Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam

AIMS

The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma.

METHODS

We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg⁻¹ with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters.

RESULTS

Ten healthy volunteers aged 21–26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 ± 13 l h⁻¹[95% confidence interval 48, 66] to 36 ± 9.8 l h⁻¹ (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration–time curve (mean difference 22 µg h⁻¹ l⁻¹, P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches.

CONCLUSIONS

Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.     

Pre-dose plasma concentration monitoring of mycophenolate mofetil in patients with autoimmune diseases

Aim

To date, neither the benefit of mycophenolic acid (MPA) therapeutic drug monitoring (TDM), the prodrug of mycophenolate mofetil (MMF), nor the optimal monitoring technique have been established in autoimmune diseases. This study was undertaken to confirm, in a cohort of new patients, the plasma MPA thresholds previously published in patients with systemic lupus erythematosus (SLE) or vasculitis.

Methods

MPA areas under the concentration–time curves between 0 and 12 h, 12 h trough concentrations and pre-dose concentrations (C₀) were determined for 23 patients with SLE and 21 with systemic vasculitis. The relationship between patients'' pharmacokinetic (PK) variables and their clinical outcomes during follow-up were analyzed.

Results

In both autoimmune diseases, at PK assessment, median MPA C₀ for patients with uncontrolled disease was significantly lower than that of patients with stable disease or in remission, 1.6 mg l^–1 (IQR 0.9–2.1 mg l^–1) vs. 2.95 mg l^–1 (IQR 1.38–3.73 mg l^–1) for SLE (P = 0.048) and 1.55 mg l^–1 (IQR 0.98–2.18 mg l^–1) vs. 3 mg l^–1 (IQR 2.2–4.4 mg l^–1) for vasculitis (P = 0.016). According to our receiver operating characteristics curve analysis, a C₀ threshold of 2.5–3 mg l^–1 was best able to discriminate a flare (SLE: 88% sensitivity, 80% specificity; vasculitis: 100% sensitivity, 90% specificity). Patients with C₀ ≥ 2.5–3 mg l^–1 at inclusion had better clinical outcomes during the 12 months following PK assessment.

Conclusion

Provided that the benefit of TDM in patients with autoimmune diseases could be confirmed by randomized, controlled trials, it might be based on the C₀ measured approximately 12 h post-dose.     

Population pharmacokinetics of oral diclofenac for acute pain in children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.
• Diclofenac is frequently used ‘off-label’ in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5–2.5 mg kg⁻¹). There is currently no licensed oral paediatric formulation of diclofenac.

WHAT THIS STUDY ADDS

• Using a new diclofenac oral suspension, a dose of 1 mg kg⁻¹ in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.

AIMS

To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml⁻¹) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.

METHODS

Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg⁻¹ dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.

RESULTS

A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V_D/F were 53.98 l h⁻¹ 70 kg⁻¹ and 4.84 l 70 kg⁻¹ respectively. Allometric size models appeared to predict adequately changes in CL and V_D with age. Of the simulated doses investigated, 1 mg kg⁻¹ gave paediatric AUC_{(0, 12 h)} to adult 50 mg AUC_{(0, 12 h)} ratios of 1.00, 1.08 and 1.18 for ages 1–3, 4–6 and 7–12 years respectively.

CONCLUSIONS

This study has shown 1 mg kg⁻¹ diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.     

Relationship between plasma,atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake

AIM

Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium.

METHODS

Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC.

RESULTS

Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l⁻¹ (IQR 0.12–0.44), the median atrial concentration was 6.02 mg kg^–1 (IQR 2.70–9.06) and median ventricular concentration was 10.0 mg kg^–1 (IQR 5.76–13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1–27.1), ventricular : plasma ratio was 34.9 (IQR 24.5–55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39–2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84).

CONCLUSIONS

This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.     

Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function

Aims

The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy.

Methods

A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CL_cr) = 50–79 ml min⁻¹], moderate [CL_cr = 30–49 ml min⁻¹], severe [CL_cr <30 ml min⁻¹]).

Results

Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration–time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m⁻² day⁻¹, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m⁻² day⁻¹ for patients with moderate renal impairment (suggested dose 1.9 mg m⁻² day⁻¹ for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m⁻² day⁻¹ in this cohort.

Conclusions

Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.     

Inhibition of oral midazolam clearance by boosting doses of ritonavir,and by 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an experimental catalytic mimic of glutathione oxidase

AIMS

We evaluated whether ‘boosting’ doses of ritonavir can serve as a positive control inhibitor for pharmacokinetic drug–drug interaction studies involving cytochrome P450 3A (CYP3A). The study also determined whether 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an investigational organoselenium compound that acts as a catalytic mimic of glutathione oxidase, inhibits CYP3A metabolism in vivo.

METHODS

Thirteen healthy volunteers received single 3-mg oral doses of midazolam on three occasions: in the control condition, during co-treatment with low-dose ritonavir (three oral doses of 100 mg over 24 h), and during co-treatment with ALT-2074 (three oral doses of 80 mg over 24 h).

RESULTS

Ritonavir increased mean (±SE) total area under the curve (AUC) for midazolam by a factor of 28.4 ± 4.2 (P < 0.001), and reduced oral clearance to 4.2 ± 0.5% of control (P < 0.001). In contrast, ALT-2074 increased midazolam AUC by 1.25 ± 0.11 (P < 0.05), and reduced oral clearance to 88 ± 8% of control.

CONCLUSIONS

Low-dose ritonavir produces extensive CYP3A inhibition exceeding that of ketoconazole (typically 10- to 15-fold midazolam AUC enhancement), and is a suitable positive control index inhibitor for drug–drug interaction studies. ALT-2074 inhibits CYP3A metabolism to a small degree that is of uncertain clinical importance.     

Evaluation of clinical activity and safety of Daflon 500 mg in type 2 diabetic female patients

Background

The incidence of cardiovascular disease in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population.

Aim

To investigate the hypoglycemic and hypocholesterolemic effects of Daflon^® 500 mg (DF) administration together with its tolerability and efficacy in reducing the cardiovascular metabolic risk factors in female patients with type 2 diabetes.

Methods

In a well-adequate controlled single-blinded randomized parallel design the tolerability and the efficacy of Daflon^® (500 mg) either alone or with oral hypoglycemic, twice daily for 45 days, was studied in 36 female patients with type 2 diabetes.

Results

None of the patients in the studied groups were reported to have any adverse events throughout the treatment period (45 days), liver and kidney function tests were within normal limits and there was no significant difference between the pre-treatment (day 0) and post-treatment (day 45) values. Female patients receiving Daflon^® either alone or with oral hypoglycemic showed significant decrease in serum glucose; fructosamine; total cholesterol; LDL–cholesterol; triglycerides; malondialdehydes (as index of lipid peroxidation) and C-reactive protein (CRB) levels along with increase in the levels of nitric oxide and blood glutathione.

Conclusion

This study has shown that Daflon^® (500 mg, twice daily for 45 days) is helpful in reducing glucose level and the risk of cardiovascular disease in type 2 diabetic patients.

Recommendation

Further clinical trials are essential for strengthening the evidence base on the role of this drug in the cardiovascular risk in diabetic patients.     

Bioactivity of enoxaparin in critically ill patients with normal renal function

Aim

In critically ill patients, reduced anti-FXa plasma activity following subcutaneous administration of enoxaparin or nadroparin has been described. In this study, we aimed to investigate the bioactivity of enoxaparin in critically ill patients and controls.

Methods

A prospective, controlled, open label study was performed on a medical intensive care unit (ICU) and a general medical ward. Fifteen ICU patients (male = 12, median age 52 years [IQR 40−65], with a median Simplified Acute Physiology Score of 30 [IQR 18−52]) and sex- and age-matched medical ward patients were included. The anti-FXa plasma activity was measured after a single subcutaneous dose of 40 mg enoxaparin. The thrombus size of a clot formed in an ex vivo perfusion chamber and endogenous thrombin potential (ETP) were measured.

Results

The anti-FXa plasma activity increased significantly after enoxaparin administration, with peak levels at 3 h after treatment, but was comparable between the ICU and medical ward groups (median 0.16 IU ml⁻¹[IQR 0−0.22 IU ml⁻¹]vs. 0.2 IU ml⁻¹[IQR 0.15−0.27 IU ml⁻¹], respectively, P= 0.13). The area under the anti-FXa activity curve from 0–12 h was similar between the groups (median 0.97 IU ml⁻¹ h [IQR 0.59−2.1] and 1.48 IU ml⁻¹ h¹[IQR 0.83−1.62], P= 0.42 for the ICU group compared with the control group, respectively). The ETP was lower in the ICU group (P < 0.05) at baseline, but it was comparable at 3 h between the groups. Thrombus size decreased at 3 h compared with predose (P= 0.029) and was not different between the groups.

Conclusion

Similar bioactivity was achieved with a standard dose of subcutaneous enoxaparin in this selected cohort of ICU and general ward patients with normal renal function.     

Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans

Aim

We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam.

Methods

In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics.

Results

Dose-normalized AUC and C_max were 37.1 ng ml⁻¹h [95% CI 35.5, 40.6] and 39.1 ng ml⁻¹ [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml⁻¹h [95% CI 36.1, 42.1] and 37.1 ng ml⁻¹ [95% CI 26.9, 51.3] for the milligram dose. CL_met was 253 ml min⁻¹ [95% CI 201, 318] vs. 278 ml min⁻¹ [95% CI 248, 311] for intravenous doses and 1880 ml min⁻¹ [95% CI 1590, 2230] vs. 2050 ml min⁻¹ [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]).

Conclusion

The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity.     

Exposure–effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis

Aims

The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.

Methods

Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C₀), maximum concentration (C_max) and area under the concentration–time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.

Results

Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l^–1 h, P= 0.048) and C_max (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l^–1, P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l^–1 h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l^–1 h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l^–1 h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).

Conclusions

This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.     

Correlation of paired toxic plasma and saliva paracetamol concentrations following deliberate self-poisoning with paracetamol

AIMS

Paracetamol is commonly used in deliberate self poisoning (DSP) and requires blood sampling to refine risk assessment. We aimed to test the agreement between plasma and saliva paracetamol concentrations in the toxic range in DSP.

METHODS

Contemporaneous paired plasma and saliva paracetamol concentrations were measured. Saliva was collected using a Sarstedt Salivette® device and the concentration was measured using a colorimetric method.

RESULTS

Fifty-six patients (44, 78% female) median age 26 years (IQR 20–41) were enrolled. The median reported paracetamol ingestion was 10 g (IQR 6–14). Specimens were collected at a median of 4 h (IQR 4–5.3) post ingestion. The median plasma and saliva paracetamol concentrations were 29 mg l⁻¹ (IQR 8–110) and 38 mg l⁻¹ (IQR 10–105) respectively [mean difference 8 mg l⁻¹, 95% confidence interval (CI) 2, 14]. Lin''s concordance correlation was 0.97 (95% CI 0.96, 0.98). There were 15 patients who were treated with N-acetylcysteine. Their median reported paracetamol ingestion was 14 g (IQR 10–23) and samples were collected at a median of 4 h post ingestion. The median plasma and saliva paracetamol concentrations were 167 mg l⁻¹ (IQR 110–200) and 170 mg l⁻¹ (IQR 103–210) respectively (mean difference 15 mg l⁻¹, 95% CI −4, 35). Lin''s concordance correlation was 0.94 (95% CI 0.88, 0.99). No patient needing treatment would have been missed using saliva concentrations only.

CONCLUSIONS

The agreement between the indications for treatment of paracetamol DSP based on plasma and saliva paracetamol concentrations extends into the toxic range, but with slightly lower agreement. Saliva may hold promise as a non-invasive method to risk stratify paracetamol poisoning.     

Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin

Aim

Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours.

Methods

An open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m⁻² eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,∞) and C_max for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (anova) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m⁻² eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed.

Results

Fourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,∞) = 1.10, 90% CI 0.91, 1.34 and C_max = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).

Conclusions

These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.     

Population pharmacokinetics and dosing optimization of teicoplanin in children with malignant haematological disease

Aim

Children with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high risk population.

Methods

The current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin were analyzed using nonmem software. The dosing regimen was optimized based on the final model.

Results

Eighty-five children (age range 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n = 143) were available for analysis. With the current recommended dose of 10 mg kg^–1 day^–1, 41 children (48%) had sub-therapeutic steady-state trough concentrations (C_ss,min<10 mg l^–1). A two compartment pharmacokinetic model with first order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg l^–1 h 18 mg kg^–1 was required for infants, 14 mg kg^–1 for children and 12 mg kg^–1 for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and C_ss,min values compared with the mg kg^–1 basis dose, making the modelling approach an important tool for dosing individualization.

Conclusions

This first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.     

Population pharmacokinetics of valganciclovir prophylaxis in paediatric and adult solid organ transplant recipients

Aim

Our aims were to quantify ganciclovir pharmacokinetics in paediatric and adult kidney, liver and lung transplant patients taking a range of valganciclovir doses to prevent herpes virus infections, including a 450 mg regimen, and to identify sources of pharmacokinetic variability.

Method

Plasma samples were collected at 2, 4, 8 and 12 weeks post-transplant and at 4, 6, 8 and 12 months post-transplant in subjects prescribed longer courses. Ganciclovir was measured by liquid chromatography/ultraviolet detection. Non-linear mixed effects modelling was used to analyze the concentration–time data and evaluate demographic and transplant-related covariates.

Results

A two compartment model with first order absorption best described the data. Given the range of body sizes, clearance and volume of distribution terms were scaled using standard weight-based allometric exponents. Creatinine clearance was included on apparent oral clearance. Final estimates in a standard 70 kg individual for apparent oral clearance, central volume of distribution, intercompartmental clearance and peripheral volume of distribution were 14.5 l h⁻¹, 87.5 l, 4.80 l h⁻¹ and 42.6 l, respectively. The median terminal half-life for kidney, liver and lung transplant recipients was 9.4, 9.5 and 8.2 h, respectively. Median exposure (i.e. AUC(0,∞) in subjects taking valganciclovir 900 mg or 450 mg once daily was 57.4 and 34.3 μg ml⁻¹ h, respectively.

Conclusion

Allometric scaling allowed simultaneous analysis of data from children and adults. Ganciclovir pharmacokinetics were similar among kidney, liver and lung transplant recipients. Ganciclovir exposure after valganciclovir 450 mg once daily may be suboptimal in some individuals and requires evaluation along with virologic outcomes data.     

Relationship between blood alcohol concentration on admission and outcome in dimethoate organophosphorus self-poisoning

AIMS

Many patients acutely poisoned with organophosphorus insecticides have co-ingested alcohol. Although clinical experience suggests that this makes management more difficult, the relationship between plasma concentration of alcohol and insecticide is unknown. We aimed to determine whether acute intoxication results in ingestion of larger quantities of insecticide in dimethoate self-poisoning and a worse clinical outcome.

METHODS

We set up a prospective study of acute dimethoate self-poisoning in Sri Lankan district hospitals. An admission plasma sample was analysed to identify the ingested insecticide; in patients with detectable dimethoate, plasma alcohol was measured.

RESULTS

Plasma from 37 of 72 (51.4%) dimethoate-poisoned patients had detectable alcohol {median concentration 1.10 g l⁻¹[110 mg dl⁻¹][interquartile range (IQR) 0.78–1.65]} a median of 3 h post ingestion. The median plasma dimethoate concentration was higher in patients who had ingested alcohol [479 µmol l⁻¹ (IQR 268–701) vs. 145 µmol l⁻¹ (IQR 25–337); P < 0.001]. Plasma dimethoate concentration was positively correlated with plasma alcohol (Spearman''s ρ= 0.34; P= 0.0032). The median alcohol concentration was higher in the 21 patients who died compared with survivors (0.94 vs. 0.0 g l⁻¹, P= 0.018). Risk of death was greater amongst individuals who consumed alcohol [odds ratio (OR) 4.3, 95% confidence interval (CI) 1.2, 16.4]; this risk was abolished by controlling for dimethoate concentration (OR 0.3, 95% CI 0.0, 8.8), indicating that deaths were not due to the direct toxic effects of alcohol.

CONCLUSIONS

Alcohol co-ingestion is associated with higher plasma concentrations of dimethoate and increased risk of death. Larger studies are required to assess this finding''s generalizability, since efforts to reduce deaths from self-poisoning may benefit from concurrent efforts to reduce alcohol consumption.     

Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose,open-label,parallel group study

Aims

Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin.

Methods

This was an open-label, parallel group study ({"type":"clinical-trial","attrs":{"text":"NCT01433458","term_id":"NCT01433458"}}NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 μg kg⁻¹ day⁻¹) between patients with mild, moderate or severe hepatic impairment (Child–Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration–time curve AUC(0–48 h) and AUC(0–∞) and serum concentration at 24 h post-dose (C_24h)] were compared between each hepatic impairment group and healthy controls.

Results

A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12–24 h and then declined following completion of infusion, with a mean terminal half-life of 7–8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study.

Conclusions

The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.     

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit

Aims

The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.

Methods

Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.

Results

Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 ± 11.1 l h^–1 at day 7; 17 ± 9.1 l h^–1 at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 ± 443 ml min^–1 at day 7 vs. 730 ± 344 ml min^–1 at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min^–1 for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time.

Conclusions

The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit.     

Pharmacokinetic–pharmacodynamic studies of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor MK-0916 in healthy subjects

Aims

To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916.

Methods

Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4–100 mg MK-0916 (n = 16). In the second study, subjects received 0.2–225 mg MK-0916 followed by daily doses of 0.2–100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [¹³C₄]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [¹³C₄]cortisone.

Results

Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1–1.8 h). Exposure (measured as the area under the concentration–time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11β-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple E_max model with an IC₅₀ of 70.4 nm. Exposure to MK-0916 was generally well tolerated.

Conclusions

These findings indicate that 11β-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.     

Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients

Aims

The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics.

Methods

Twenty patients (m/f 15/5, age 25–86 years, body weight 60–121 kg, APACHE II 7–40, estimated glomerular filtration rate 19–157 ml min^–1, albumin 11.7–30.1 g l^–1, total bilirubin <0.1–36.1 mg dl^–1) treated with intravenous ceftriaxone were recruited from two ICUs. Timed plasma samples were obtained using an opportunistic study protocol. Ceftriaxone concentrations were determined by high-performance liquid chromatography; unbound concentrations were determined after ultrafiltration using a new method which maintains physiological pH and temperature. The pharmacokinetics was described by a one-compartment model, the protein-binding characteristics by Michaelis–Menten kinetics.

Results

For total drug, the volume of distribution was 20.2 l (median; interquartile range 15.6–24.5 l), the half-life 14.5 h (10.0–25.5 h) and the clearance 0.96 l h^–1 (0.55–1.28 l h^–1). The clearance of unbound drug was 1.91 l h^–1 (1.46–6.20 l h^–1) and linearly correlated with estimated glomerular filtration rate (slope 0.85, y-intercept 0.24 l h^–1, r² = 0.70). The unbound fraction was higher in ICU patients (33.0%; 20.2–44.5%) than reported in healthy volunteers, particularly when renal impairment or severe hyperbilirubinaemia was present. In all patients, unbound concentrations during treatment with ceftriaxone 2 g once daily remained above the EUCAST susceptibility breakpoint (≤1 mg l^–1) throughout the whole dosing interval.

Conclusions

Protein binding of ceftriaxone is reduced and variable in ICU patients due to hypoalbuminaemia, but also to altered binding characteristics. Despite these changes, the pharmacokinetics of unbound ceftriaxone is governed by renal function. For patients with normal or reduced renal function, standard doses are sufficient.     

Bioequivalence of Eslicarbazepine Acetate from Two Different Sources of its Active Product Ingredient in Healthy Subjects

Purpose

To compare the bioavailability (BA) and pharmacokinetic (PK) properties and to demonstrate the bioequivalence (BE) between two active product ingredient (API) sources of eslicarbazepine acetate (ESL) in healthy volunteers.

Design, subjects and methods

Forty healthy male and female subjects aged 18–40 years were randomized to treatment with 400 or 800 mg ESL marketed (MF) formulation [current active pharmaceutical ingredient (API) source] and 400 or 800 mg ESL to-be-marketed (TBM) formulation (new API source) under a gender-balanced, two-period, two-sequence crossover open-label study design. Subjects were assigned to receive either 400 or 800 mg ESL dose strengths, and each was randomly administered on two occasions—either a single oral tablet of MF or a single oral tablet of TBM—separated by a washout period of at least 7 days. Formulations were to be considered bioequivalent if, for both 400 or 800 mg ESL dosage strengths, the test (TBM)/reference (MF) geometric mean ratios (GMR) and 90 % confidence intervals (90 % CI) of the area under the plasma concentration-time curve (AUC) and peak plasma concentration (C_max) were within the predetermined range of 80–125 %.

Results

Test/reference GMR (90 % CI) for the C_max and AUC was respectively 100 % (94–109 %) and 96 % (94–98 %) following 400 mg ESL and 100 % (95–105 %) and 100 % (97–103 %) following 800 mg ESL.

Conclusion

Oral tablet formulations of either 400 or 800 mg ESL from the new API source were found to be bioequivalent to the corresponding marketed Zebinix^® formulation according to the regulatory definition of bioequivalence.