Clinically relevant QTc prolongation due to overridden drug–drug interaction alerts: a retrospective cohort study

AIMS

To investigate whether, in patients in whom drug–drug interaction (DDI) alerts on QTc prolongation were overridden, the physician had requested an electrocardiogram (ECG), and if these ECGs showed clinically relevant QTc prolongation.

METHODS

For all patients with overridden DDI alerts on QTc prolongation during 6 months, data on risk factors for QT prolongation, drug class and ECGs were collected from the medical record. Patients with ventricular pacemakers, patients treated on an outpatient basis, and patients using the low-risk combination of cotrimoxazole and tacrolimus were excluded. The magnitude of the effect on the QTc interval was calculated if ECGs before and after overriding were available. Changes of the QTc interval in these cases were compared with those of a control group using one QTc-prolonging drug.

RESULTS

In 33% of all patients with overridden QTc alerts an ECG was recorded within 1 month. ECGs were more often recorded in patients with more risk factors for QTc prolongation and with more QTc overrides. ECGs before and after the QTc override were available in 29% of patients. Thirty-one percent of patients in this group showed clinically relevant QTc prolongation with increased risk of torsades de pointes or ventricular arrhythmias. The average change in QTc interval was +31 ms for cases and −4 ms for controls.

CONCLUSIONS

Overriding the high-level DDI alerts on QTc prolongation rarely resulted in the preferred approach to subsequently record an ECG. If ECGs were recorded before and after QTc overrides, clinically relevant QTc prolongation was found in one-third of cases. ECG recording after overriding QTc alerts should be encouraged to prevent adverse events.     

Translational pharmacokinetic–pharmacodynamic modelling; application to cardiovascular safety data for PF-00821385, a novel HIV agent

AIM

To assess the translation of pharmacokinetic–pharmacodynamic (PK–PD) relationships for heart rate effects of PF-00821385 in dog and man.

METHODS

Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5–120 mg kg⁻¹, n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK–PD models were fitted using nonlinear mixed effects.

RESULTS

Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm µM⁻¹[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm µM⁻¹ (95% CI 0.54, 1.14) in man.

CONCLUSIONS

The preclinical translational of concentration–response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.     

Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis

Aims

To determine whether thiazolidinedione use is associated with a risk of bladder cancer.

Methods

We searched MEDLINE and EMBASE in June 2012 (with PubMed update to July 2013) and conducted meta-analysis on the overall risks of bladder cancer with pioglitazone or rosiglitazone and the risk with different categories of cumulative dose or duration of drug use.

Results

We screened 230 citations and included 18 studies, comprising five randomized controlled trials (RCTs) and 13 observational studies. Meta-analysis showed a significantly higher overall risk of bladder cancer with pioglitazone in RCTs [7878 participants; odds ratio (OR) 2.51, 95% confidence interval (CI) 1.09–5.80] and observational studies (>2.6 million patients; OR for ‘ever’ users vs. non-users 1.21, 95% CI 1.09–1.35). Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 g of pioglitazone (OR 1.64, 95% CI 1.28–2.12). A significantly increased risk was found with both 12–24 months (OR 1.41, 95% CI 1.16–1.71) and >24 months (OR 1.51, 95% CI 1.26–1.81) cumulative durations of pioglitazone exposure. No significant risk was seen with rosiglitazone in RCTs (OR 0.84, 95% CI 0.35–2.04) or ‘ever’ users vs. non-users in observational studies (OR 1.03, 95% CI 0.94–1.12); the evidence for any relationship between bladder cancer risk and rosiglitazone cumulative duration is limited and inconsistent. Direct comparison of pioglitazone to rosiglitazone ‘ever’ users yielded an OR of 1.25 (95% CI 0.91–1.72).

Conclusions

A modest but clinically significant increase in the risk of bladder cancer with pioglitazone was found, which appears to be related to cumulative dose and duration of exposure. We recommend that prescribers limit pioglitazone use to shorter durations.     

Incidence and risk of hypertension with vandetanib in cancer patients: a systematic review and meta-analysis of clinical trials

Aim

To perform a systematic review and meta-analysis of published clinical trials to determine incidence rate and overall risk of hypertension with vandetanib in cancer patients.

Methods

A comprehensive literature search for studies published up to March 2012 was performed. Summary incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials.

Results

A total of 11 trials with 3154 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension in patients with cancer were 24.2% [95% confidence interval (CI), 18.1–30.2%] and 6.4% (95% CI, 3.3–9.5%), respectively. Subgroup analysis demonstrated that the pooled incidences of all-grade and high-grade hypertension were 21.8% [95% CI, 15–30.5%] and 7.6% (95% CI, 2.8–18.8%), respectively, among non-small-cell lung cancer (NSCLC) patients, and 32.1% (95% CI: 27.3–37.3%) and 8.8% (5.9%–12.9%), respectively, among MTC patients, and 15.4 (95% CI: 3.2–33.7%) and 3.4% (95% CI: 1%–11.1%) respectively, among non-MTC/NSCLC tumors patients. Furthermore, vandetanib was associated with a significant increased risk of all-grade hypertension (RR 5.1, 95% CI: 3.76–6.92, P = 0.000) and high-grade hypertension (RR 8.06, 95% CI: 3.41–19.04, P = 0.000) in comparison with controls.

Conclusions

There is a significant risk of developing hypertension in cancer patients receiving vandetanib. Appropriate monitoring and treatment is strongly recommended to prevent cardiovascular complications.     

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects

AIM

To characterize the effects of lamotrigine on QT interval in healthy subjects.

METHODS

Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic–pharmacodynamic (PK–PD) modelling.

RESULTS

Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo −7.48 ms, 90% CI −10.49, −4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK–PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied.

CONCLUSIONS

Therapeutic doses of lamotrigine (50–200 mg b.d.) were not associated with QT prolongation in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes.
• Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder.
• Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients.

WHAT THIS STUDY ADDS

• This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines.
• The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia''s and Bazett''s).
• The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man.

     

Risk of Falling and Hypnotic Drugs: Retrospective Study of Inpatients

Background

Falls and related injuries remain a concern for patient safety in many hospitals and nursing care facilities. In particular, reports examining the relationship between accidents and drugs with a sedative effect have been increasing; however, the analysis of correlation between the background factors of fall accidents and the detailed therapeutic category of drugs is insufficient.

Objectives

Our objective was to estimate fall risk following the administration of hypnotics in inpatients within an acute hospital. We assessed the relationship between falls and hypnotic drugs compared with other medicines.

Study Design and Setting

An inpatient population-based study was carried out at Gunma University Hospital, where all inpatients admitted between 1 October and 31 December 2007 were included. Over a 3-month follow-up period, all reports of falling accidents from ward medical staff were investigated.

Results and Discussion

Falls occurred in 1.8 % of males and 1.3 % of females in the study population (n = 3,683). The mean age of patients who experienced falls (64.7 ± 19.5 years) was significantly higher than that of patients who did not (56.2 ± 20.2 years). Multivariate analysis revealed the following drugs as high-risk factors for falling: hypnotics (odds ratio [OR] 2.17, 95 % CI 1.44–3.28), antiepileptics (OR 5.06, 95 % CI 2.70–9.46), opioids (OR 3.91, 95 % CI 2.16–7.10), anti-Alzheimer’s (OR 5.74, 95 % CI 1.62–20.3), anti-Parkinson’s (OR 5.06, 95 % CI 1.58–16.24), antidiabetics (OR 3.08, 95 % CI 1.63–5.84), antihypertensives (OR 2.24, 95 % CI 1.41–3.56), and antiarrhythmics (OR 2.82, 95 % CI 1.36–5.86). Multivariate logistic regression analysis of hypnotics, brotizolam, zopiclone, and estazolam revealed a significant association with an increased risk of inpatient falling accidents, while zolpidem, triazolam, flunitrazepam, and nitrazepam did not.

Conclusion

The present findings suggest that the risk of falling accidents in hospitals differs according to the type of hypnotic drug administered. The appropriate selection of hypnotic drugs, therefore, might be important for reducing the number of patient falls.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0019-3) contains supplementary material, which is available to authorized users.     

Intake of St John's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

Aims

Our objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John''s wort and the antidiabetic drug metformin.

Methods

We performed an open cross-over study in 20 healthy male subjects, who received 1 g of metformin twice daily for 1 week with and without 21 days of preceding and concomitant treatment with St John''s wort. The pharmacokinetics of metformin was determined, and a 2 h oral glucose tolerance test was performed.

Results

St John''s wort decreased the renal clearance of metformin but did not affect any other metformin pharmacokinetic parameter. The addition of St John''s wort decreased the area under the glucose concentration–time curve [702 (95% confidence interval, 643–761) vs. 629 min*mmol/L (95% confidence interval, 568–690), P = 0.003], and this effect was caused by a statistically significant increase in the acute insulin response.

Conclusions

St John''s wort improves glucose tolerance by enhancing insulin secretion independently of insulin sensitivity in healthy male subjects taking metformin.     

Understanding drug preferences,different perspectives

Aims

To compare the values regulators attach to different drug effects of oral antidiabetic drugs with those of doctors and patients.

Methods

We administered a ‘discrete choice’ survey to regulators, doctors and patients with type 2 diabetes in The Netherlands. Eighteen choice sets comparing two hypothetical oral antidiabetic drugs were constructed with varying drug effects on glycated haemoglobin, cardiovascular risk, bodyweight, duration of gastrointestinal complaints, frequency of hypoglycaemia and risk of bladder cancer. Responders were asked each time which drug they preferred.

Results

Fifty-two regulators, 175 doctors and 226 patients returned the survey. Multinomial conditional logit analyses showed that cardiovascular risk reduction was valued by regulators positively (odds ratio 1.98, 95% confidence interval 1.11–3.53), whereas drug choices were negatively affected by persistent gastrointestinal problems (odds ratio 0.24, 95% confidence interval 0.14–0.41) and cardiovascular risk increase (odds ratio 0.49, 95% confidence interval 0.27–0.87). Doctors and patients valued these effects in a similar manner to regulators. The values that doctors attached to large changes in glycated haemoglobin and that both doctors and patients attached to hypoglycaemia and weight gain also reached statistical significance. No group''s drug choice was affected by a small absolute change in risk of bladder cancer when presented in the context of other drug effects. When comparing the groups, the value attached by regulators to less frequent hypoglycaemic episodes was significantly smaller than by patients (P = 0.044).

Conclusions

Regulators may value major benefits and risks of drugs for an individual diabetes patient mostly in the same way as doctors and patients, but differences may exist regarding the value of minor or short-term drug effects.     

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol

Aim

To study the differences in QT_c interval on ECG in response to a single oral dose of rac-sotalol in men and women.

Methods

Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration–QTc analyses were performed using a linear mixed effects model.

Results

Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QT_cI) most effectively removed the heart rate dependency of the QT_c interval. Mean QT_cI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QT_cI in both genders. The largest mean change in QT_cI (ΔQT_cI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean C_max 1.8 μg ml⁻¹ (range 1.1–2.8) vs. 1.4 μg ml⁻¹ (range 0.9–1.9), P = 0.0009). The slope of the concentration–ΔQT_cI relationship was steeper in women (30 ms per μg ml⁻¹ vs. 23 ms per μg ml⁻¹ in men; P = 0.0135).

Conclusions

The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.     

Hospitalizations for gastrointestinal and cardiovascular events in the CADEUS cohort of traditional or Coxib NSAID users

AIMS

To assess hospital admission rates for gastrointestinal (GI) or cardiovascular (CV) events in real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs).

METHODS

CADEUS is a real-life population-based cohort study of 23 535 coxib (celecoxib or rofecoxib) and 22 919 traditional NSAID (tNSAID) users. Each hospitalization reported between index day (NSAID delivery) and questionnaire submission (median = 75 days) was explored using hospital discharge summaries. An expert committee validated blindly serious GI and CV events according to predefined criteria.

RESULTS

Coxib users were older and had more GI history than tNSAID users. There were 21 hospitalizations for GI events, 12 in the coxib cohort and nine in the tNSAID cohort (respectively one and three upper GI haemorrhages and no ulcer perforations). Rates of GI events were 0.39 per 1000 patients [95% confidence interval (CI) 0.18, 0.75] for tNSAID users and 0.51 per 1000 patients (95% CI 0.26, 0.89) for coxib users. There were 21 hospitalizations for CV events, 13 in the coxib cohort and eight in the tNSAID cohort. None was fatal. Rates of CV events were, respectively, 0.59 (95% CI 0.24, 1.22), 0.51 (95% CI 0.19, 1.11) and 0.35 (95% CI 0.15, 0.69) per 1000 patients for celecoxib, rofecoxib and tNSAIDs. GI or CV event rates were not different between products even for patients >60 years old.

CONCLUSIONS

Hospitalization rates for GI bleeding were 10–20 times lower than expected from published randomized clinical trials, probably because of differences in drug usage and concomitant gastroprotection. CV event rates conformed to those expected from general population data. These results emphasize the necessity of developing population healthcare databases to explore such low event rates.     

Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia

Aim

The use of corticosteroids as adjunctive therapy might be effective in patients with community-acquired pneumonia (CAP). Oral administration of dexamethasone is a practical and safer alternative to the intravenous route. Since patients hospitalized with pneumonia might have delayed gastric emptying, this study explored systemic exposure in terms of area under the concentration–time curve (AUC) of oral dexamethasone in patients hospitalized with CAP.

Methods

In this randomized, open label study, 30 patients admitted with CAP were randomized to receive either 4 mg intravenous or 6 mg oral dexamethasone for 4 consecutive days. Serial blood samples were obtained before and after drug administration.

Results

Median AUC to infinity was 626 μg l⁻¹ h (IQR 401–1161) for the intravenous group and 774 μg l⁻¹ h (IQR 618–1146) for the oral group. The AUC ratio of 6 mg oral and 4 mg intravenous dexamethasone was 1.22 (95% confidence interval (CI) 0.81, 1.82)_, which represents a bioavailability of 81% (95% CI 54, 121) after correction for differences in dexamethasone dose.

Conclusions

Bioavailability of oral dexamethasone in patients hospitalized with pneumonia is sufficient. This makes oral dexamethasone an appropriate alternative for intravenous administration in these patients.     

Association between Clostridium difficile infection and antimicrobial usage in a large group of English hospitals

Aims

This study aimed to determine the association between the reduction in the number of Clostridium difficile infection (CDI) cases reported by the English National Health Service (NHS) hospitals and concurrent antimicrobial use.

Methods

A retrospective ecological study for January 2005 to December 2008 was conducted using data from 26 of the 29 NHS trusts (i.e. a trust manages one or more hospitals) located in the North West Strategic Health Authority of England. Antimicrobial use data, for patients of all ages, were provided by IMS Health, and CDI case data for patients aged ≥65 years were provided by the Health Protection Agency. Antimicrobial use was converted into defined daily doses (DDDs). The overall association between antimicrobial use and CDI for the trusts was investigated using multilevel models.

Results

Our study shows a positive significant association between the CDI cases and the use of the following antimicrobials: ‘third-generation cephalosporins’ [11.62 CDI cases per 1000 DDDs; 95% confidence interval (CI), 5.92–17.31]; ‘fluoroquinolones’ (4.79 CDI cases per 1000 DDDs; 95% CI, 2.83–6.74); and ‘second-generation cephalosporins’ (4.25 CDI cases per 1000 DDDs; 95% CI, 1.66–6.83). The strength of this association was not significantly different (95% CI) among the antimicrobial groups.

Conclusions

This study shows that the reduction in the number of CDI cases reported by the English NHS hospitals is associated with concurrent reductions in antimicrobial use. This means that the number of CDI cases over time decreased in a similar fashion to the usage of various antimicrobials.     

Effectiveness of Unfractionated Heparin in Normal Saline versus Dextrose for Achieving and Maintaining Therapeutic Anti–Factor Xa Levels in Patients with Non-ST-Elevation Acute Coronary Syndrome

Background:

Unfractionated heparin (UFH) administered by IV infusion is effective in preventing myocardial infarction and death after non-ST-elevation acute coronary syndrome. At the authors’ centre, preparations of UFH in 0.9% sodium chloride (normal saline; UFH-NS) were used during a shortage of commercially available UFH in dextrose 5% in water (UFH-D5W), the usual preparation. Anecdotal observations raised concerns about the effectiveness of the saline-based preparation in achieving minimally therapeutic anticoagulation.

Objective:

To compare the effectiveness of UFH-NS and UFH-D5W for achieving and maintaining therapeutic anti–factor Xa levels in patients with non-ST-elevation acute coronary syndrome.

Methods:

A retrospective cohort study was conducted with 2 groups of 100 consecutive patients who received either UFH-NS or UFH-D5W for a minimum of 24 h after non-ST-elevation acute coronary syndrome in accordance with a weight-based dosing nomogram.

Results:

A minimally therapeutic level of anti-Xa (≥ 0.31 IU/mL) was achieved within 24 h for 92% of the patients receiving UFH-D5W and 67% of those receiving UFH-NS (absolute risk difference 25%, 95% confidence interval [CI] 13.4%–36.6%; p < 0.001). Infusion of UFH-NS was associated with lower probability of achieving minimally therapeutic anticoagulation (hazard ratio [HR] 2.30, 95% CI 1.68–3.15; p < 0.001) and maintaining therapeutic anticoagulation (HR 2.31, 95% CI 1.69–3.17; p < 0.001) relative to UFH-D5W. Significant differences in the numbers of patients with subtherapeutic and therapeutic anticoagulation, favouring UFH-D5W, were observed at each of the first, second, and third anti-Xa measurements (p < 0.05). Patients receiving UFH-NS required a greater median number of adjustments to the infusion rate during the first 48 h (1.0 v. 0.5 adjustment per day, p < 0.001). There was no difference between groups in terms of major reductions in hemoglobin.

Conclusions:

Infusion of UFH-NS was inferior to UFH-D5W for achieving and maintaining therapeutic anticoagulation in patients with non-ST-elevation acute coronary syndrome. Until further study, saline-based heparin infusions should be used with caution, and patients should be monitored closely to ensure timely achievement and maintenance of therapeutic anticoagulation.     

Inter-study variability of preclinical in vivo safety studies and translational exposure–QTc relationships – a PKPD meta-analysis

Background and Purpose

Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans.

Experimental Approach

We derived typical ΔQTc predictions at therapeutic exposure (ΔQTc_THER) with 95% confidence intervals (95%CI) for 3 K_v11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2–6 studies including 10–32 dogs per compound) to derive meta-predictions of typical ΔQTc_THER. Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature.

Key Results

The 95%CIs of study-predicted ΔQTc_THER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1–69%). Meta-ΔQTc_THER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline.

Conclusions and Implications

Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical–clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.Tables of Links

Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

Aims

To characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients.

Methods

Plasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme.

Results

A one-compartment model with Michaelis–Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839–0.968] and 0.176 U ml⁻¹ (95% CI: 0.154–0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68–3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml⁻¹ h⁻¹ (95% CI: 1.41–1.88) and 1.60 U ml⁻¹ (95% CI: 1.14–2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml⁻¹) for at least 94% of all patients.

Conclusions

The population PK model for C1INH supports a dosing scheme on a 50 U kg⁻¹ basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration.     

Bayesian model of Hamilton Depression Rating Score (HDRS) with memantine augmentation in bipolar depression

Aim

Presynaptic and post‐synaptic glutamatergic modulation is associated with antidepressant activity that takes several weeks to reach a maximal full effect. Limiting mood elevating effects after single drug administration may be the result of compensatory synaptic processes. Therefore, using augmentation treatment with agents having presynaptic and post‐synaptic effects on the glutamatergic system, this study aims to evaluate the effect of augmentation therapy on the rate of change in mood elevation in patients with bipolar depression.

Methods

In a pilot study, 29 outpatients with bipolar depression on a stable lamotrigine dose regimen received placebo or memantine pills daily (titrated up by 5 mg week^–1 to 20 mg) in a randomized, double‐blind, parallel group, 8 week study. Patients were evaluated weekly using the 17‐item Hamilton Depression Rating Score (HDRS) and all data were analyzed simultaneously. Linear, exponential, maximal effect, Gompertz and inverse Bateman functions were evaluated using a Bayesian approach population pharmacodynamic model framework. In these models, differences in parameters were examined across the memantine and placebo augmentation groups.

Results

A Gompertz function with a treatment switch on the parameter describing the speed of HDRS decline (γ, 95% confidence interval [CI]) best described the data (γ_memantine = 1.8, 95% CI 0.9, 3.6), γ_placebo = 1.2, 95% CI 0.5, 3.5)). Between subject variability was identified on baseline HDRS (2.9, 95% CI 1.5, 4.4) and amplitude of score improvement (4.3, 95% CI 2.7, 6.5).

Conclusions

This pharmacodynamic approach identified an increased speed of response after memantine augmentation, compared with placebo augmentation in bipolar depression patients.     

Effectiveness of pharmaceutical care for patients with chronic obstructive pulmonary disease (PHARMACOP): a randomized controlled trial

AIMS

Few well-designed randomized controlled trials have been conducted regarding the impact of community pharmacist interventions on pharmacotherapeutic monitoring of patients with chronic obstructive pulmonary disease (COPD). We assessed the effectiveness of a pharmaceutical care programme for patients with COPD.

METHODS

The pharmaceutical care for patients with COPD (PHARMACOP) trial is a single-blind 3 month randomized controlled trial, conducted in 170 community pharmacies in Belgium, enrolling patients prescribed daily COPD medication, aged ≥50 years and with a smoking history of ≥10 pack-years. A computer-generated randomization sequence allocated patients to an intervention group (n = 371), receiving protocol-defined pharmacist care, or a control group (n = 363), receiving usual pharmacist care (1:1 ratio, stratified by centre). Interventions focusing on inhalation technique and adherence to maintenance therapy were carried out at start of the trial and at 1 month follow-up. Primary outcomes were inhalation technique and medication adherence. Secondary outcomes were exacerbation rate, dyspnoea, COPD-specific and generic health status and smoking behaviour.

RESULTS

From December 2010 to April 2011, 734 patients were enrolled. Forty-two patients (5.7%) were lost to follow-up. At the end of the trial, inhalation score [mean estimated difference (Δ),13.5%; 95% confidence interval (CI), 10.8–16.1; P < 0.0001] and medication adherence (Δ, 8.51%; 95% CI, 4.63–12.4; P < 0.0001) were significantly higher in the intervention group compared with the control group. In the intervention group, a significantly lower hospitalization rate was observed (9 vs. 35; rate ratio, 0.28; 95% CI, 0.12–0.64; P = 0.003). No other significant between-group differences were observed.

CONCLUSIONS

Pragmatic pharmacist care programmes improve the pharmacotherapeutic regimen in patients with COPD and could reduce hospitalization rates.     

No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study

Aims

Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug–drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration–time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy.

Methods

In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC_0–12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1–2 g day^–1) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined.

Results

MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml^–1 mg^–1 [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml^–1 mg^–1 (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml^–1 mg^–1 (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml^–1 mg^–1 (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min–max: 0.5–10.0)] than EC-MPS intake alone [3 h (1.5–12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5–5.0)] ± pantoprazole [1.0 h (0.5–6.0), P = 0.928). No impact on MPAG pharmacokinetics or IMPDH activity was found.

Conclusion

Pantoprazole influences EC-MPS and MMF pharmacokinetics but as it had no impact on MPA pharmacodynamics, the immunosuppressive effect of the drug was not impaired.