An acenocoumarol dose algorithm based on a South-Eastern European population

Aim

To develop and validate an algorithm for the prediction of therapeutic dose of acenocoumarol in Romanian patients.

Methods

The inclusion criteria for entry to the study was age ≥18 years and starting acenocoumarol treatment for at least one of the following clinical indications: acute deep vein thrombosis of the lower limbs, persistent or permanent atrial fibrillation, and/or the presence of valvular prostheses requiring prolonged oral anticoagulant therapy. The patients were followed up for 3 months. Patients admitted to the internal medicine, cardiology, and geriatrics wards of the Municipal Clinical Hospital, Cluj-Napoca and “Niculae St?ncioiu” Heart Institute between October 2009 and June 2011 who fulfilled the inclusion criteria were included in the study. Clinical and demographic data that could influence the acenocoumarol stable dose were recorded for each patient. Genetic analysis included the genotyping the CYP2C9*2 and *3, and the VKORC1 -1693 G?>?A polymorphisms. The patients were randomly divided into two groups: (1) the main group on which the development of the clinical and genetic algorithms for acenocoumarol dose prediction was based; (2) the validation group.

Results

The study included 301 patients, of whom 155 were women (51.5 %) and 146 were men (48.5 %). The median age of the patient cohort was 66 (women, 57; men, 73) years. After randomization the main group comprised 200 patients (66.4 %) and the validation group 101 patients (33.6 %). Age and body mass index explained 18.8 % (R ²) of the variability in acenocoumarol weekly dose in patients in the main group. When the genetic data were added to the algorithm, the CYP2C9*2 and *3 polymorphisms and the VKORC1 -1693 G?>?A polymorphism accounted for 4.7 and 19. 6 % of acenocoumarol dose variability, respectively. For the main group, we calculated a mean absolute error of 5 mg/week (0.71 mg/day). In the validation group, clinical parameters explained 22.2 % of the weekly acenocoumarol dose variability. Genetic polymorphisms increased the R ² coefficient to 32.8 %.

Conclusion

We have developed and validated an accurate algorithm for prediction of the stable therapeutic dose of acenocoumarol in a Romania population.     

Warfarin dose prediction in children using pharmacometric bridging—comparison with published pharmacogenetic dosing algorithms

Purpose

Numerous studies have investigated causes of warfarin dose variability in adults, whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children.

Method

An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for warfarin, with CYP2C9 and VKORC1 genotype, age and target international normalized ratio (INR) as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external data set of children 0–18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children.

Results

Overall, the bridged model predicted INR response well in 64 warfarin-treated Swedish children (median age 4.3 years), but with a tendency to overpredict INR in children ≤2 years old. The bridged model predicted 20 of 49 children (41 %) within ± 20 % of actual maintenance dose (median age 7.2 years). In comparison, the published dosing algorithms predicted 33–41 % of the children within ±20 % of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within ±20 % of actual dose to 70 %.

Conclusion

A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children.     

The Impact of Inpatient Versus Outpatient Initiation on Early Warfarin Dosing

Background and Objectives

Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients.

Patients and Methods

We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms. Clinicians and participants were blinded to dose during the first 28 days. We compared groups, based on location at the time of the first warfarin dose request, in relation to the following outcomes: percentage of time in the therapeutic international normalized ratio (INR) range (PTTR) during the first 4 weeks, time to first therapeutic INR, time to maintenance dose, and the difference between predicted and observed maintenance doses.

Results

A total of 527 participants started warfarin as inpatients and 488 as outpatients. There was no difference in PTTR based on location: 43.2 % for inpatient versus 47.4 % for outpatient initiation [mean adjusted difference ?2.2 %; 95 % confidence interval (CI) ?5.9 to 1.6]. Similarly, there were no differences in time to first therapeutic INR [hazard ratio (HR) 1.06; 95 % CI 0.91–1.24] or to maintenance dose (HR 0.96; 95 % CI 0.81–1.14). There was no evidence of interaction between study intervention (pharmacogenetically vs. clinically guided therapy) and location of initiation for these main outcomes. The difference between predicted and observed maintenance doses was similar for both locations.

Conclusion

The warfarin dosing algorithms performed similarly for subjects who initiated warfarin as inpatients and outpatients, regardless of whether dosing was pharmacogenetically or clinically guided.

     

Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing

Purpose

We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data.

Methods

PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation).

Results

The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]?=?target AUC[mg?×?h/L]?×?3.04L/h?×?(ABW/16.1)^0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients.

Conclusions

We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.     

