The effect of decontamination procedures on the pharmacodynamics of venlafaxine in overdose

AIMS

To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination.

METHODS

Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t₉₀) of seizure, respectively.

RESULTS

A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03–0.08), 0.19 (0.09–0.35) and 0.75 (0.30–0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25–0.89), 0.71 (0.35–1.22) and 0.25 (0.08–0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t₉₀ values for first seizure was 26 h and was not affected by dose or decontamination procedure.

CONCLUSION

SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring.     

The pharmacokinetics of sertraline in overdose and the effect of activated charcoal

Aims

To investigate the pharmacokinetics (PK) of sertraline in overdose and the effect of single dose activated charcoal (SDAC).

Methods

Patients presenting to a toxicology unit with sertraline overdoses had demographic and clinical information recorded, and serial serum collected for measurement of sertraline concentrations. Monolix® version 4.2 was used to develop a population PK model of sertraline overdose and the effect of SDAC. Uncertainty in dose time was accounted for by shifting dose time using lag time with between subject variability (BSV). BSV on relative fraction absorbed was used to model uncertainty in dose.

Results

There were 77 timed sertraline concentrations measured in 28 patients with sertraline overdoses with a median dose of 1550 mg (250–5000 mg). SDAC was given to seven patients between 1.5 and 4 h post-overdose. A one compartment model with lag time of 1 h and first order input and elimination adequately described the data. Including BSV on both lag time and relative fraction absorbed improved the model. The population PK parameter estimates for absorption rate constant, volume of distribution and clearance were 0.895 h⁻¹, 5340 l and 130 l h⁻¹, respectively. The calculated half-life of sertraline following overdose was 28 h (IQR 19.4−30.6h). When given up to 4 h post-overdose, SDAC significantly increased the clearance of sertraline by a factor of 1.9, decreased the area under the curve and decreased the maximum plasma concentration (C_max).

Conclusions

Sertraline had linear kinetics in overdose with parameter values similar to those in therapeutic use. SDAC is effective in increasing clearance when given 1.5 to 4 h post-overdose.     

Electrocardiogram changes and arrhythmias in venlafaxine overdose

AIMS

To investigate serial electrocardiogram (ECG) parameters, haemodynamic changes and arrhythmias following venlafaxine overdose.

METHODS

The study included 369 venlafaxine overdoses in 273 patients presenting to a toxicology unit where an ECG was available. Demographic information, details of ingestion, haemodynamic effects [heart rate and blood pressure (BP)] and complications (arrhythmias and conduction defects) were obtained. ECG parameters (QT, QRS) were measured manually and analysed by visual inspection, including plotting QT–HR pairs on a QT nomogram.

RESULTS

The median ingested dose was 1500 mg [interquartile range (IQR) 600–3000 mg; range 75–13 500 mg). Tachycardia occurred in 54% and mild hypertension (systolic BP >140 mmHg) in 40%. Severe hypertension (systolic BP >180 mmHg) and hypotension (systolic BP <90 mmHg) occurred in 3% and 5%, respectively. No arrhythmias occurred based on continuous telemetry, and conduction defects were found in only seven of 369 admissions; five of these conduction defects were pre-existing abnormalities. In 22 admissions [6%, 95% confidence interval (CI) 4–10] there was an abnormal QT–HR pair, with larger doses being more likely to be associated with an abnormal QT. The median maximum QRS width was 85 ms (IQR 80–90 ms; range 70–145 ms) and the QRS was greater than 120 ms in only 24 admissions (7%, 95% CI 4–10).

CONCLUSIONS

Venlafaxine overdose causes only minor abnormalities in the QT and QRS intervals, unlikely to be associated with major arrhythmias, except possibly with large doses.     

High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings

Aims

To investigate the QT interval after high dose droperidol using continuous 12-lead Holter recordings.

Methods

This was a prospective study of patients given droperidol with a continuous Holter recording. Patients were recruited from the DORM II study which included patients with aggression presenting to the emergency department. Patients initially received 10 mg droperidol as part of a standardized sedation protocol. An additional 10 mg dose was given after 15 min if required and further doses at the clinical toxicologist''s discretion. Continuous 12-lead Holter recordings were obtained for 2–24 h utilizing high resolution digital recordings with automated QT interval measurement. Electrocardiograms were extracted hourly from Holter recordings. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine if it was abnormal. QT_cF (Fridericia''s HR correction) was calculated and >500 ms was defined as abnormal.

Results

Forty-six patients had Holter recordings after 10–40 mg droperidol and 316 QT–HR pairs were included. There were 32 abnormal QT measurements in four patients, three given 10 mg and one 20 mg. In three of the four patients QT_cF >500 ms but only in one taking methadone was the timing of QT_cF >500 ms consistent with droperidol dosing. Of the three other patients, one took amphetamines, one still had QT prolongation 24 h after droperidol and one took a lamotrigine overdose. No patient given >30 mg had a prolonged QT. There were no arrhythmias.

