Branislava Miljković

Impact of age, weight and concomitant treatment on lamotrigine pharmacokinetics

What is known and Objective:  Lamotrigine metabolism may be substantially altered with concomitant administration of valproic acid and/or carbamazepine. Such alterations may require the adjustment of lamotrigine dose to ensure optimal treatment efficacy and safety.

Getting the balance right: Established and emerging therapies for major depressive disorders

Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.

Low Fresh Gas Flow Balanced Anesthesia Versus Target Controlled Intravenous Infusion Anesthesia in Laparoscopic Cholecystectomy: A Cost-Minimization Analysis

BACKGROUND Laparoscopic surgery is widely recognized as a well-tolerated and effective method for cholecystectomy. It is also considered cost saving because it has been associated with a decreased hospital length of stay. Variables that might lead to increased costs in laparoscopic surgery are the technique and drugs used in anesthesia. OBJECTIVE The goal of this study was to compare the costs of 2 anesthetic techniques used in laparoscopic cholecystectomy (LC)--balanced versus IV anesthesia--from the standpoint of an outpatient surgical department, with a time horizon of 1 year. METHODS Patients scheduled to undergo elective LC were enrolled in this prospective case study. Patients were randomly allocated to receive balanced anesthesia, administered as low fresh gas flow (LFGF) with inhalational sevoflurane and IV sufentanil in a target controlled infusion (LFGF SS group), or IV anesthesia, administered as IV propofol/sufentanil in a target controlled infusion (TCI group). We used a microcosting procedure to measure health care resource utilization in individual patients to detect treatment differences. The costs of medications used for the induction and maintenance of anesthesia during surgery were considered for LFGF SS and TCI. Other end points included duration of anesthesia; mean times to early emergence, tracheal extubation, orientation, and postanesthesia discharge (PAD); pain intensity before first analgesia; number of analgesics required in the first 24 hours after surgery; and prevalences of nausea, vomiting, and agitation. RESULTS A total of 60 patients were included in this analysis (male/female ratios in the LFGF SS and TCI groups: 11/19 and 12/18, respectively; mean [SD] ages, 48 [7.9] and 47 [8.6] years; and mean [SD] body mass indexes, 26 [2.0] and 26 [3.0] kg/m2). The costs of anesthetics were significantly lower with LFGF SS compared with TCI (euro17.40 [euro2.66] vs euro22.01 [euro2.50] [2006 euros]). Times to early emergence and tracheal extubation were significantly shorter with LFGF SS than TCI (5.97 [1.16] vs 7.73 [1.48] minutes and 7.57 [1.07] vs 8.87 [1.45] minutes, respectively). There were no significant between-group differences in mean duration of anesthesia; times to orientation and PAD; pain intensity before first analgesia; number of analgesics required in the first 24 hours; or prevalences of nausea, vomiting, and agitation. Because no clinically significant differences in the anesthetic results were observed, a cost-minimization analysis was conducted and found that using LFGF SS, the outpatient surgical department could realize a budget savings of euro454 per 100 patients. For the nearly 1000 expected patients per year, the savings for the department was calculated as euro4540. CONCLUSION The results from this cost analysis in these patients who underwent elective LC suggest that the use of sevoflurane through the LFGF technique would be cost saving in this outpatient surgical department.

Population pharmacokinetics of topiramate in adult patients with epilepsy using nonlinear mixed effects modelling

The objective of the study was to develop population pharmacokinetic model of topiramate (TPM) using nonlinear mixed effects modelling approach. Data were collected from 78 adult epileptic patients on mono- or co-therapy of TPM and other antiepileptic drugs, such as carbamazepine (CBZ), valproic acid, lamotrigine, levetiracetam, phenobarbital and pregabalin. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography with fluorescence detection. A one-compartment model with first order absorption and elimination was used to fit the concentration-time TPM data. Volume of distribution of TPM was estimated at 0.575 l/kg. The influence of demographic, biochemical parameters and therapy characteristics of the patients on oral clearance (CL/F) was evaluated. Daily carbamazepine dose (DCBZ) and renal function estimated by Modification of diet in renal disease (MDRD) formula significantly (p<0.001) influenced CL/F and were included in the final model: CL/F · (l/h)=1.53(l/h) · [1+0.476 · DCBZ(mg/day)/1000(mg/day)] · EXP[0.00476 · [MDRD(ml/ min)-95.72(ml/min)]]. Increase of CL/F with DCBZ and MDRD was best described by linear and exponential models. Mean TPM CL/F during CBZ co-therapy was 2.46 l/h, which is higher for 60.8% than in patients not co-treated with CBZ. Evaluation by bootstrapping showed that the final model was stable. The predictive performance was evaluated by adequate plots and indicated satisfactory precision. This model allows individualisation of TPM dosing in routine patient care, especially useful for patients on different CBZ dosing regimen.

Evaluation of Single‐Point Sampling Strategies for the Estimation of Moclobemide Exposure in Depressive Patients

Because moclobemide pharmacokinetics vary considerably among individuals, monitoring of plasma concentrations lends insight into its pharmacokinetic behavior and enhances its rational use in clinical practice. The aim of this study was to evaluate whether single concentration—time points could adequately predict moclobemide systemic exposure. Pharmacokinetic data (full 7‐point pharmacokinetic profiles), obtained from 21 depressive inpatients receiving moclobemide (150 mg 3 times daily), were randomly split into development (n = 18) and validation (n = 16) sets. Correlations between the single concentration—time points and the area under the concentration—time curve within a 6‐hour dosing interval at steady‐state (AUC0–6) were assessed by linear regression analyses. The predictive performance of single‐point sampling strategies was evaluated in the validation set by mean prediction error, mean absolute error, and root mean square error. Plasma concentrations in the absorption phase yielded unsatisfactory predictions of moclobemide AUC0–6. The best estimation of AUC0–6 was achieved from concentrations at 4 and 6 hours following dosing. As the most reliable surrogate for moclobemide systemic exposure, concentrations at 4 and 6 hours should be used instead of predose trough concentrations as an indicator of between‐patient variability and a guide for dose adjustments in specific clinical situations.

Are local clinical guidelines useful in promoting rational use of antibiotic prophylaxis in caesarean delivery

Objectives To identify changes in prescribing patterns of antibiotic prophylaxis in Caesarean delivery after introduction of local clinical guidelines. To identify changes in outcomes of prescribing antibiotics following the implementation of local clinical guidelines on antibiotic prophylaxis. Setting University of Belgrade, Medical School, Clinic of Gynaecology and Obstetrics “Narodni front” Belgrade, Serbia. Method A quantitative retrospective analysis of antibiotic use before (January–June 2005), and following (January–June 2006) implementation of guidelines on antibiotic prophylaxis in two wards. Patients who underwent Caesarean section prior to (261) and following (281) introduction of local guidelines, participated in this study. Main outcome measures Drug utilization cost presented as the number of DDD/100 bed days/eur, the average duration of hospital stay, number of wound infections. Results There was a significant change in prescribing patterns of antibiotic prophylaxis in Caesarean section following introduction of local guidelines. The use of ceftriaxone, amikacin and metronidazole decreased (57.47% vs. 11.74%; 9.19% vs. 4.27%; 61.69% vs. 46.26%, respectively). On the other hand, the use of “older” antibiotics such as gentamicin, cefuroxime, cefazolin and ampicillin increased (14.56% vs. 29.18%; 9.2% vs. 17.44%; 9.58% vs. 45.2% and 0% vs. 3.9%, respectively). DDD/100 bed days/eur analysis revealed a 47% decrease of total cost for prophylactic antibiotic treatment in Caesarean section following local guideline implementation. In contrast, rate of wound infections and duration of hospital stay were not significantly different in both groups. Conclusion In an attempt to ensure cost-effective prophylactic use of antibiotics in Caesarean delivery, local clinical guidelines were introduced. They resulted in changes in prescribing patterns of antibiotics. There was a significant decrease in use of ‘third’ generation of cephalosporin’s whereas the use of “older” antibiotics with proven efficacy and safety increased. In contrast, there was no significant change in treatment outcomes such as wound infection and average hospital stay.

Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders. WHAT THIS STUDY ADDS VPA does not significantly affect PK or metabolism of MCB at steady state. CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. AIM To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. METHODS Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales. RESULTS CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l(-1); 95% confidence interval (CI) -4.84863, -0.66194; P = 0.01] and C(max) by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h(-1) kg(-1); 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l(-1); 95% CI -0.77479, -0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good. CONCLUSIONS VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB-CBZ PK interaction needs to be further evaluated in a more comprehensive study.

Clinical response and plasma concentrations of amitriptyline and its metabolite-nortriptyline in depressive patients

SummaryAlthough many attempts have been made, to date no convincing evidence exists of a relationship between plasma concentrations of amitriptyline (AT), its active metabolite nortriptyline (NT) and clinical response. Fifteen patients with primary depression (according to DSM-IV) were divided in two groups according to given doses: (I) 6 patients received 3×50 mg of AT daily; and (II) 9 patients received 3×25 mg of AT daily, for 6 weeks. The clinical status was determined with Hamilton Depression Rating Scale. Both investigated doses were therapeutically effective. AT and NT plasma concentrations were assayed by high performance liquid chromatography. Following administration of 3×50 mg of AT daily, the correlation of concentrations of AT, NT, total AT+NT and clinical response were rAT=−0.702 (P<0.1), rNT=−0.761 (P<0.1), rAT+NT=−0.741 (P<0.1). The linear and very high correlation were also present with concentrations of AT, NT, total AT+NT and clinical response in depressive patients on 3×25 mg AT daily: rAT=−0.785 (P<0.02), rNT=−0.811 (P<0.01), rAT+NT=−0.848 (P<0.01). Our results support a high correlation between AT/NT plasma concentrations and clinical response indicating that therapeutic monitoring of AT and its metabolite, NT, can provide eventual clinical response.

Effect of Long-term Topiramate Therapy on Serum Bicarbonate and Potassium Levels in Adult Epileptic Patients

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide that is structurally different from other antiepileptic drugs. TPM inhibits carbonic anhydrase activity, which is associated with loss of bicarbonate from the kidney and consequently metabolic acidosis or electrolyte imbalance. Objective: The objectives of the study were to investigate the influence of TPM therapy on bicarbonate and potassium levels in adult epileptic patients. Methods: Data were collected from 59 adult patients on monotherapy or co-therapy of TPM and other antiepileptic drugs. Serum bicarbonate and potassium levels were available from all patients. Steady-state TPM trough concentrations were determined in blood samples by high-performance liquid chromatography. Data analysis was performed by SPSS software (version 17, Chicago, IL). Results: Patients were divided into group A (duration of therapy shorter than or equal to 5 years) and group B (duration of therapy longer than 5 years). Significant difference (P < 0.05) in serum bicarbonate levels was observed between these 2 groups. Bicarbonate levels were linearly related to the TPM therapy duration. No correlation was found between the TPM dose or patient age and bicarbonate or potassium levels, as well as between therapy duration and potassium level. Linear regression analysis showed no significant association among 54 available TPM trough concentrations and bicarbonate or potassium levels. Conclusions: Results highlight the frequent occurrence of lower bicarbonate level associated with prolonged TPM therapy. Monitoring bicarbonate levels in patients on long-term TPM therapy might be useful.

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets.

The aim of this case study was to develop a drug‐specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus™ software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration–time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate‐release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro–in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright