Measurement Of Plasma Drug Concentrations Research Articles

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase1 Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Towards Precision Medicine in Clinical Practice: Alinity C vs. UHPLC-MS/MS in Plasma Aripiprazole Determination.

Therapeutic drug monitoring improves the benefit-risk balance of antipsychotic therapy. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) is considered the gold-standard method for measuring plasma drug concentrations; however, the Alinity C system has emerged as a promising alternative. This is the first study aimed at comparing UHPLC-MS/MS versus Alinity C in measuring plasma concentrations of aripiprazole and dehydroaripiprazole. A total of 86 plasma samples were analyzed. The active moiety of aripiprazole was measured in 60 samples using both systems and 26 samples were analyzed twice using Alinity C with an intermediate period of 6 months to assess its reproducibility. Spearman's correlation revealed a good association between the two assays (rs = 0.96) and no significance differences were found by McNemar's test when classifying samples between infra-, supra- and therapeutic ranges. Passing-Bablock regression showed a good correlation among methods (rs = 0.93) and a slope of 1.12 indicating a slight tendency of Alinity C to measure higher values than UHPLC-MS/MS. In addition, a good intra-method correlation across the two sequential analyses with Alinity C was obtained (rs = 0.99). Nonetheless, clinical decisions could be different in 15% of the cases depending on the chosen method. No differences were found in active moiety determination by Alinity C depending on the concentration of aripiprazole and dehydroaripiprazole of the samples.

Real-Time Monitoring of Antibiotics in the Critically Ill Using Biosensors.

By ensuring optimal dosing, therapeutic drug monitoring (TDM) improves outcomes in critically ill patients by maximizing effectiveness while minimizing toxicity. Current methods for measuring plasma drug concentrations, however, can be challenging, time-consuming, and slow to return an answer, limiting the extent to which TDM is used to optimize drug exposure. A potentially promising solution to this dilemma is provided by biosensors, molecular sensing devices that employ biorecognition elements to recognize and quantify their target molecules rapidly and in a single step. This paper reviews the current state of the art for biosensors regarding their application to TDM of antibiotics in the critically ill, both as ex vivo point-of-care devices supporting single timepoint measurements and in vivo devices supporting continuous real-time monitoring in situ in the body. This paper also discusses the clinical development of biosensors for TDM, including regulatory challenges and the need for standardized performance evaluation. We conclude by arguing that, through precise and real-time monitoring of antibiotics, the application of biosensors in TDM holds great promise for enhancing the optimization of drug exposure in critically ill patients, offering the potential for improved outcomes.

Clinical impact of plasma concentrations of first-line antituberculosis drugs.

The clinical significance of low antituberculosis (anti-TB) drug concentrations has not been fully elucidated. To investigate the clinical consequences of first-line drug concentrations in adult patients with drug-susceptible pulmonary TBin South Africa (SA). We conducted a pharmacokinetic study nested within the control arm of the Improving Treatment Success (IMPRESS) trial(NCT02114684) in Durban, SA. During the first 2 months of treatment, participants received weight-based dosing of first-line anti-TBdrugs (rifampicin, isoniazid, pyrazinamide and ethambutol), and had plasma drug concentrations measured at 2 and 6 hours after drugadministration during the 8th week of treatment. Intermediate (8 weeks), end-of-treatment (6 months) and follow-up TB outcomes wereassessed using World Health Organization criteria. We measured plasma drug concentrations on available samples in 43 participants. Peak drug concentrations were below thetherapeutic range in 39/43 (90.7%) for rifampicin, 32/43 (74.4%) for isoniazid, 27/42 (64.3%) for pyrazinamide and 5/41 (12.2%) forethambutol. At the end of the intensive phase of treatment (week 8), 20.9% (n=9/43) of participants remained culture positive. We did notfind a relationship between the concentrations of first-line drugs and treatment outcomes at week 8. All participants were cured at the endof treatment, and there were no relapses during the 12-month follow-up period. Treatment outcomes were favourable despite low drug concentrations as defined by current reference thresholds.

Sex Is the Main Determinant of Levodopa Clinical Pharmacokinetics: Evidence from a Large Series of Levodopa Therapeutic Monitoring.

Different studies, mostly with limited cohorts, have suggested the effects of patients' characteristics on levodopa (LD) pharmacokinetics. We primarily aimed at investigating in a large population the relationship between patients' features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics. The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject's chronically taken first-morning LD dose intake. Five hundred patients, 308 males (61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III "off" score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax) (R2 = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2 = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males. This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability.

Designing drug occupancy studies with PET neuroimaging: Sample size, occupancy ranges and analytical methods

Molecular neuroimaging is today considered essential for evaluation of novel CNS drugs; it is used to quantify blood-brain barrier permeability, verify interaction with key target and determine the drug dose resulting in 50% occupancy, IC50. In spite of this, there has been limited data available to inform on how to optimize study designs.Through simulations, we here evaluate how IC50 estimation is affected by the (i) range of drug doses administered, (ii) number of subjects included, and (iii) level of noise in the plasma drug concentration measurements. Receptor occupancy is determined from PET distribution volumes using two different methods: the Lassen plot and Likelihood estimation of occupancy (LEO). We also introduce and evaluate a new likelihood-based estimator for direct estimation of IC50 from PET distribution volumes.For estimation of IC50, we find very limited added benefit in scanning individuals who are given drug doses corresponding to less than 40% receptor occupancy. In the range of typical PET sample sizes (5–20 subjects) each extra individual clearly reduces the error of the IC50 estimate.In all simulations, likelihood-based methods gave more precise IC50 estimates than the Lassen plot; four times the number of subjects were required for the Lassen plot to reach the same IC50 precision as LEO.

Dosing of Bedaquiline with Rifamycins reduces Rifabutin Plasma Concentrations

Bedaquiline (BDQ), a diarylquinoline mycobacterial ATP synthase inhibitor approved in the United States for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin (RIF), an essential part of drug-sensitive tuberculosis treatment. BDQ is used more broadly in some other countries and has been evaluated for treatment of non-tuberculosis mycobacterial infections, often in combination with rifabutin (RBT). We examined the pharmacokinetic interactions of BDQ plus either RIF or RBT in 33 healthy volunteers. Subjects were randomly assigned to receive two single 400 mg doses of BDQ, given 29 days apart, and either RBT 300 mg or RIF 600 mg, given daily from day 20 to 41 after the first dose of BDQ. Blood samples were collected prior to dosing and at multiple subsequent time points to measure plasma drug concentrations, including those of the rifamycin primary metabolites. BDQ treatment had little effect on the disposition of RIF but resulted in a dramatic shortening of the half-life of RBT and decreased exposure to it. When the drugs were administered together (Day 29) the peak rifamycin concentrations and peak rifamycin metabolite concentrations were reduced significantly (p &lt;0.001). This appeared to result from reduced absorption and raises a concern that doses of BDQ and the rifamycins, particularly RBT should be staggered when the two drugs are given on the same day. The optimum time between dosing should be determined.

High-Performance Liquid Chromatography for the Simultaneous Estimation of Cefoperazone and Sulbactam in Rat Plasma and its Importance in Therapeutic Drug Monitoring

Therapeutic drug monitoring and pharmacokinetic studies of antibiotics need a sensitive and precise measurement ofplasma drug concentrations. In the present study, we developed a rapid, sensitive and selective chromatographicmethod for simultaneous estimation of cefoperazone (CEF) and sulbactam (SAL) in male Wistar rat plasma. A novelliquid phase extraction method has adopted the preparation of plasma sample preparation. The CEF and SAL wereeluted on a peerless Basic C18 (25 cm; 4.6 mm x 5 μm) column maintained at controlled environmental conditions.The gradient mobile phase comprised of 10 mM ammonium acetate and acetonitrile. A UV detector was set at 250nm and retention times for CEF and SAL were approximately 5.6 and 14.2 min, respectively. The proposed HPLCmethod was validated according to the US FDA guidelines with respect to the linearity, accuracy, precision, detectionand quantitation limits, robustness and specificity. Calibration curves of CEF and SAL were linear across theconcentration range of 600-1000 and 6-10 μg/mL, with correlation coefficients (r2) >0.9977 and (r2) >0.9987,respectively. The limits of detection for CEF and SAL were 70.48 and 0.35 μg/mL, respectively. Additionally, CEFand SAL were stable in plasma for at least 24 h when stored at room temperature and 2-8 C. Furthermore, thedeveloped chromatographic method was effectively utilized to measure the plasma CEF and SAL concentrations in apharmacokinetics study after intravenous injection to the healthy male Wistar rats.

Survey on request form content and result reporting in therapeutic drug monitoring service among laboratories in Czechia and Slovakia.

IntroductionThe aim of the study was to investigate current practice and policies of therapeutic drug monitoring (TDM) service requesting and result reporting in Czechia and Slovakia.Materials and methodsAll 149 laboratories that measure plasma drug concentrations were given an online questionnaire during a regular external quality assessment TDM cycle. The questionnaire consisted of 17 questions. The optimal TDM practice was defined as the application of all elements (age, body weight, time of sampling, date of the first administration, time of the last dose administration, the dose, the dosing interval, the route of administration, information on reason of testing, and information on other co–administered drugs) needed for reporting a recommendation for further drug dosing (positive response to question number 16).ResultsThe response rate was 69%, 103 out of 149 laboratories measuring drug concentrations. Only 12% (12 out of 103 laboratories) of the laboratories implemented all elements needed for optimal TDM practice and reported a recommendation. Both paper and electronic request forms were used by 77 out of 103 (75%) laboratories. A total of 69 out of 103 laboratories (67%) specified the type of sampling tube on their request form. Cystatin C was used for prediction of renal drug elimination by 24% (25 out of 103) of participants.ConclusionsSmall number of laboratories implemented all elements needed for optimal TDM practice and report a recommendation on further dosing. Further efforts in education on optimal TDM practice as well as harmonization of service are desirable.

Therapeutic drug monitoring of pazopanib: Using cost-neutral PK-guided interventions to optimize exposure.

3598 Background: Pazopanib is an approved treatment for renal cell carcinoma (RCC) and soft tissue sarcoma (STS). At the currently registered fixed dose of 800 mg QD, 20% of patients (pts) do not attain the efficacy threshold of Cmin ≥ 20.5 mg/L (Suttle et al, 2014), providing a strong rationale for therapeutic drug monitoring (i.e. individualizing the dose based on measured plasma drug concentrations). Previous studies provided cost-neutral alternatives to absolute dose increments to optimize exposure (i.e. splitting intake moments or concomitant intake with food (Groenland et al, 2020; Lubberman et al, 2019)). This study aimed to investigate the feasibility, tolerability and efficacy of TDM of pazopanib, using cost-neutral interventions. Methods: Patients starting treatment with pazopanib at the standard dose of 800 mg QD in modified fasting state were included in the prospective DPOG TDM study (www.trialregister.nl, NL6695). PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Pazopanib concentrations were measured with LC-MS/MS and Cmin was calculated. In case of Cmin &lt; 20.5 mg/L and acceptable toxicity, a dose intervention was recommended. As a first step, intake moments were split (i.e. 400 mg BID). Secondly, concomitant intake with food was recommended. Results: In total, 34 pts were included (19 STS, 15 RCC), of whom 158 PK samples were collected. Eleven pts (32%) were underdosed and had at least 1 PK sample below the target. In 24% of the pts a PK-guided intervention could be performed, which was successful in 6 pts (75%). Median Cmin increased from 15 mg/L to 32 mg/L (p = 0.027). Eventually, 3 pts went back to 800 mg QD due to toxicity, after which Cmin remained ≥ 20.5 mg/L in 2 pts. In pts with adequate exposure throughout the study, median Cmin was 32 mg/L (range 23 – 65 mg/L). In 3 pts, a PK-guided intervention could not be performed, due to progression (n = 1) or logistical issues (n = 2). Twelve pts (35%) received a dose reduction due to toxicity (lowest dose was 200 mg QAD), exposure remained adequate at this reduced dose in all pts. For STS pts, median PFS was 19.8 months in pts with Cmin &lt; 20.5 mg/L who did need an intervention vs. 6.4 months in pts with all Cmin ≥ 20.5 mg/L (not significant). For RCC pts, this was 15.5 months vs. 7.4 months, respectively (not significant). Conclusions: This prospective study shows that PK-guided dose optimization of pazopanib using cost-neutral interventions is feasible in daily practice. A PK-guided intervention was performed in 24% of the patients, which was successful in 75% of these patients. Clinical trial information: NL6695 .

Medication adherence during laboratory workup for primary aldosteronism: pilot study.

PurposeCurrent hypertension guidelines stipulate that all incompatible medications be stopped before performing laboratory screening for aldosteronism, but patient adherence is unclear. We measured plasma drug concentrations to determine drug adherence and potential drug bias during biochemical tests.Patients and methodsPlasma concentrations of 10 antihypertensive drugs were quantified by mass spectrometry in 24 consecutive ambulatory patients with uncontrolled hypertension routinely evaluated for aldosteronism. Drug screening was done before (first visit), and on the day of biochemical tests (second visit) after stopping all incompatible medications. Concentrations above those expected at trough dosing interval defined same-day dose intake.ResultsOn the first and second visits, 76% vs 77% of prescribed antihypertensive doses could be verified in plasma. A total of 33% of patients were found to be nonadherent and showed divergent plasma drug results relative to prescriptions (21% drugs not detected/13% unprescribed drugs found) on first visit, 25% on the second (0%/25%), and 46% for both. A total of 21% used medication incompatible with the biochemical tests on the second visit. Moreover, 17% of drug concentrations were below expected trough levels on the first vs 15% on the second visit. This analysis revealed additional four (17%) vs three (13%) nonadherent patients who failed same-day dose intake and remained undetected by qualitative drug tests.ConclusionNonadherence was frequent during laboratory evaluations for aldosteronism advocating cautious interpretation of results. A multicenter study is desirable to set the stage for new screening protocols that should incorporate also incentives and checks of drug adherence.

MEDICATION ADHERENCE AND UNREPORTED DRUG USE DURING WORKUP FOR PRIMARY ALDOSTERONISM

Objective: Non-adherence to prescribed medication and unreported use of incompatible drugs may lead to misinterpretations of aldosterone-to-renin ratios during workup for primary aldosteronism but data are lacking. We compared antihypertensive drug prescriptions with measured plasma drug concentrations in patients with difficult-to-treat hypertension evaluated for possible aldosteronism. Design and method: Newly referred patients to our clinic with uncontrolled blood pressure despite 2 or more antihypertensives were prospectively recruited over 12 months. On the 1st visit, incompatible renin-angiotensin system inhibitors, beta-blockers, diuretics and central acting agents were routinely stopped before aldosterone-to-renin ratio determinations on a subsequent 2nd visit. Ca-antagonists and doxazosin were allowed. Patients with severe comorbidity or incompatible but mandatory drugs were excluded. Plasma concentrations of 10 prescribed antihypertensives (8 incompatible) out of 18 used were systematically determined on both visits by LC-MS/MS. Results were additionally compared with expected therapeutic concentration ranges. Results: Twenty-four patients were included: 42% female, age 54 ± 13 years, all with standardized glomerular filtration rate > 60. Mean interval between visits was 15 ± 6 days and average numbers of prescribed antihypertensives 3.2 ± 1.1 on the 1st vs. 1.1 ± 0.7 on the 2nd. In total, 76% of all antihypertensive prescriptions (60/79) were checked for presence in plasma on the 1st visit and 77% on the 2nd visit (20/26). On the 1st visit, 33% of patients showed discrepancies between prescriptions and plasma results (21% non-adherence/13% unprescribed drug use), 25% on the 2nd visit (0%/25%) and 46% for both visits combined (21%/29%). Unreported incompatible drugs were detected in 21% on the 2nd visit. For 1st and 2nd visits, 59% vs. 78% of plasma drug levels were within ± 50% of expected peak, 57% vs. 35% between peak and trough, and 17% vs. 15% below trough levels. Non-adherence because of previous day drug intake was thus suspected by quantitative analysis in additional 4 vs. 3 patients (17% vs. 13%). Conclusions: Unreported drug use is frequent during clinical work-up for primary aldosteronism and laboratory results need cautious interpretations in view of possible medication bias. Quantitative analysis of plasma drug concentrations may increase the sensitivity of non-adherence screening.

Mycobactericidal activity of bedaquiline plus rifabutin or rifampin in ex vivo whole blood cultures of healthy volunteers: A randomized controlled trial.

BackgroundBedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture.MethodsSubjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA).ResultsSingle oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation.ConclusionsThe combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacological therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01873950.

Pharmacokinetics and pharmacodynamics of intravenous romifidine and propranolol administered alone or in combination for equine sedation

ObjectivePropranolol has been suggested for anxiolysis in horses, but its sedation efficacy and side effects, both when administered alone and in combination with α2-adrenoceptor agonists, remain undetermined. This study aimed to document the pharmacokinetics and pharmacodynamics of propranolol, romifidine and their combination. Study designRandomized, crossover study. AnimalsSix adult horses weighing 561 ± 48 kg. MethodsPropranolol (1 mg kg−1; treatment P), romifidine (0.1 mg kg−1; treatment R) or their combination (treatment PR) were administered intravenously with a minimum of 1 week between treatments. Alertness, behavioral responsiveness (visual and tactile) and physiologic variables were measured before and up to 960 minutes after drug administration. Blood was collected for blood gas and acid-base analyses and measurement of plasma drug concentrations. Data were analyzed using repeated-measures analysis of variance or Friedman with Holm–Sidak and Wilcoxon rank-sum tests (p < 0.05). ResultsSystemic clearance significantly decreased and the area under the concentration-time curve significantly increased for both drugs in PR compared with P and R. Both PR and R decreased behavioral responsiveness and resulted in sedation for up to 240 and 480 minutes, respectively. Sedation was deeper in PR for the first 16 minutes. Heart rate significantly decreased in all treatments for at least 60 minutes, and PR significantly increased the incidence of severe bradycardia (<20 beats minute−1). Conclusions and clinical relevanceAlthough not associated with reduced behavioral responsiveness or sedation alone, propranolol augmented romifidine sedation, probably through alterations in romifidine pharmacokinetics, in horses administered PR. The occurrence of severe bradycardia warrants caution in the co-administration of these drugs at the doses studied.

Dexamethasone Delivery by an Implant-Mediated Drug Delivery System in the Canine Mandible.

A newly introduced implant-mediated drug delivery system (IMDDS) showed promising results in a rabbit tibia model. The aim of the present study is to evaluate whether dexamethasone administered by the IMDDS has sustained effects in the canine mandible - a different anatomic location, in a different species. IMDDS was installed at the mesial root of the second premolar site in the mandibles of six beagle dogs. After complete healing, 10 mg dexamethasone was administered through the IMDDS. The same amount of drug was administered to five control animals by intramuscular injection. The release pattern was monitored for 2 weeks by measuring plasma drug concentrations. A sustained plasma dexamethasone concentration was detected after a peak at 6 hours until the end of the observation period, despite individual variations. The concentration was lower than reported in the rabbit tibia model. In contrast, plasma concentration of the control group showed an early peak at 2 hours and decreased rapidly. Dexamethasone was effectively released from the IMDDS for a prolonged time in the canine mandible model.

The pharmacokinetics of mianserin suppositories for rectal administration in dogs and healthy volunteers: a pilot study.

BackgroundWe formulated mianserin suppositories for the treatment of delirium and evaluated their pharmacokinetics by measuring plasma drug concentrations in dogs and healthy human volunteers.MethodsMianserin suppositories were prepared by a melting technique using Tetramide® tablets and Witepsol H-15 as the suppository base. Pharmacokinetics of this 30-mg mianserin preparation were evaluated in three beagle dogs and three healthy adult males, in line with ethics committee approval. Plasma mianserin levels were determined using gas chromatography–mass spectrometry.ResultsIn dogs, the maximum plasma mianserin concentration (Cmax) was 1.3 ± 0.4 ng/mL, the time to Cmax (tmax) was 5.5 ± 4.3 h, and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) was 18.9 ± 1.9 h・ng/mL. In humans, the Cmax was 14.6 ± 6.3 ng/mL, the tmax was 8 h, and the AUC0-24 was 266 ± 103 h・ng/mL.ConclusionsThe current study characterized the pharmacokinetics of mianserin suppositories in dogs and humans. As compared to oral administration, the suppositories produced a lower Cmax and a delayed tmax, although AUC0-24 values were comparable. It will be necessary to identify an appropriate dose that produces an adequate plasma mianserin concentration for effective and safe clinical use.Trial registrationUMIN000013853.

Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers.

Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative side effects. Most second-generation antipsychotics have potent antagonistic effects on histamine H1 receptor (H1R). Positron emission tomography (PET) can measure the H1R occupancy (H1RO) in vivo, although there are no reports regarding antipsychotics. We studied the H1RO of olanzapine and quetiapine in vivo with respect to their plasma concentrations and subjective drowsiness by performing human PET imaging studies with [(11)C]doxepin, a potent PET ligand of H1R. Six healthy Japanese male volunteers were enrolled. Cross-randomized PET imaging was performed after a single oral administration of olanzapine (2.5 mg), quetiapine (25 mg), or placebo. PET data were analyzed by region of interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations by liquid chromatography/tandem mass spectrometry and evaluated subjective sleepiness. The binding potential ratios of olanzapine and quetiapine in the cerebral cortex were significantly lower than that of the placebo. The H1RO values of olanzapine and quetiapine in the cortex were approximately 61-80 and 56-81%, respectively. The binding potential ratios of the drugs were significantly lower than that of the placebo in the dorsolateral prefrontal and lateral temporal cortices, and anterior and posterior cingulate gyri. The H1RO values in the cortex were significantly correlated with subjective sleepiness but not plasma drug concentrations. Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.

Pregnancy and Contraceptive Use Among Women Participating in the FEM-PrEP Trial

Pregnancy among study participants remains a challenge for trials of new HIV prevention agents despite promotion and provision of contraception. We evaluated contraceptive use, pregnancy incidence, and study drug adherence by contraceptive method among women enrolled in the FEM-PrEP trial of once-daily oral tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) for HIV prevention. We required women to be using effective non-barrier contraception at enrollment. At each monthly follow-up visit, women were counseled on contraceptive use and tested for pregnancy. TDF-FTC adherence was determined by measuring plasma drug concentrations at 4-week intervals. We used Cox proportional hazards models to assess factors associated with incident pregnancy and multivariate logistic regression to examine the relationship between contraceptive method used at enrollment and TDF-FTC adherence. More than half of women were not using effective contraception before enrollment. Ninety-eight percent of these women adopted either injectable (55%) or oral (43%) contraceptives. The overall pregnancy rate was 9.6 per 100 woman-years. Among injectable users and new users of combined oral contraceptives (COCs), the rates were 1.6 and 35.1, respectively. New users of injectables had significantly greater odds of adhering to TDF-FTC than new COC users [odds ratio (95% confidence interval): 4.4 (1.7 to 11.6), P = 0.002], existing COC users [3.1 (1.3 to 7.3), P = 0.01], and existing injectable users [2.4 (1.1 to 5.6), P = 0.04]. Women using COCs during FEM-PrEP, particularly new adopters, were more likely to become pregnant and less likely to adhere to study product than injectable users. HIV prevention trials should consider requiring long-acting methods, including injectables, for study participation.

Non-VKA Oral Anticoagulants: Accurate Measurement of Plasma Drug Concentrations.

Non-VKA oral anticoagulants (NOACs) have now widely reached the lucrative market of anticoagulation. While the marketing authorization holders claimed that no routine monitoring is required and that these compounds can be given at fixed doses, several evidences arisen from the literature tend to demonstrate the opposite. New data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of at least dabigatran. Information regarding the association of rivaroxaban and apixaban exposure and the bleeding risk is available in the drug approval package on the FDA website. These reviews suggest that accumulation of these compounds increases the risk of experiencing a bleeding complication. Therefore, in certain patient populations such as patients with acute or chronic renal impairment or with multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This paper aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.