Conclusion

QT prolongation was observed with high dose droperidol. However, there was little evidence supporting droperidol being the cause and QT prolongation was more likely due to pre-existing conditions or other drugs.     

Evaluation of a QT nomogram for risk assessment after antidepressant overdose

AIMS

A QT-heart rate nomogram has recently been proposed as a means of identifying patients at risk of torsades de pointes after antidepressant overdose, based on published cases of drug-induced torsades de pointes. The present study sought to examine the performance of the nomogram in patients who ingest an antidepressant overdose but do not develop arrhythmia.

METHODS

A retrospective case control study of patients presenting to hospital after overdose of citalopram, mirtazapine and venlafaxine was carried out. The primary outcome variable was QT higher than the nomogram, and was compared with occurrence of QT_c (QT corrected by Bazett''s formula) greater than ≥440 ms and QT_c≥500 ms, with comparison between drugs. Data are expressed as proportions in each group with 95% confidence intervals.

RESULTS

There were 858 electrocardiograms from 541 patients. QT was higher than the nomogram in 2.4% (1.4, 4.1%), whereas QT_c was ≥440 ms in 23.1% (95% CI 19.8, 26.8%), and QT_c was ≥500 ms in 1.1% (0.5, 2.5%). Citalopram overdose was more likely to be associated with QT higher than the nomogram compared with the other agents (difference 7.0%, 95% CI 2.9, 11.9%, P = 0.001) and more likely to be associated with QT_c≥440 ms (difference = 11.0%, 95% CI 2.6, 19.0%, P = 0.013).

CONCLUSIONS

The QT nomogram was associated with a lower false positive rate than widely accepted QT_c criteria, and allowed detection of different effects of individual drugs. The nomogram offers potential advantages over QT_c criteria and merits further investigation in a clinical setting.     

Maraviroc modelling strategy: use of early phase 1 data to support a semi-mechanistic population pharmacokinetic model

AIMS

To model the basic pharmacokinetic (PK) characteristics of maraviroc to construct an integrated semi-mechanistic PK model for use in later population PK analyses.

METHODS

Three analyses were performed utilizing intravenous, oral and radiolabel data. Firstly, a PK disposition model was developed from data from 20 healthy males who received 3, 10 or 30 mg of intravenous maraviroc. Secondly, a sigmoid E_maxvs dose model of dose-normalized non-compartmental AUC from oral dosing in 134 healthy young males and females across five phase 1 studies was constructed. This described absorption dose non-linearities and tested for the influence of food, formulation and dose frequency on model parameters. The third analysis developed a mass balance model for both absorption and disposition of maraviroc with 300 mg solution and predicted the mass balance after administration of 100 mg tablet formulation.

RESULTS

A four-compartment PK model best described the intravenous data and no influence of dose was found on clearance. Total clearance was 48 l h⁻¹ (2.2% SE). The main covariate effect in the non-compartmental analysis reproduced the dose-dependency of food through a five-fold increase in the ED₅₀ of the sigmoid E_max model. The mass balance models calculated that 33.3% and 22.9% of 300 mg solution and 100 mg tablet doses, respectively, are systemically available, and first-pass metabolism extracts 62% of an absorbed dose, estimating a hepatic blood flow of 101 l h⁻¹.

CONCLUSIONS

The analysis demonstrates a novel integration approach to build a maraviroc semi-mechanistic population PK model for further use in volunteers and patients.     

Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

Aims

Given the similarities in QT_c response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QT_c interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin.

Methods

Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration.

Results

A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QT_c prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans.

Conclusions

Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QT_c prolongation in humans. Furthermore, the risk of QT_c prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule.     

The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects

AIMS

This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.

METHODS

Healthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.

RESULTS

Sildenafil exposure was slightly higher [AUC_∞ geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (E_max+) and maximum negative (E_max–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.

CONCLUSION

The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.     

Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study

AIMS

To assess steady-state effects of therapeutic and supra-therapeutic doses of prucalopride on the QT interval using a novel design involving a parallel placebo group with nested crossover for positive control.

METHODS

A double-blind, double-dummy, placebo- and active-controlled study was conducted in 120 healthy male and female volunteers ({"type":"clinical-trial","attrs":{"text":"NCT00903747","term_id":"NCT00903747"}}NCT00903747). Volunteers were randomized to receive prucalopride 2–10 mg once daily (therapeutic and supratherapeutic doses, respectively) (group 1), placebo with 400 mg moxifloxacin on day 1 (group 2a), or placebo with moxifloxacin on day 15 (group 2b). Twelve-lead 24 h Holter ECGs recorded at various time-points were evaluated blind and centrally.

RESULTS

Estimated mean difference in study specific corrected QT interval (QT_cSS) time-matched change from baseline between prucalopride (2 and 10 mg) and placebo was <5 ms at all time points (maximum mean difference: 3.83 ms at 3.5 h post dose on day 5 with 2 mg [90% Cl −0.33, 6.38 ms]). Upper limits of the two-sided 90% CI for QT_cSS were all <10 ms. There were no outlying QT_cSS values >450 ms and no subjects had an increase >60 ms following prucalopride. Moxifloxacin produced the expected significant changes in QT_cSS (>5 ms, maximum of +12.7 ms at 5 h post dose) at all time-points except 1 h post dose. Prucalopride resulted in small increases in heart rate (maximum of 5.8 beats min^–1), which were similar for 2 and 10 mg. Prucalopride was well tolerated after first day of treatment.

CONCLUSION

Prucalopride at both therapeutic and supra therapeutic doses has no clinically significant effects on cardiac repolarisation in healthy volunteers.     

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males

AIMS

Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males.

METHODS

In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20–46 years) in each panel received single oral doses of 5–400 mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0–48 h post dose and plasma DPP-4 inhibition from 0–24 h post dose. The results were compared with historical data from young, healthy non-Japanese males.

RESULTS

Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2–6 h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9–14 h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73–1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50 mg resulted in weighted average DPP-4 inhibition from 0–24 h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia.

CONCLUSIONS

The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.     

Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C

AIM

To use non-linear mixed effects modelling and simulation techniques to predict whether PF-04878691, a toll-like receptor 7 (TLR7) agonist, would produce sufficient antiviral efficacy while maintaining an acceptable side effect profile in a ‘proof of concept’ (POC) study in chronic hepatitis C (HCV) patients.

METHODS

A population pharmacokinetic–pharmacodynamic (PKPD) model was developed using available ‘proof of pharmacology’ (POP) clinical data to describe PF-04878691 pharmacokinetics (PK) and its relationship to 2′,5′-oligoadenylate synthetase (OAS; marker of pharmacology) and lymphocyte levels (marker of safety) following multiple doses in healthy subjects. A second model was developed to describe the relationship between change from baseline OAS expressed as fold change and HCV viral RNA concentrations using clinical data available in HCV patients for a separate compound, CPG-10101 (ACTILON™), a TLR9 agonist. Using these models the antiviral efficacy and safety profiles of PF-04878691 were predicted in HCV patients.

RESULTS

The population PKPD models described well the clinical data as assessed by visual inspection of diagnostic plots, visual predictive checks and precision of the parameter estimates. Using these relationships, PF-04878691 exposure and HCV viral RNA concentration was simulated in HCV patients receiving twice weekly administration for 4 weeks over a range of doses. The simulations indicated that significant reductions in HCV viral RNA concentrations would be expected at doses >6 mg. However at these doses grade ≥3 lymphopenia was also predicted.

CONCLUSIONS

The model simulations indicate that PF-04878691 is unlikely to achieve POC criteria and support the discontinuation of this compound for the treatment of HCV.     

Development of population PK model with enterohepatic circulation for mycophenolic acid in patients with childhood-onset systemic lupus erythematosus

AIM

This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE).

METHODS

MPA concentration–time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post-dose). Sampling times were pre-dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7-O-MPA-β-glucuronide (MPAG) concentrations using nonlinear mixed effect modelling.

RESULTS

PK analysis included 186 MPA and MPAG concentrations (mg l^–1) from 19 patients. cSLE patients, age range 10–28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL₁/F 25.3 l h^–1, V₃/F 20.9 l, V₄/F 234 l and CL₂/F 19.8 l h^–1.

CONCLUSION

The final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms.     

Safety, tolerability, pharmacokinetics and pharmacodynamics of ascending single and multiple doses of lecozotan in healthy young and elderly subjects

AIMS

To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects.

METHODS

Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD.

RESULTS

Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t_max and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly.

CONCLUSIONS

Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer''s disease.     

Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572

AIMS

S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated.

METHODS

A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty-four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h (n = 12) or ATV 400 mg every 24 h (n = 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study.

RESULTS

The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co-administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration–time curve during a dosing interval (AUC(0,τ)), observed maximal concentration (C_max), and concentration at the end of dosing interval at steady state (C_τ) by 62%, 34% and 121%, respectively. Co-administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C_max, and C_τ by 91%, 50% and 180%, respectively.

CONCLUSIONS

Co-administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co-administered with ATV and ATV/RTV.     

Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide

AIMS

To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans.

METHODS

An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non-linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles.

