Diclofenac readily penetrates the cerebrospinal fluid in children

AIMS

The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children.

METHODS

A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg⁻¹. Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection.

RESULTS

In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 μg l⁻¹. At 5.5 h the CSF concentration was 0.1 μg l⁻¹, and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 μg l⁻¹ (range 70–272 μg l⁻¹). No serious or unexpected adverse effects were reported.

CONCLUSIONS

Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans.

WHAT THIS STUDY ADDS

• Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg⁻¹, sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h.

     

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies

Aim

This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.

Methods

We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.

Results

The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0–3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5–1.2, decreasing to 0.3–0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l⁻¹).

Conclusions

The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.     

Amoxicillin/clavulanic acid-warfarin drug interaction: a randomized controlled trial

AIMS

To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy.

METHODS

In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo.

RESULTS

The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P= 0.94). The day 7–day 1 factor II, R(–) and S(–) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P= 0.81, P= 0.45, P= 0.75, respectively).

CONCLUSION

Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.     

Pharmacy students provide care comparable to pharmacists in an outpatient anticoagulation setting

Objective

To evaluate whether student participation in ambulatory clinics influenced the percentage of therapeutic international normalized ratio (INR) results among patients on chronic warfarin therapy.

Methods

Medical records in outpatient anticoagulation clinics managed by pharmacists under physician protocol were reviewed retrospectively in 2 university-affiliated clinics in Amarillo and Lubbock, TX. Pharmacy student activities included patient interviews, vital sign measurements, fingersticks, counseling, and documentation. Patient visits were conducted by a precepted pharmacy student or a pharmacist without a student, and the INR was measured at the subsequent patient visit.

Results

Records of 1,958 anticoagulation patient visits were reviewed; 865 patients were treated by pharmacists, and 1093 were treated by precepted students. The follow-up INR was therapeutic for 48.5% of third-year (P3) students'' patients, 45.6% of fourth-year (P4) students'' patients, 51.2% of residents'' patients, and 44.7% of pharmacists''s patients (p = 0.23). Eight variables were associated with the follow-up INR (baseline INR, warfarin noncompliance, held warfarin doses, a warfarin dosage adjustment, diet change, alcohol use, tobacco use, and any medication changes).

Conclusion

Student participation in the patient-care process did not compromise patient care and no significant difference in patient outcomes was found between patients in an anticoagulation clinic cared for by precepted students and those cared for by pharmacists.     

Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects

AIM

To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor.

METHODS

A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events.

RESULTS

Udenafil reached peak plasma concentrations at 0.8–1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3–12.1 h in the single-dose study. The area under the time–concentration curves (AUC) and maximum plasma concentrations (C_max) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred.

CONCLUSIONS

Udenafil was safe and well tolerated in healthy volunteers. The AUC and C_max of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection.
• Udenafil is newly developed as a PDE-5 inhibitor.

WHAT THIS STUDY ADDS

• This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects.
• Udenafil was safe and well tolerated in healthy Korean subjects.
• The AUC and C_max of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

     

Time course of the increase in 4beta-hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy

AIMS

To investigate the time course of the increase in 4β-hydroxycholesterol and carbamazepine plasma concentrations during treatment of paediatric patients with epilepsy.

METHODS

Eight paediatric patients with newly diagnosed epilepsy were studied. Blood samples were drawn before and after about 1, 2, 4, 8 and 16 weeks of carbamazepine treatment. The plasma concentrations of 4β-hydroxycholesterol were determined by gas chromatography–mass spectrometry and carbamazepine and its epoxide metabolite by high-performance liquid chromatography.

RESULTS

The basal plasma concentrations of 4β-hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml⁻¹. Carbamazepine treatment increased mean plasma 4β-hydroxycholesterol significantly already after 1 week of treatment (from 43 to 80 ng ml⁻¹, P < 0.001). 4β-Hydroxycholesterol concentrations continued to increase until at least 8 weeks of treatment and the concentrations in the final samples (8–23 weeks of treatment) varied between 122 and 494 ng ml⁻¹. Plasma concentrations of carbamazepine and its epoxide metabolite reached steady state at 1–2 weeks after last dose change.

CONCLUSIONS

Carbamazepine treatment of paediatric patients with epilepsy resulted in an induction of CYP3A4/5 and a concomitant increase in plasma 4β-hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1–2 weeks, the increase in 4β-hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4β-hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• CYP3A4 converts cholesterol into 4β-hydroxycholesterol.
• We have suggested that 4β-hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments.
• The kinetics of 4β-hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4β-hydroxycholesterol can be used as a CYP3A marker.

WHAT THIS STUDY ADDS

• The concentration of 4β-hydroxycholesterol increases very slowly during CYP3A4/5 induction in paediatric patients.
• Whereas induction of CYP3A4/5 was apparently complete within 1–2 weeks of carbamazepine treatment, plasma 4β-hydroxycholesterol levels continued to increase until at least 8 weeks of treatment.

     

Formulation of long-acting nifedipine tablets influences the heart rate and sympathetic nervous system response in hypertensive patients

AIMS

The haemodynamic responses to nifedipine vary between short- and long-acting formulations. However, the latter have not been compared despite marked differences in their constitution. Our 1-month randomized, crossover study was designed to compare the 30-mg osmotic, constant-release nifedipine gastrointestinal therapeutic system (N-GITS) with an encapsulated mini-tablet Coracten XL.

METHODS

Forty-four hypertensive patients aged 63 ± 7 years were studied. The formulation was changed on day 15 and (for a single dose) day 30. At days 0, 14, 15, 29 and 30, patients were monitored for 6 h after dosing, during which blood pressure (BP), heart rate (HR) and plasma levels of norepinephrine (NE) and nifedipine were measured. The primary outcome was the difference in plasma NE between formulations at the time of peak nifedipine level.

RESULTS

Systolic BP decreased rapidly after the first dose of Coracten, achieving nadir at 5 h. HR rose by 1.2 ± 8.8 beats min⁻¹. After N-GITS HR fell by 2.4 ± 7.7 beats min⁻¹ (P = 0.159). Plasma NE was higher in the Coracten- (480 ± 38.3 pg ml⁻¹) than N-GITS-treated patients (343 ± 75.0 pg ml⁻¹) at the time of peak nifedipine concentrations (4 and 5 h, respectively) and their change from baseline was significantly (P = 0.0046) different. A similar difference between the drugs was seen again at days 15 and 30, at 5 h after switching formulations.

CONCLUSIONS

This study suggests that two different formulations of once-daily nifedipine result in different BP and plasma NE responses, and that switching between formulations causes opposite effects upon the sympathetic nervous response to falling BP.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Pharmacokinetic and pharmacodynamics studies are usually carried out separately with theoretical linking or interpretations.
• The pharmacokinetics of short- vs. long-acting formulations of nifedipine is well known, but the pharmacokinetics of different once-a-day formulations of nifedipine is generally not well known by the practising physician.

WHAT THIS STUDY ADDS

• This study provides practical patient-based information linking pharmacokinetics to pharmacodynamics in one of the target populations of patients, those with hypertension, who might receive the two different drugs.

     

Efavirenz concentrations in HIV-infected patients with and without viral hepatitis

AIMS

Data on efavirenz in HIV/viral hepatitis co-infected patients is non-consensual, probably due to liver function heterogeneity in the patients included.

METHODS

A case control study was performed on 27 HIV-infected patients, with controlled and homogenous markers of hepatic function, either mono-infected or co-infected with HBV/HCV, to ascertain the influence of viral hepatitis on efavirenz concentrations over a 2-year follow-up period.

RESULTS

No differences were found in efavirenz concentrations between groups both during and at the end of the follow-up period: control (2.43 ± 1.91 mg l^–1) vs. co-infected individuals (2.37 ± 0.37 mg l^–1).

CONCLUSION

It was concluded that HBV/HCV infections in themselves do not predispose to an overexposure to efavirenz.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• HIV-1 co-infection with HBV/HCV is the most important factor determining efavirenz-induced liver toxicity. Higher efavirenz plasma concentrations have been reported in these patients facilitating concentration drug-related adverse effects.
• It is not known whether changes in efavirenz disposition are due to the hepatitis infection/inflammation or to liver failure. As a consequence, the guidelines for the application of therapeutic drug monitoring of efavirenz in HBV/HCV co-infected patients have not been established.

WHAT THIS STUDY ADDS

• The present study has shown that HBV/HCV infection in itself does not predispose to higher efavirenz plasma concentrations. In the absence of hepatic failure, the risk of efavirenz concentration-dependent toxicity is not increased.
• Thus, therapeutic drug monitoring indications in co-infected patients with hepatic function within the normal range should be the same as in HIV-1 mono-infected patients.

     

Population pharmacokinetic modelling of aripiprazole and its active metabolite,dehydroaripiprazole, in psychiatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers.
• The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole.

WHAT THIS STUDY ADDS

• The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach.
• The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM.

AIMS

The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK).

METHODS

A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10–30 mg day¹).

RESULTS

A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h¹. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20–0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype.

CONCLUSIONS

This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated.     

Population pharmacokinetic and pharmacodynamic modelling of the effects of nicorandil in the treatment of acute heart failure

AIMS

The aims of the study were 1) to evaluate the pharmacokinetics of nicorandil in healthy subjects and acute heart failure (AHF) patients and 2) to evaluate the exposure-response relationship with pulmonary arterial wedge pressure (PAWP) in AHF patients and to predict an appropriate dosing regimen for nicorandil.

METHODS

Based on the data from two healthy volunteer and three AHF patient studies, models were developed to characterize the pharmacokinetics and pharmacodynamics of nicorandil. PAWP was used as the pharmacodynamic variable. An asymptotic exponential disease progression model was used to account for time dependent changes in PAWP that were not explained by nicorandil exposure. The modelling was performed using NONMEM version V.

RESULTS

The pharmacokinetics of nicorandil were characterized by a two-compartment model with linear elimination. CL, V1 and V2 in AHF patients were 1.96, 1.39 and 4.06 times greater than in healthy subjects. Predicted plasma concentrations were assumed to have an immediate concentration effect relationship on PAWP. An inhibitory E_max model with E_max of −11.7 mmHg and EC₅₀ of 423 µg l⁻¹ was considered the best relationship between nicorandil concentrations and PAWP. PAWP decreased independently of nicorandil exposure. This drug independent decline was described by an asymptotic decrease of 6.1 mmHg with a half-life of 5.3 h.

CONCLUSIONS

AHF patients have higher clearance and initial distribution volume of nicorandil compared with healthy subjects. The median target nicorandil concentration to decrease PAWP by 30% is predicted to be 748 µg l⁻¹, indicating that a loading dose of 200 µg kg⁻¹ and a maintenance dose of 400 µg kg⁻¹ h⁻¹ would be appropriate for the initial treatment of AHF.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Nicorandil injection is used for unstable angina and for acute heart failure in Japan.
• The pharmacokinetics of nicorandil following oral administration have been described in healthy subjects.

WHAT THIS STUDY ADDS

• This paper describes the differences in nicorandil pharmacokinetics between healthy subjects and acute heart failure patients.
• A population pharmacokinetic-pharmacodynamic model for nicorandil in acute heart failure patients is described using pulmonary artery wedge pressure as the biomarker.
• A rational guide for initial dosing of nicorandil to achieve a target effect on pulmonary artery wedge pressure was based on pharmacokinetic and pharmacodynamic principles.

     

Ibudilast in healthy volunteers: safety,tolerability and pharmacokinetics with single and multiple doses

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibudilast is an oral drug approved in Asia for asthma.
• Tolerability of 10-mg regimens has been described previously.
• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.

WHAT THIS STUDY ADDS

• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
• Higher-dose regimens are relevant for testing in new neurological indications.
• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).

AIMS

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.

METHODS

Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.

RESULTS

Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T_max was 4–6 h. Mean (SD) steady-state plasma C_max and AUC_0–24 were 60 (25) ng ml⁻¹ and 1004 (303) ng h ml⁻¹, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.

CONCLUSIONS

Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day⁻¹) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.     

Influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients

Aims

To investigate the influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients.

Methods

A total of 174 Asian patients (Chinese, n = 96; Malays, n = 50; Indians, n = 28) who had stable daily warfarin doses for at least 1 month were recruited. Following genomic DNA extraction from venous blood, pharmacogenetic analysis of APOE and VKORC1 genes was done by DNA sequencing.

Results

The majority of the Asian patients (78%) harboured the APOE ε3/ε3 genotype. Different APOE genotypes were found not to have any significant influence on mean daily warfarin dose requirements. Warfarin dose requirements in the pooled Asian patients homozygous for the VKORC1 H1 haplotype were significantly lower compared with patients homozygous for the H7 haplotype (H1-H1 vs. H7-H7: 2.79 ± 1.06 mg day⁻¹vs. 5.45 ± 2.3 mg day⁻¹, P < 0.001).

Conclusions

The present study suggests that APOE variants have minimal impact on warfarin dose requirements in Asian patients, probably due to the low frequency of ε4 allele containing genotypes.

What is already known about this subject

• Recent studies on pharmacogenetics of warfarin have implicated apolipoproteinE (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin.
• Studies among Caucasian and African Americans showed a significant but conflicting role of apolipoproteinE (APOE) isoforms in warfarin pharmacogenetics.
• The contribution of APOE isoforms in influencing variations in warfarin requirements in Asian subjects remains to be investigated.

What this study adds

• This is the first report of a population study in Asians exploring the role of isoforms encoded by three APOE alleles (ε2, ε3, ε4) in influencing warfarin dose requirements.
• The present study showed that the APOE ε3/ε3 isoform is the predominant genotype in the Asian population.
• The study also showed that APOE isoforms may not be important in affecting warfarin pharmacodynamics in Asian patients. It also suggested that the impact of different APOE isoforms depended on the frequency of APOE genotypes in the population, in particular the ε4 allele containing genotypes.

     

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

Aims

The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives.

Methods

An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban.

Results

During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (E_max) for INR after co-administration was 2.79–4.15 (mean PT E_max 41.0–62.7 s), compared with 1.41–1.74 (mean PT E_max 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug.

Conclusions

The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR.     

The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam

AIMS

To measure and compare the concentration–time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing.

METHODS

Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration–time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model.

RESULTS

For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04–0.07) and 0.004 (range 0.002–0.006), respectively. The concentration–time profiles in oral fluid paralleled those in blood.

CONCLUSION

After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Concentration–time profiles of drugs in oral fluid generally run parallel to those in blood.
• In general, oral fluid contains more parent drug than metabolites.
• For some benzodiazepines it has been shown that concentrations are lower in oral fluid than in blood.

WHAT THIS STUDY ADDS

• The concentration–time profile of oxazepam in oral fluid after a single dose of oxazepam runs parallel to blood and is dose dependent.
• Concentration ratios (oral fluid/blood and oral fluid/serum) of oxazepam and oxazepam glucuronide after controlled intake of a single dose of oxazepam are presented.

     

Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers

AIMS

To investigate the transfer of chloroquine and its major bioactive metabolite desethylchloroquine across the placenta and into breast milk.

METHODS

In Papua New Guinea, chloroquine (CQ; 25 mg base kg⁻¹) is recommended for prophylaxis of malaria during pregnancy, and at the Alexishafen Health Centre women are routinely prescribed CQ at the time of delivery. Fetal-cord and maternal serum samples were collected at delivery (n = 19) and milk samples were collected from day 3 to day 17–21 after delivery (n = 16). CQ and its primary active metabolite desethylchloroquine (DECQ) were quantified by high-performance liquid chromatography. For both CQ and DECQ cord/maternal ratios (C/M) were calculated to characterize placental transfer, and infant exposure via milk was estimated by standard methods.

RESULTS

The median (interquartile range) C/M was 1.1 (0.9, 1.6) for CQ and 1.2 (0.5, 1.8) for DECQ. The average concentration in milk over the time of sampling was 167 μg l⁻¹ (27, 340) for CQ and 54 μg l⁻¹ (22, 106) for DECQ. Estimated absolute and relative infant doses were 34 μg kg⁻¹ day⁻¹ (7, 50) and 15 μg kg⁻¹ day⁻¹ (4, 26), and 2.3% (0.5, 3.6) and 1.0% (0.4, 2.0) for CQ and DECQ (as CQ equivalents), respectively.

CONCLUSION

Infant exposure to CQ and DECQ during pregnancy will be similar to that in the maternal circulation, and dependent on maternal dose and frequency. The median CQ + DECQ relative infant dose of 3.2% (as CQ equivalents) was low, confirming that use of CQ during lactation is compatible with breastfeeding.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The literature on placental and milk transfer of chloroquine and its major bioactive metabolite desethylchloroquine is sparse and incomplete.

WHAT THIS STUDY ADDS

• We have provided data on the transplacental transfer of chloroquine and desethylchloroquine in Melanesian women (n = 19), measured transfer of these drugs into breast milk (n = 16) and estimated absolute and relative infant doses for the breastfed infant.
• The data for desethylchloroquine are novel.
• In all three areas we have significantly increased both quantity and quality of the available database.

     

Glucagon is absorbed from the rectum but does not hasten recovery from hypoglycaemia in patients with type 1 diabetes

AIMS

A failure to secrete glucagon during hypoglycaemia is near universal in patients with type 1 diabetes 5 years after disease onset and may contribute to delayed counter-regulation during hypoglycaemia. Rectal glucagon delivery may assist glucose recovery following insulin-induced hypoglycaemia in such patients and has not been previously studied.

METHODS

Six male patients (age 21–38 years) with type 1 diabetes (median duration 10 years) without microvascular complications, were studied supine after an overnight fast on two separate occasions at least 14 days apart. After omission of their usual morning insulin and 45 min rest, hypoglycaemia was induced by an intravenous insulin infusion which was terminated when capillary glucose concentration reached 2.5 mmol l⁻¹. Subjects were randomized to insert a rectal suppository containing 100 mg indomethacin alone (placebo) or 100 mg indomethacin plus 1 mg glucagon at the hypoglycaemic reaction. Serial measurements were made for 120 min.

RESULTS

In the two groups, mean (SD) plasma glucose concentrations fell to a similar nadir of 1.8 (0.7) mmol l⁻¹ (placebo) and 2.1 (1.2) mmol l⁻¹ (glucagon). Peak plasma glucagon following hypoglycaemia was higher in the glucagon group; 176 (32) ng l⁻¹vs. 99 (22) ng l⁻¹ after placebo (P = 0.006). However, the glucose recovery rate over 120 min after hypoglycaemia did not differ significantly.

CONCLUSIONS

Our results provide evidence for the absorption of glucagon from the rectum. They also indicate that 1 mg does not constitute a useful mode of therapy to hasten recovery from hypoglycaemia in patients with type 1 diabetes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Patients with type 1 diabetes experience recurrent hypoglycaemia and have abnormal glucose counter regulatory responses with a failure to secrete glucagon. It is unknown if rectal glucagon is absorbed and what effect this may have on counter regulation from hypoglycaemia.

WHAT THIS STUDY ADDS

• A rectal suppository of glucagon results in a rise in plasma glucagon with metabolic effects in normal subjects. Similarly rectal glucagon results in a rise in plasma glucagon in patients with type 1 diabetes, but 1 mg does not improve recovery rates from experimental hypoglycaemia when compared with placebo.
• Larger doses of glucagon per rectum may provide pharmacological circulating concentrations with resulting therapeutic benefit during recovery from hypoglycaemia and deserves further study.

     

Pharmacokinetics and clinical efficacy of lorazepam in children with severe malaria and convulsions

AIM

To investigate the pharmacokinetics and clinical efficacy of intravenous (i.v.) and intramuscular (i.m.) lorazepam (LZP) in children with severe malaria and convulsions.

METHODS

Twenty-six children with severe malaria and convulsions lasting ≥5 min were studied. Fifteen children were given a single dose (0.1 mg kg⁻¹) of i.v. LZP and 11 received a similar i.m. dose. Blood samples were collected over 72 h for determination of plasma LZP concentrations. Plasma LZP concentration–time data were fitted using compartmental models.

RESULTS

Median [95% confidence interval (CI)] LZP concentrations of 65.1 ng ml⁻¹ (50.2, 107.0) and 41.4 ng ml⁻¹ (22.0, 103.0) were attained within median (95% CI) times of 30 min (10, 40) and 25 min (20, 60) following i.v. and i.m. administration, respectively. Concentrations were maintained above the reported therapeutic concentration (30 ng ml⁻¹) for at least 8 h after dosing via either route. The relative bioavailability of i.m. LZP was 89%. A single dose of LZP was effective for rapid termination of convulsions in all children and prevention of seizure recurrence for >72 h in 11 of 15 children (73%, i.v.) and 10 of 11 children (91%, i.m), without any clinically apparent respiratory depression or hypotension. Three children (12%) died.

CONCLUSION

Administration of LZP (0.1 mg kg⁻¹) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without significant cardiorespiratory effects. I.m administration of LZP may be more practical in rural healthcare facilities in Africa, where venous access may not be feasible.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Lorazepam (LZP) may be a more useful anticonvulsant to stop convulsions in children with severe malaria (SM) than diazepam, since it has a longer duration of action and can be given by other routes, such as intramuscular (i.m.).
• There are no studies describing both the pharmacoknetics and clinical efficacy of LZP in African children, particularly those with SM.
• We have undertaken a study with LZP, administered either intravenously (i.v.) or i.m., to children with SM and convulsions in order to describe and compare the pharmacokinetic profiles of LZP following administration via both routes and determine whether the currently recommended dose of LZP (0.1 mg kg⁻¹) is effective in terminating convulsions in this group.

WHAT THIS STUDY ADDS

• Administration of LZP (i.v. or i.m.) at the currently recommended dose (0.1 mg kg⁻¹) resulted in rapid achievement of plasma LZP concentrations within the reported effective therapeutic range without clinically significant cardiorespiratory effects.
• A single dose of LZP was effective in the rapid termination of convulsions in all children, and prevention of seizure recurrence for >72 h in 11 of 15 (73%) children and 10 of 11 (91%) children after i.v. and i.m. administration, respectively.

     

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men

AIMS

Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects.

METHODS

Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day⁻¹ (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days.

RESULTS

Brivaracetam was rapidly absorbed (t_max∼2 h) and eliminated (t_1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-β-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily.

CONCLUSIONS

Brivaracetam was well tolerated by healthy male volunteers at doses of 200–800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.
• Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy.

WHAT THIS STUDY ADDS

• We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses.