Measure Of Drug Exposure Research Articles

Fetal behavior and gestational serotonin reuptake inhibitor exposure: relationships between behavior, drug dosage, plasma drug level, and a measure of drug bioeffect

Determination of the relationships between drug dosage, maternal and infant (cord blood) plasma drug concentrations, and serotonin reuptake inhibitor (SRI) bioeffect on offspring neurobehavior is crucial to assessing the effects of gestational SRI exposure. Measurement of maternal and cord blood platelet serotonin (5-HT) provides an index of inhibitory bioeffect at the 5-HT transporter and complements other measures of drug exposure. Three groups of mother-infant pairs were evaluated: (1) mothers with depression untreated with SRIs (DEP, n = 17), (2) mothers treated for depression with SRIs (DEP + SRI, n = 17), and (3) mothers who were not depressed and untreated (ND, n = 29). Fetal movement was assessed using a standardized ultrasound imaging and rating protocol. Maternal and cord blood platelet 5-HT levels were obtained from all participants. For the SRI + DEP group, maternal and infant plasma drug concentrations and an estimate of third-trimester maternal SRI drug exposure were obtained. As expected, substantially lower median platelet 5-HT levels were observed in the DEP + SRI group than in the non-exposed, combined ND and DEP groups. In non-exposed mothers and infants, platelet 5-HT levels were not affected by the presence of maternal depression. Lower maternal and infant platelet 5-HT levels were associated with more immature fetal movement quality. Although these data are limited by small sample size, the bioeffect index of in vivo platelet 5-HT transporter inhibition appears to provide a valuable approach for elucidating and possibly predicting the effects of gestational SRI exposure on fetal and perinatal neurobehavior.

A validated UPLC-MS/MS method for the quantification of immunosuppressive drugs in peripheral blood mononuclear cells using liquid-liquid extraction with low temperature purification without complex pretreatment steps

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0–128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2–20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

O-092 Prevalence of multiple gestation births and perinatal outcomes in pregnancies secondary to clomiphene citrate treatment: a nationwide cohort study

Abstract Study question Is the incidence of multiple gestation births higher in pregnancies obtained after clomiphene citrate (CC) treatment compared to spontaneous pregnancies? Summary answer The rate of multiple gestation births in pregnancies obtained after CC treatment is significantly increased compared to spontaneous pregnancies. What is known already CC is a selective estrogen modulator frequently used to induce ovulation in infertile women. Data regarding the prevalence of multiple gestation births and adverse perinatal outcomes after CC are contradicting and based on meta-analysis of small sample size studies. Multiple gestations are frequently associated with complications such as preeclampsia, premature labor, and growth restriction, which contribute to higher mortality and morbidity rates. Study design, size, duration Using the French National Health Data System (SNDS) spanning 2013 to 2019, we conducted a nationwide cohort study including all pregnancies lasting more than 22 weeks of gestation, in women aged between 18-43 years. Participants/materials, setting, methods For each women, the first pregnancy during study was included. Women with the dispensing of IVF/ICSI treatment and/or gonadotrophins were excluded. Pregnancies exposed to CC (during the period [-60days,-11days] before the beginning of the pregnancy) were 1:10 matched to unexposed pregnancies. Pregnancies exposed to CC between 12 to 2months or less than 11 days before the beginning of the pregnancy were excluded to mitigate misclassification bias. The primary outcome was the multiple gestation birth rate. Main results and the role of chance Of 3,173,013 pregnancies, 32,010 (10 ‰) occurred in women exposed to clomiphene. The multiple pregnancy rate was significantly higher in pregnant women exposed with CC compared to matched controls (odd ratio 4.1, 95% CI [3.9-4.3]) such as twin pregnancies (OR 4.1, 95% CI [3.9-4.3]) and triple or more pregnancies (OR 5.1, 95% CI [3.8-7.2]). Women exposed to CC presented significantly more adverse obstetrical and perinatal outcomes, including stillbirths, premature delivery threats, premature rupture of membranes, gestational diabetes, placenta previa, gravid hypertension, pre-eclampsia, preterm birth, small for gestational age (SGA), C-section rate, and major birth defect rate. After stratification on multiple pregnancy and adjustment on confounders (history of psychiatric disease, diabetes, arterial hypertension, obesity and embryo reduction during pregnancy), women exposed to CC had a significantly higher risk of stillbirth, gestational diabetes, placenta previa, pre-eclampsia, preterm delivery and SGA in case of singleton pregnancies. Additionally, in the case of multiple pregnancies, they had a higher risk of placenta previa, preterm delivery, and SGA compared to non-exposed women. Limitations, reasons for caution The use of filled prescriptions as a measure of drug exposure could be subject to bias such as misclassification bias, although we attempt to mitigate it. Wider implications of the findings Clomiphene use is strongly associated with multiple gestation births and with adverse obstetrical and perinatal outcomes even in singleton pregnancies. These findings should provide awareness of practitioners and patients about its use. It underscore the importance of attentively monitoring follicular growth during the treatment process to avoid multiple pregnancies. Trial registration number NA

Evaluation of limited-sampling strategies to calculate AUC(0-24) and the role of CYP3A5 in Chilean pediatric kidney recipients using extended-release tacrolimus.

Background: Kidney transplantation (KTx) requires immunosuppressive drugs such as Tacrolimus (TAC) which is mainly metabolized by CYP3A5. TAC is routinely monitored by trough levels (C0) although it has not shown to be a reliable marker. The area-under-curve (AUC) is a more realistic measure of drug exposure, but sampling is challenging in pediatric patients. Limited-sampling strategies (LSS) have been developed to estimate AUC. Herein, we aimed to determine AUC(0-24) and CYP3A5 genotype in Chilean pediatric kidney recipients using extended-release TAC, to evaluate different LSS-AUC(0-24) formulas and dose requirements. Patients and methods: We analyzed pediatric kidney recipients using different extended-release TAC brands to determine their trapezoidal AUC(0-24) and CYP3A5 genotypes (SNP rs776746). Daily TAC dose (TAC-D mg/kg) and AUC(0-24) normalized by dose were compared between CYP3A5 expressors (*1/*1 and *1/*3) and non-expressors (*3/*3). We evaluated the single and combined time-points to identify the best LSS-AUC(0-24) model. We compared the performance of this model with two pediatric LSS-AUC(0-24) equations for clinical validation. Results: Fifty-one pharmacokinetic profiles were obtained from kidney recipients (age 13.1 ± 2.9years). When normalizing AUC(0-24) by TAC-D significant differences were found between CYP3A5 expressors and non-expressors (1701.9 vs. 2718.1ng*h/mL/mg/kg, p < 0.05). C0 had a poor fit with AUC(0-24) (r 2 = 0.5011). The model which included C0, C1 and C4, showed the best performance to predict LSS-AUC(0-24) (r 2 = 0.8765) and yielded the lowest precision error (7.1% ± 6.4%) with the lowest fraction (9.8%) of deviated AUC(0-24), in comparison to other LSS equations. Conclusion: Estimation of LSS-AUC(0-24) with 3 time-points is an advisable and clinically useful option for pediatric kidney recipients using extended-release TAC to provide better guidance of decisions if toxicity or drug inefficacy is suspected. The different CYP3A5 genotypes associated with variable dose requirements reinforce considering genotyping before KTx. Further multi-centric studies with admixed cohorts are needed to determine the short- and long-term clinical benefits.

Gallium-68-labeled Peptide PET Quantifies Tumor Exposure of PD-L1 Therapeutics.

Immune checkpoint therapy (ICT) is currently ineffective in a majority of patients. Tumor drug exposure measurements can provide vital insights into mechanisms involved in the resistance of solid tumors to those therapeutics; however, tools to quantify in situ drug exposure are few. We have investigated the potential of programmed death-ligand 1 (PD-L1) pharmacodynamics, quantified using PET, to inform on the tumor exposure of anti-PD-L1 (aPD-L1) therapeutics. To noninvasively quantify PD-L1 levels, we first developed a novel peptide-based gallium-68-labeled binder, [68Ga]Ga-DK223, and evaluated its in vivo distribution, pharmacokinetics, and PD-L1 specificity in preclinical models of triple-negative breast cancer and urothelial carcinoma with variable PD-L1 expression. We then quantified baseline and accessible PD-L1 levels in tumors as a noninvasive pharmacodynamic measure to assess tumor exposure to two aPD-L1 antibodies (avelumab and durvalumab). DK223 exhibited a KD of 1.01±0.83 nmol/L for PD-L1 and inhibited the PD-1:PD-L1 interaction in a dose-dependent manner. [68Ga]Ga-DK223 provides high-contrast PET images within 60 minutes of administration and detects PD-L1 in an expression-dependent manner in xenograft models. PD-L1 pharmacodynamics measured using [68Ga]Ga-DK223-PET revealed that avelumab and durvalumab had similar exposure early during therapy, but only durvalumab exhibited sustained exposure at the tumor. [68Ga]Ga-DK223 detected variable PD-L1 levels and exhibited salient features required for clinical translation. [68Ga]Ga-DK223-PET could be useful for quantifying total PD-L1 levels at baseline and accessible PD-L1 levels during therapy to understand drug exposure at the tumor, thus supporting its use for guiding and optimizing ICT.

High Intrapulmonary Rifampicin and Isoniazid Concentrations Are Associated With Rapid Sputum Bacillary Clearance in Patients With Pulmonary Tuberculosis.

Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi. Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models. Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP)

IntroductionIncreased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical...

Bidirectional influence of heroin and cocaine escalation in persons with dual opioid and cocaine dependence diagnoses.

Persons with dual severe opioid and cocaine use disorders are at risk of considerable morbidity, and the bidirectional relationship of escalation of mu-opioid agonists and cocaine use is not well understood. The aim of this study was to examine the bidirectional relationship between escalation of heroin and cocaine use in volunteers dually diagnosed with opioid and cocaine dependence (OD + CD). Volunteers from New York with OD + CD (total n = 295; male = 182, female = 113; age ≥ 18 years) were interviewed with the Structured Clinical Interview for the DSM-IV Axis I Disorders and Kreek-McHugh-Schluger-Kellogg scales for dimensional measures of drug exposure, which also collect ages of 1st use and onset of heaviest use. Time of escalation was defined as age of onset of heaviest use minus age of 1st use in whole years. Times of escalation of heroin and cocaine were positively correlated in both men (Spearman r = .34, 95% confidence interval [CI: .17, .48], p < .0001) and women (Spearman r = .51, [.27, .50], p < .0001) volunteers. After we adjusted for demographic variables, a Cox regression showed that time of cocaine escalation was a predictor of time of heroin escalation (hazard ratio [HR] = 0.97, 95% CI [0.95, 0.99], p = .003). Another Cox regression showed that this relationship is bidirectional, because time of heroin escalation was also a predictor of time of cocaine escalation (HR = 0.98, [0.96-0.99], p = .016). In these adjusted models, gender was not a significant predictor of time of escalation of either heroin or cocaine. Therefore, escalation did not differ robustly by gender when adjusting for demographics and other major variables. Overall, rapid escalation of cocaine use was a predictor of rapid escalation of heroin use, and vice versa, in persons with dual severe opioid and cocaine use disorders. These findings suggest a shared vulnerability to rapid escalation of these 2 drugs in persons with dual severe opioid and cocaine use disorders. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Multicenter Retrospective Study of Vancomycin Dosing by Weight Measures in Children.

Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies. This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes. Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough <10 µg/mL, and 63% had a ratio of AUC to MIC <400 μg-hr/mL. Three percent had a supratherapeutic initial trough >20 µg/mL or ratio of AUC to MIC >600 μg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity. Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure.

A systematic, concept-based method of developing the exposure measure for drug safety and effectiveness studies.

In drug safety and effectiveness studies based on secondary data, the choice of an appropriate exposure measure for a given outcome can be challenging. Different measures of exposure can yield different estimates of treatment effect and safety. There is a knowledge gap with respect to developing and refining measures of drug exposure, to ensure that the exposure measure addresses the study question and is suitable for statistical analysis. We present a transparent, step-by-step approach to the development of drug exposure measures involving secondary data. This approach would be of interest to students and investigators with initial training in pharmacoepidemiology. We illustrate the approach using a study about Parkinson's disease. We described the exposure specifications according to the study question. Next, we refined the exposure measure by linking it to knowledge about four major concepts in drug safety and effectiveness studies: drug use patterns, duration, timing, and dose. We then used this knowledge to guide the ultimate choice of exposure measure: time-varying, cumulative 6-month exposure to tamsulosin (a drug used to treat prostate hyperplasia). The proposed approach links exposure specifications to four major concepts in drug safety and effectiveness studies. Formulating subject-matter knowledge about these major concepts provides an avenue to develop the rationale and specifications for the exposure measure.

Use of Electronic Health Records to Identify Exposure-Response Relationships in Critically Ill Children: An Example of Midazolam and Delirium.

Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children <18 years of age hospitalized in the pediatric intensive care unit at Duke University; these children were administered midazolam during mechanical ventilation and had ≥1 Cornell Assessment of Pediatric Delirium (CAPD) score. We used individual-level data extracted from the EHR and a previously published population pharmacokinetic (PK) model developed in critically ill children to simulate plasma concentrations at the time of CAPD scores in 1,000 representative datasets. We used multilevel repeated measures models, with clustering at patient and simulation levels, to evaluate the associations between measures of drug exposure (e.g., concentration and area under concentration time curve) and delirium scores. We included 61 children, median age 1.5 years (range = 0.1-16.3), with 181 CAPD assessments. We identified similarities between simulated Empirical Bayesian parameter estimates from the EHR cohort and those from the PK model population. We identified a stronger association between drug concentration at the time of score and CAPD scores (coefficient 1.78; 95% confidence interval: 1.66-1.90) compared with cumulative dose per kilogram and CAPD scores (coefficient -0.01; 95% confidence interval: -0.01 to -0.01). EHR and PK models can be leveraged to investigate exposure-response relationships in critically ill children.

One Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics.

Tuberculosis (TB) remains a global health problem despite almost universal efforts to provide patients with highly effective chemotherapy, in part, because many infected individuals are not diagnosed and treated, others do not complete treatment, and a small proportion harbor Mycobacterium tuberculosis (Mtb) strains that have become resistant to drugs in the standard regimen. Development and approval of new drugs for TB have accelerated in the last 10 years, but more drugs are needed due to both Mtb’s development of resistance and the desire to shorten therapy to 4 months or less. The drug development process needs predictive animal models that recapitulate the complex pathology and bacterial burden distribution of human disease. The human host response to pulmonary infection with Mtb is granulomatous inflammation usually resulting in contained lesions and limited bacterial replication. In those who develop progressive or active disease, regions of necrosis and cavitation can develop leading to lasting lung damage and possible death. This review describes the major vertebrate animal models used in evaluating compound activity against Mtb and the disease presentation that develops. Each of the models, including the zebrafish, various mice, guinea pigs, rabbits, and non-human primates provides data on number of Mtb bacteria and pathology resolution. The models where individual lesions can be dissected from the tissue or sampled can also provide data on lesion-specific bacterial loads and lesion-specific drug concentrations. With the inclusion of medical imaging, a compound’s effect on resolution of pathology within individual lesions and animals can also be determined over time. Incorporation of measurement of drug exposure and drug distribution within animals and their tissues is important for choosing the best compounds to push toward the clinic and to the development of better regimens. We review the practical aspects of each model and the advantages and limitations of each in order to promote choosing a rational combination of them for a compound’s development.

Real-World Infliximab Pharmacokinetic Study Informs an Electronic Health Record-Embedded Dashboard to Guide Precision Dosing in Children with Crohn's Disease.

Standard-of-care infliximab dosing regimens were developed prior to the routine use of therapeutic drug monitoring and identification of target concentrations. Not surprisingly, subtherapeutic infliximab concentrations in pediatric Crohn's disease (CD) are common. The primary aim was to conduct a real-world pharmacokinetic (PK) evaluation to discover blood biomarkers of rapid clearance, identify exposure targets, and a secondary aim to translate PK modeling to the clinic. In a multicenter observational study, 671 peak and trough infliximab concentrations from 78 patients with CD were analyzed with a drug-tolerant assay (Esoterix; LabCorp, Calabasas, CA). Individual area under the curve (AUC) estimates were generated as a measure of drug exposure over time. Population PK modeling (nonlinear mixed-effect modeling) identified serum albumin, antibody to infliximab, erythrocyte sedimentation rate (ESR), and neutrophil CD64 as biomarkers for drug clearance. Week 14 and week 52 biochemical remitters (fecal calprotectin<250µg/g) had higher infliximab exposure (AUC) throughout induction. The optimal infliximab AUC target during induction for week 14 biochemical remission was 79,348µg*h/mL (area under the receiver operating characteristic curve (AUROC) 0.77, [0.63-0.90], 85.7% sensitive, and 64.3% specific) with those exceeding the AUC target more likely to achieve a surgery-free week 52 biochemical remission (OR 4.3, [1.2-14.6]). Pretreatment predictors for subtherapeutic week 14 AUC included neutrophil CD64>6 (OR 4.5, [1.4-17.8]), ESR>30mm/h (OR 3.8, [1.4-11]), age<10years old (OR 4.2, [1.2-20]), and weight<30kg (OR 6.6, [2.1-25]). We created a decision-support PK dashboard with an iterative process and embedded the modeling program within the electronic health record. Model-informed precision dosing guided by real-world PKs is now available at the bedside in real-time.

Alzheimer's disease and related dementias risk: Comparing users of non-selective and M3-selective bladder antimuscarinic drugs.

Bladder antimuscarinic (BAM) drug use is associated with increased risk of Alzheimer's disease and related dementias (ADRD). It is hypothesized that BAMs with non-selective receptor binding may increase ADRD risk more than M3-selective BAMs. This study compared ADRD risk for users of non-selective and M3-selective BAMs and examines ADRD risk associated with overall BAM use. Retrospective cohort study of Medicare claims for 71 688 individuals who used BAM drugs during 2007-2009 without an ADRD diagnosis. We compared ADRD incidence (2011-2016) between non-selective BAM users (fesoterodine, flavoxate, oxybutynin, tolterodine, trospium) and M3-selective BAM users (darifenacin, solifenacin). Logistic regressions compared individuals using target drugs in the same category of total standardized daily doses (TSDD) as a standardized measure of drug exposure, and adjusted for age, sex, race/ethnicity, healthcare utilization, other medication use, socioeconomic status, and comorbidities. Secondary analyses compared ADRD risk associated with different doses of BAMs overall. Non-selective BAM use (compared to M3-selective) was not significantly associated with ADRD incidence. Odds ratios for non-selective use were 0.97 (CI: 0.89-1.04) for 1-364 TSDD, 0.94 (CI: 0.83-1.06) for 365-729, 1.00 (CI: 0.87-1.16) for 730-1094, and 1.03 (CI: 0.88-1.20) for >1094. Higher TSDD of BAMs overall (combining both non-selective and M3-selective BAMs), when compared to 1-364 TSDD, were associated with increased ADRD incidence (OR = 1.05 (CI: 0.99-1.10) for 365-729, OR = 1.11 (CI: 1.05-1.17) for 730-1094, and OR = 1.10 (CI: 1.04-1.15) for >1094). Non-selective and M3-selective BAM users had similar odds of ADRD incidence, and BAM use overall was significantly associated with ADRD incidence.

Optimal Dose or Optimal Exposure? Consideration for Linezolid in Tuberculosis Treatment

Exploring different ways of minimizing linezolid toxicity without compromising efficacy is a major quest in the treatment of drug-resistant tuberculosis (TB). The recently published study by Diacon et al. (1) indicates superior early bactericidal activity (EBA) from an intensive linezolid regimen (1,200 mg daily); however, this dosage has been associated with significant toxicity (2). Given the importance of optimal dose titration, the EBA of linezolid remains to be better characterized in relation to the area under the concentration-time curve (AUC0–24)/MIC ratio, which is the optimal pharmacokinetic/pharmacodynamic (PK/PD) marker of efficacy from hollow fiber system model (2, 3). The authors’ current analysis of EBA refers only to dose category, which is a crude measure of drug exposure. Clinical validation of the current efficacy and resistance suppression target of an AUC0–24/MIC of &gt;100 (2, 3) is also needed from studies like that by Diacon et al. (1). Since in clinical practice, the MIC data are often unavailable during the early phase of the treatment, dose selection could be guided by AUC0–24/MIC thresholds based on the “critical concentration” of linezolid (1 mg/liter) for Mycobacterium tuberculosis (4).

Methodological features of clinical pharmacokinetic–pharmacodynamic studies of antibacterials and antifungals: a systematic review

Pharmacokinetic (PK)-pharmacodynamic (PD) indices relate measures of drug exposure to antibacterial effect. Clinical PK-PD studies aim to correlate PK-PD indices with outcomes in patients. Optimization of dosing based on pre-clinical studies means that PK-PD relationships are difficult to establish; therefore studies need to be designed and reported carefully to validate pre-clinical findings. To describe the methodological features of clinical antibacterial and antifungal PK-PD studies that reported the relationship between PK-PD indices and clinical or microbiological responses. Studies published between 1980 and 2015 were identified through systematic searches. Methodological features of eligible studies were extracted. We identified 85 publications containing 97 PK-PD analyses. Most studies were small, with fewer than 100 patients. Around a quarter were performed on patients with infections due to a single specific pathogen. In approximately one-third of studies, patients received concurrent antibiotics/antifungals and in some other studies patients received other treatments that may confound the PK-PD-outcome relationship. Most studies measured antimicrobial concentrations in blood/serum and only four measured free concentrations. Most performed some form of regression, time-to-event analysis or used the Hill/Emax equation to examine the association between PK-PD index and outcome. Target values of PK-PD indices that predict outcomes were investigated in 52% of studies. Target identification was most commonly done using recursive partitioning or logistic regression. Given the variability in conduct and reporting, we suggest that an agreed set of standards for the conduct and reporting of studies should be developed.

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study

The polymorphic CYP2D6 enzyme metabolises the antipsychotic drugs risperidone and aripiprazole to their active metabolites, 9OH-risperidone and dehydroaripiprazole. The aim of this study was to quantify the effect of CYP2D6 genetic variability on risperidone and aripiprazole exposure and treatment in a large patient population. We retrospectively obtained patient data from a routine therapeutic drug monitoring database at the Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway, between Jan 1, 2005, and Oct 15, 2018. Individuals included in our analyses were CYP2D6-genotyped patients treated with risperidone or aripiprazole. Inclusion criteria for measurement of pharmacokinetic parameters (drug and metabolite serum concentrations) were oral administration of risperidone or aripiprazole, information known about prescribed daily dose and comedications, and aged older than 18 years. Exclusion criteria included polypharmacy with drugs known to be CYP2D6 inhibitors or CYP3A4 inducers or inhibitors. Treatment failure was analysed in all patients treated with risperidone or aripiprazole without these criteria. The first endpoint in our analysis was the metabolism of risperidone to 9OH-risperidone and aripiprazole to dehydroaripiprazole, estimated by the log-transformed ratio between the concentrations of metabolite and parent drug (ie, the metabolic ratio for risperidone [9OH-risperidone]/[risperidone] and the metabolic ratio for aripiprazole [dehydroaripiprazole]/[aripiprazole]). Endpoint two was measurement of drug exposure, quantified by the dose-normalised sum of parent drug and active metabolite serum concentrations (ie, active moiety). The third endpoint of treatment failure was measured as the number of patients switched from risperidone or aripiprazole to another antipsychotic drug within 1 year after the last therapeutic drug monitoring analysis of risperidone or aripiprazole. Patient subgroups were defined by CYP2D6 genotype-determined metaboliser status: poor metabolisers, intermediate metabolisers, normal metabolisers, and ultrarapid metabolisers. ANOVA was used to assess the differences in metabolic ratios, active moieties, and daily doses between individual metaboliser categories, and risperidone and aripiprazole therapeutic failures were compared by logistic regression using the normal metaboliser subgroup as a reference. 1288 risperidone-treated patients and 1334 aripiprazole-treated patients were included in the study, of whom 725 (56%) risperidone-treated and 890 (67%) aripiprazole-treated patients were eligible for the pharmacokinetic analyses. CYP2D6 genotype significantly changed risperidone and aripiprazole metabolism resulting in an approximately 1·6-times and 1·4-times increase in risperidone and aripiprazole active moiety exposure in poor and intermediate metabolisers compared with normal metabolisers, respectively (odds ratios [OR] for the risperidone dose-normalised active moiety concentration 1·568, 95% CI 1·401-1·736, and 1·373, 1·213-1·532; and for the aripiprazole dose-normalised active moiety concentration 1·585, 1·447-1·724, and 1·476, 1·263-1·688, respectively; p<0·0001 for all). Compared with doses for normal metabolisers, clinicians reduced daily doses of risperidone and aripiprazole administered to poor metabolisers by 19% (95% CI 5-35, p=0·010) and 15% (95% CI 1-28, p=0·033) respectively. The incidence of switching from risperidone to another antipsychotic was increased in ultrarapid metabolisers (OR 2·934, 95% CI 1·437-5·989, p=0·003) and poor metabolisers (1·874, 1·128-3·112, p=0·015); by contrast, the incidence of switching from aripiprazole to another antipsychotic was not significantly related to CYP2D6 metaboliser status. CYP2D6 genotype had a substantial clinical effect on risperidone and aripiprazole exposure and on the therapeutic failure of risperidone. Pre-emptive CYP2D6 genotyping would be valuable for individualising risperidone and aripiprazole dosing and treatment optimisation. H2020 program U-PGx, The Swedish Research Council, the Swedish Brain foundation, and the South-Eastern Norway Regional Health Authority.

Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study

IntroductionIndividualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in...

Prescription duration and treatment episodes in oral glucocorticoid users: application of the parametric waiting time distribution.

PurposeGlucocorticoids are widely used medications. In many pharmacoepidemiological studies, duration of individual prescriptions and definition of treatment episodes are important issues. However, many data sources lack this information. We aimed to estimate duration of individual prescriptions for oral glucocorticoids and to describe continuous treatment episodes using the parametric waiting time distribution.MethodsWe used Danish nationwide registries to identify all prescriptions for oral glucocorticoids during 1996–2014. We applied the parametric waiting time distribution to estimate duration of individual prescriptions each year by estimating the 80th, 90th, 95th and 99th percentiles for the interarrival distribution. These corresponded to the time since last prescription during which 80%, 90%, 95% and 99% of users presented a new prescription for redemption. We used the Kaplan–Meier survival function to estimate length of first continuous treatment episodes by assigning estimated prescription duration to each prescription and thereby create treatment episodes from overlapping prescriptions.ResultsWe identified 5,691,985 prescriptions issued to 854,429 individuals of whom 351,202 (41%) only redeemed 1 prescription in the whole study period. The 80th percentile for prescription duration ranged from 87 to 120 days, the 90th percentile from 116 to 150 days, the 95th percentile from 147 to 181 days, and the 99th percentile from 228 to 259 days during 1996–2014. Based on the 80th, 90th, 95th and 99th percentiles of prescription duration, the median length of continuous treatment was 113, 141, 170 and 243 days, respectively.ConclusionOur method and results may provide an important framework for future pharmacoepidemiological studies. The choice of which percentile of the interarrival distribution to apply as prescription duration has an impact on the level of misclassification. Use of the 80th percentile provides a measure of drug exposure that is specific, while the 99th percentile provides a sensitive measure.