RESULTS

Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54 µg g⁻¹ were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations from 13.9 to 52.8 µg g⁻¹ (n = 4, LY2181308 750 mg) were observed associated with a median survivin mRNA and protein inhibition of 20% ± 34 (SD) (n = 9) and 23% ± 63 (SD) (n = 10), respectively. The human PK parameters were adequately estimated: central V_d, 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00) l h⁻¹, peripheral V_ds, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922) l, mean elimination clearance 23.1 l h⁻¹ (5.6, 33.4) and mean terminal half-life, 32.7 days (range 22–52 days).

CONCLUSION

The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750 mg.     

Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study

AIMS

To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects.

METHODS

Forty-five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg⁻¹ in a dose-escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20-week follow-up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non-compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab.

RESULTS

Adverse events were generally brief in duration, mild or moderate in intensity and non-dose-dependent. No serious adverse events were observed in the sirukumab-treated subjects. Both C_max and AUC(0,∞) increased in an approximately dose-proportional manner. Median terminal half-life ranged from 18.5 to 29.6 days. A two-compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V₁), the inter-compartmental clearance (Q) and the peripheral volume of distribution (V₂) were 0.364 l day⁻¹, 3.28 l, 0.588 l day⁻¹ and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C-reactive protein was observed in all sirukumab-treated dose groups, although no clear dose–response relationship was observed. No subjects were positive for antibodies to sirukumab.

CONCLUSIONS

Sirukumab had a well-tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg⁻¹ in healthy subjects.     

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.

     

A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours

AIMS

This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours.

METHODS

Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m⁻² infused intravenously over 30 min.

RESULTS

CA4P was generally well tolerated at ≤65 mg m⁻². Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m⁻², including two episodes of reversible ataxia at 85 mg m⁻². For CA4P, at 50 mg m⁻², mean (SD) peak plasma concentration (C_max) was 0.99 (0.33) µm, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) µm h and terminal elimination half-life (t_1/2) was 1.81 (0.61) h. At 65 mg m⁻², C_max was 1.73 (0.62) µm, AUC(0,t) was 3.19 (1.47) µm h and t_1/2 was 1.90 (0.61) h. One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass.

CONCLUSION

Doses ≤65 mg m⁻² given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50–65 mg m⁻² have been selected for further studies.     

Effect of experimental hyperlipidaemia on the electrocardiographic effects of repeated doses of halofantrine in rats

BACKGROUND AND PURPOSE

Halofantrine can cause a prolongation of the cardiac QT interval, leading to serious ventricular arrhythmias. Hyperlipidaemia elevates plasma concentration of halofantrine and may influence its tissue uptake. The present study examined the effect of experimental hyperlipidaemia on QT interval prolongation induced by halofantrine in rats.

EXPERIMENTAL APPROACH

Normolipidaemic and hyperlipidaemic rats (induced with poloxamer 407) were given 4 doses of halofantrine (i.v., 4–40 mg·kg⁻¹·d⁻¹) or vehicle every 12 h. Under brief anaesthesia, ECGs were recorded before administration of the vehicle or drug and 12 h after the first and last doses. Blood samples were taken at the same time after the first and last dose of halofantrine. Hearts were also collected 12 h after the last dose. Plasma and heart samples were assayed for drug and desbutylhalofantrine using a stereospecific method.

KEY RESULTS

In the vehicle group, hyperlipidaemia by itself did not affect the ECG. Compared to baseline, QT intervals were significantly higher in both normolipidaemic and hyperlipidaemic rats after halofantrine. In hyperlipidaemic rats, plasma but not heart concentrations of the halofantrine enantiomers were significantly higher compared to those in normolipidaemic rats. Despite the lack of difference in the concentrations of halofantrine in heart, QT intervals were significantly higher in hyperlipidaemic compared to those in normolipidaemic rats.

CONCLUSIONS AND IMPLICATIONS

The unbound fraction of halofantrine appeared to be the controlling factor for drug uptake by the heart. Our data suggested a greater vulnerability to halofantrine-induced QT interval prolongation in the hyperlipidaemic state.     

Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers

AIMS

Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug.

METHODS

This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h).

RESULTS

Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration–time curve (AUC_τ) and maximum concentration (C_max), with changes of −55% [90% confidence interval (CI) −62, −45] and −36% (90% CI −49, −21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUC_τ (−7%; 90% CI −23, 13) and increased C_max (23%; 90% CI −1, 53), while increasing efavirenz AUC_τ (17%; 90% CI 6, 29) and not changing C_max when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz.

CONCLUSIONS

When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered.
• Furthermore, voriconazole increases the systemic exposure of efavirenz.
• Co-administration was therefore initially contraindicated.

WHAT THIS STUDY ADDS

• The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety.
• Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication.