of imipenem dosage in critically ill patients.

Antibiotic dosing in critically ill patients is complicated by variations in the pharmacokinetics of antibiotics in this group. The dosing of imipenem/cilastatin is usually determined by severity of illness and renal function. To determine the correlation between estimated glomerular filtration rates (eGFRs) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and imipenem trough levels in critically ill patients. This prospective observational study was done in the surgical intensive care unit (ICU) at Steve Biko Academic Hospital, Pretoria, South Africa. Imipenem trough levels were measured by high-performance liquid chromatography and compared with eGFRs calculated with the CKD-EPI equation. Correlation was evaluated by the Pearson product-moment correlation coefficient. The study population consisted of 68 critically ill patients aged between 18 and 81 years; 43 (63%) were male, and the mean weight was 78 kg (range 40 - 140). On admission, 30 patients (44%) had sepsis, 16 (24%) were admitted for trauma, and 22 (32%) were admitted for miscellaneous surgical conditions. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ranged from 4 to 39 (mean 18). The 28-day mortality rate was 29%. The mean albumin level was 16 g/L (range 7 - 25), the mean creatinine level 142 μmol/L (range 33 - 840), and the mean eGFR 91 mL/min/1.73 m2 (range 6 - 180). Imipenem trough levels ranged between 3.6 and 92.2 mg/L (mean 11.5). The unadjusted Pearson product-moment correlation coefficient between eGFR and imipenem trough level was -0.04 (p=0.761). Considering the high mortality rate of sepsis in ICUs and the rapid global increase in antimicrobial resistance, it is crucial to dose antibiotics appropriately. Owing to the variability of antibiotic pharmacokinetics in critically ill patients, this task becomes almost impossible when relying on conventional dosing guidelines. This study found that eGFRs do not correlate with imipenem blood levels in critically ill patients and should not be used to determine the dose of imipenem/cilastatin. Instead, the dose should be individualised for patients through routine therapeutic drug monitoring.

Genomewide association study identifies a novel variant associated with tacrolimus trough concentration in Chinese renal transplant recipients.

Tacrolimus (TAC) is an immunosuppressant widely used in kidney transplantation. TAC displays considerable interindividual variability in pharmacokinetics (PKs). Genetic and clinical factors play important roles in TAC PKs. We enrolled a total of 251 Chinese renal transplant recipients and conducted a genomewide association study (GWAS), linkage disequilibrium (LD), and one-way analysis of variance (ANOVA) to find genetic variants affecting log-transformed TAC trough blood concentration/dose ratio (log[C0 /D]). In addition, we performed dual luciferase reporter gene assays and multivariate regression models to evaluate the effect of the genetic variants. The GWAS results showed that all 23 genomewide significant single-nucleotide polymorphisms (p < 5 × 10-8 ) were located on chromosome 7, including CYP3A5*3. LD, conditional association analysis, and one-way ANOVA showed that rs75125371 T > C independently influenced TAC log(C0 /D). Dual luciferase reporter gene assays indicated that rs75125371 minor allele (C) was significantly associated with increased normalized luciferase activity than the major allele (T) in the Huh7 cells (p=1.2 × 10-5 ) and HepaRG cells (p=0.0097). A model inclusive of age, sex, hematocrit, CYP3A5*3, and rs75125371 explained 37.34% variance in TAC C0 . These results suggest that rs75125371 T > C is a functional and population-specific variant affecting TAC C0 in Chinese renal transplant recipients.

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting Haloperidol Exposure in Healthy and Disease Populations.

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly used in the management of several medical conditions, including psychotic disorders. Due to the large interindividual variability among patients taking haloperidol, it is very likely for them to experience either toxic or subtherapeutic effects. We intend to develop a haloperidol PBPK model for identifying the potential sources of pharmacokinetic (PK) variability after intravenous and oral administration by using the population-based simulator, PK-Sim. The model was initially developed and evaluated to predict the PK of haloperidol and its reduced metabolite in adult healthy population after intravenous and oral administration. After evaluating the developed PBPK model in healthy adults, it was used to predict haloperidol–rifampicin drug–drug interaction and was extended to tuberculosis patients. The model evaluation was performed using visual assessments, prediction error, and mean fold error of the ratio of the observed-to-predicted values of the PK parameters. The predicted PK values were in good agreement with the corresponding reported values. The effects of the pathophysiological changes and enzyme induction associated with tuberculosis and its treatment, respectively, on haloperidol PK, have been predicted precisely. For all clinical scenarios that were evaluated, the predicted values were within the acceptable two-fold error range.

The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis.

Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). We searched the literature regarding withdrawn drugs due to safety-related issues (n =391) to compare them with all available small-molecule drugs (n =1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC-1 (Anatomical Therapeutic Chemical) level and ADR. We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6-2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9-3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4±0.8years), followed by achiral drugs (55.4±0.9years, P< .01) and chiral mixtures (52.4±1.4years, P< .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P= .02), in 1961-1980 (P< .001) or 1981-2000 (P< .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P= .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P< .01) and cardiovascular ADRs (P< .01). Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.

Model-Informed Rationale for Early Therapeutic Drug Monitoring of Colistin in Critically Ill Patients.

Adequate colistin exposure is important for microbiological clearance. This study was performed in critically ill patients >18 years old to develop a simplified nonparametric pharmacokinetic (PK) model of colistin for routine clinical use and to determine the role of dose optimization. The Non-Parametric Adaptive Grid algorithm within the Pmetrics software package for R was used to develop a PK model from 47 patients, and external validation of the final model was performed in 13 patients. A 1-compartment multiplicative gamma error model with 0-order input and first-order elimination of colistin was developed with creatinine clearance and serum albumin as covariates on elimination rate constant. An R2 for observed vs individual predicted colistin concentrations of 0.92 was obtained in the validation cohort. High interindividual variability in colistin steady-state area under the plasma concentration-time curve (AUC) from from 120 hours to 144 hours (coefficient of variation=80.1%) and a high interoccasion variability (median coefficient of variation of AUC from time 0 to hours predicted every 8hours for initial 96hours after starting colistin=23.8) was predicted in patients who received this antibiotic for a period of over 152hours (n=22). With the model-suggested dose regimen, only 20% of simulated profiles achieved AUC from time 0 to 24 hours in the range of 50 to 60mg• h/L due to high variability in population PK. In this group of patients, steady-state colistin concentrations were predicted to be achieved >96hours after initiation of colistimethate sodium. This study advocates the need for early and repeated therapeutic drug monitoring and dose optimization in critically ill patients to achieve adequate therapeutic concentration of colistin.

Saliva as Blood Alternative in Therapeutic Monitoring of Teriflunomide-Development and Validation of the Novel Analytical Method.

Therapeutic drug monitoring (TDM) is extremely helpful in individualizing dosage regimen of drugs with narrow therapeutic ranges. It may also be beneficial in the case of drugs characterized by serious side effects and marked interpatient pharmacokinetic variability observed with leflunomide and its biologically active metabolite, teriflunomide. One of the most popular matrices used for TDM is blood. A more readily accessible body fluid is saliva, which can be collected in a much safer way comparing to blood. This makes it especially advantageous alternative to blood during life-threatening SARS-CoV-2 pandemic. However, drug’s saliva concentration is not always a good representation of its blood concentration. The aim of this study was to verify whether saliva can be used in TDM of teriflunomide. We also developed and validated the first reliable and robust LC-MS/MS method for quantification of teriflunomide in saliva. Additionally, the effect of salivary flow and swab absorptive material from the collector device on teriflunomide concentration in saliva was evaluated. Good linear correlation was obtained between the concentration of teriflunomide in plasma and resting saliva (p < 0.000016, r = 0.88), and even better between plasma and the stimulated saliva concentrations (p < 0.000001, r = 0.95) confirming the effectiveness of this non-invasive method of teriflunomide’s TDM. The analyzed validation criteria were fulfilled. No significant influence of salivary flow (p = 0.198) or type of swab in the Salivette device on saliva’s teriflunomide concentration was detected. However, to reduce variability the use of stimulated saliva and synthetic swabs is advised.

Reproducibility and Optimal Arterial Input Function Selection in Dynamic Contrast-Enhanced Perfusion MRI in the Healthy Brain.

Dynamic contrast-enhanced MRI (DCE-MRI) has seen increasing use for quantification of low level of blood-brain barrier (BBB) leakage in various pathological disease states and correlations with clinical outcomes. However, currently there exists limited studies on reproducibility in healthy controls, which is important for the establishment of a normality threshold for future research. To investigate the reproducibility of DCE-MRI and to evaluate the effect of arterial input function (AIF) selection and manual region of interests (ROI) delineation vs. automated global segmentation. Prospective. A total of 16 healthy controls; 11 females; mean age 28.7 years (SD 10.1). A 3T; GE DCE; 3D TFE T1WI. 2D TSE T2. The influx constant Ki , a measure of BBB permeability, and Vp , the blood plasma volume, was calculated using the Patlak model. Cerebral blood flow (CBF) was calculated using Tikhonov model free deconvolution. Manual tissue ROIs, drawn by H.J.S. (30+ years of experience), were compared to automatic tissue segmentation. Intraclass correlation coefficient (ICC) and repeatability coefficient (RC) was used to assess reproducibility. Bland-Altman plots were used to evaluate agreement between measurements day 1 vs. day 2, and manual vs. segmentation method. Ki showed excellent reproducibility in both white and gray matter with an ICC between 0.79 and 0.82 and excellent agreement between manual ROI and automatic segmentation, with an ICC of 0.89 for Ki in WM. Furthermore, Ki values in gray and white matter conforms with histological tissue characteristics, where gray matter generally has a 2-fold higher vessel density. The highest reproducibility measures of Ki (ICC=0.83), CBF (ICC=0.77) and Vd (ICC=0.83) was obtained with the AIF sampled in the internal carotid artery (ICA). DCE-MRI shows excellent reproducibility of pharmacokinetic variables derived from healthy controls. 2 TECHNICAL EFFICACY: Stage 2.