Journal of Clinical Pharmacology最新文献

This article describes how a model-based analysis was used to aid development of a novel formulation technology. Paracetamol (acetaminophen) was used as the motivating example with 4 different formulations (2 developmental and 2 commercial) compared using stochastic (Monte Carlo) pharmacokinetic (PK)-pharmacodynamic (PD) simulations to explore potential differences in pharmacodynamic outcomes. PK models were developed from data collected during an intensively sampled, 4-arm crossover trial in 25 fasted healthy subjects, administered 1 g of paracetamol in 4 different formulations. The PK models were linked to a previously published PD model that quantified pain relief over time following tonsillectomy. The number needed to treat (NNT) was the primary numeric used to compare effectiveness. The developmental formulations were likely to produce faster and greater analgesia with an NNT (compared with placebo) to reduce pain by 50% over a 45-minute interval post dose of 2.75 and 2.88 compared with 4.31 and 3.2 for the commercial products. Over the course of 1 hour, all formulations were comparable. The stochastic simulations provided support that the novel formulation technology was likely to provide a clinically meaningful advantage and should be developed further.

RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non-adenosine triphosphate (ATP)-competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy volunteers. All participants received a single dose followed by 48 hours of pharmacokinetics, pharmacodynamics, and safety/tolerability assessments. The pharmacodynamics were measured by changes in ERK phosphorylation (pERK) in peripheral blood mononuclear cells, ex vivo stimulated by phorbol 12-myristate 13-acetate (PMA). Forty-eight participants received 6 doses (50, 100, 200, 400, 600, 800 mg). RO5068760 was well tolerated up to 800 mg. There were no clinically significant safety findings, including laboratory, electrocardiogram, ophthalmological assessment, and fecal occult blood tests. Of the total 13 adverse events (n = 12), 11 were mild, 2 were moderate, and none were severe, and only 5 were considered by the investigator as possibly related to treatment. RO5068760 was absorbed with a t(max), of 2 hours. Disposition appeared to be biphasic with a terminal elimination t(1/2) of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for C(max) and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

The purpose of this article is to determine prescribing rates and adherence to guidelines with regard to antipsychotic polypharmacy, high-dose prescribing, and sedative use in an outpatient population. A prospective case-note audit involving 250 consecutive attendees of an outpatient clinic was carried out. Data were analyzed using descriptive statistical methods. Differences between the groups were estimated using t test and chi(2) where applicable. Results showed that the rate of polypharmacy was 17.4%. Reasons for polypharmacy were documented in 53% of cases. High-dose antipsychotics were used in 2.5% of the monotherapy group and in 38% of the polypharmacy group. An ECG was done in 35% of patients on high-dose antipsychotic therapy. In the monotherapy group, 6.2% versus 26.5% in the polypharmacy group of patients were on at least 1 sedative or hypnotic (odds ratio [OR], 5.47; 95% confidence interval [CI], 2.02-14.82; P < .001). Forty-two percent of patients prescribed sedatives had schizophrenia spectrum disorders, and none of the patients were diagnosed with anxiety disorders. The current study confirms that despite repeated recommendations against the practice, polypharmacy rates remain consistent at the 20% level. Thorough documentation, calculating the total antipsychotic dose, and obtaining an ECG would constitute good practice.

This study was carried out to compare the efficacy of intravenous sodium valproate with intramuscular haloperidol in patients with acute mania. A total of 30 patients meeting DSM-IV criteria for acute manic episodes were enrolled. They were randomly assigned to 2 groups of 15 patients each. Both groups were treated twice daily with haloperidol (10 mg, intramuscular) and sodium valproate (500 mg, intravenous). The patients were assessed on days 1, 5, 9, and 13. Improvement in symptoms was assessed by reduction in the Young Mania Rating Scale (YMRS). Outcome criterions for analysis were latency of response and remission; additional drugs were required for sedation. At the end of the 2-week study period, overall response rate in both the groups was similar (P > .1). In comparison to haloperidol group, patients treated with sodium valproate showed faster response, and on day 5, significant reduction in YMRS score was observed in the group treated with sodium valproate (P < .05). Total amount of lorazepam was less in patients treated with sodium valproate. Extrapyramidal symptom episodes were observed in 60% of patients treated with haloperidol. Sodium valproate in the treatment of acute mania is as efficacious as haloperidol but provides a faster response. It is safer compared to haloperidol.

Amiodarone inhibits the metabolism of warfarin. Previous studies characterizing this drug interaction have focused on the effect of adding amiodarone to stable doses of warfarin. The objective of this study was to assess whether simultaneous initiation of warfarin and amiodarone results in early alteration of the international normalized ratio (INR) response to warfarin. Patients initiated on warfarin and amiodarone during the same hospitalization were included in the amiodarone (AMIO) group. Patients initiated on warfarin alone (n = 42) were identified for the CONTROL group. The AMIO and CONTROL groups were matched based on age, gender, and ejection fraction <40% using propensity score matching (final n = 18 patients per group). Total and average daily warfarin dose was lower in the AMIO group, yet INR values were similar on each day between the 2 groups. More patients in the AMIO group had an INR greater than 2 during the 5-day observation period as compared to the CONTROL group. In addition, there were trends toward greater deviation from INR values expected with a 5-mg daily warfarin dose among AMIO group patients. Simultaneous initiation of warfarin and amiodarone leads to an enhanced pharmacodynamic response to warfarin early in therapy. Although these data should be viewed as hypothesis generating, cautious dosing and monitoring with simultaneous initiation of warfarin and amiodarone may be warranted.

Therapeutic drug monitoring is necessary when using tacrolimus (FK) due to the associated side effects. The aim of this study was to compare the chemiluminescent assay (CMIA) system with the previously established Abbott IMx Tacrolimus II microparticle enzyme immunoassay (MEIA) in liver transplant recipients and evaluate its accuracy. Between March and June 2008, all blood samples from the liver transplant recipients at the hospital were tested for FK trough level using 2 different methods, CMIA and MEIA. The posttransplant time, hematocrit, and other clinical parameters during the study period were recorded. FK trough level was analyzed in 398 samples from 57 liver transplant recipients by CMIA and MEIA. The correlation in FK level between the 2 methods was excellent (r(2) = 0.941). However, the FK level was underestimated in MEIA by more than 23% in samples with an FK level of less than 3.5 ng/mL and by 6.8% in those with an FK level between 3.5 and 5 ng/mL. CMIA is superior to MEIA in measuring low FK level, allowing the FK level to be maintained at less than 5 ng/mL in selected liver transplant recipients. The effects of maintaining low levels of FK should be evaluated in liver transplant recipients.