A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms

Purpose

Warfarin dosing is affected by clinical and genetic variants, but the contribution of the genotype associated with warfarin resistance in pharmacogenetic algorithms has not been well assessed yet. We developed a new dosing algorithm including polymorphisms associated both with warfarin sensitivity and resistance in the Italian population, and its performance was compared with those of eight previously published algorithms.

Methods

Clinical and genetic data (CYP2C9*2, CYP2C9*3, VKORC1 –1639?G > A, and VKORC1 3730?G > A) were used to elaborate the new algorithm. Derivation and validation groups comprised 55 (58.2% men, mean age 69?years) and 40 (57.5% men, mean age 70?years) patients, respectively, who were on stable anticoagulation therapy for at least 3 months with different oral anticoagulation therapy (OAT) indications.

Results

Performance of the new algorithm, evaluated with mean absolute error (MAE) defined as the absolute value of the difference between observed daily maintenance dose and predicted daily dose, correlation with the observed dose and R² value, was comparable with or slightly lower than that obtained using the other algorithms. The new algorithm could correctly assign 53.3%, 50.0%, and 57.1% of patients to the low (≤25 mg/week), intermediate (26–44?mg/week) and high (≥ 45?mg/week) dosing range, respectively. Our data showed a significant increase in predictive accuracy among patients requiring high warfarin dose compared with the other algorithms (ranging from 0% to 28.6%).

Conclusions

The algorithm including VKORC1 3730?G > A, associated with warfarin resistance, allowed a more accurate identification of resistant patients who require higher warfarin dosage.     

Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants

Objectives

To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population.

Methods

A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration–time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients.

Results

For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants.

Conclusions

Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU.     

Influence of refill adherence method when comparing level of adherence for different dosing regimens

Purpose

To examine the impact of two methods when estimating refill adherence in patients using bisphosphonates with different dosing regimens.

Methods

In the Swedish Prescribed Drug Register, 18,203 new users of bisphosphonates aged 18–85 years were identified between 1 July 2006 and 30 June 2007 and followed for a maximum of 2 years. The patients were categorised based on dosing regimen: one tablet daily, one tablet weekly, switching between these regimens, and other regimens. Refill adherence was estimated with Continuous measure of Medication Acquisition (CMA, adherent if CMA?≥?80 %) and the maximum gap method (adherent if gaps <45 days). Differences in adherence between patients in the groups were assessed with logistic regression models controlling for confounding factors.

Results

The proportion of patients classified as adherent was higher using CMA compared with patients classified as adherent using the maximum gap method. Patients on one tablet weekly had significantly lower adherence compared with patients on one tablet daily in the main analyses of both methods (the maximum gap method: 73 % vs. 80 %; adjusted OR?=?0.71; 95 % CI 0.57–0.89 and CMA: 84 % vs. 88 %, adjusted OR?=?0.75; 95 % CI 0.57–0.99). Patients using the other two dosing regimens had significantly lower adherence compared with patients on one tablet daily using both methods.

Conclusion

Choice of method has an impact on the estimates of refill adherence to bisphosphonates. Patients on one tablet weekly dosing had lower adherence compared with patients on one tablet daily dosing using both methods.     

VKORC1 −1639G>A and CYP2C9*3 are the major genetic predictors of phenprocoumon dose requirement

Purpose

Phenprocoumon, similar to other coumarin-derived anticoagulants, is associated with a large variation in the individual dose requirement to achieve stable anticoagulation. Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and the liver enzyme cytochrome P450 2C9 (CYP2C9) effectively account for the variability in warfarin and acenocoumarol response but are less well-defined pharmacogenetic predictors in phenprocoumon therapy.

Methods

A retrospective study was performed on 185 outpatients attending anticoagulation clinics in Austria and Germany. These patients were genotyped for the VKORC1 ?1639G>A and 3730G>A polymorphisms as well as for the CYP2C9 *2 and *3 polymorphisms using a reverse hybridisation-based teststrip assay.

Results

The VKORC1 ?1639A allele, which was present at a frequency of 41.4% in the study cohort, significantly reduced the mean weekly phenprocoumon dose by 3 mg (19%) in the heterozygous and by 6.7 mg (43%) in the homozygous state compared to wild-type carriers (15.5?±?6.8 mg, p?<?0.0001). A stepwise multiple regression analysis revealed that VKORC1 ?1639G>A, age and CYP2C9*3 were the major independent determinants of phenprocoumon dose, accounting for 14.2, 9.1 and 4.7% of its variability, respectively (p?≤?0.0007). The CYP2C9*2 polymorphism had a marginal influence (1.4%) and failed to reach statistical significance (p?=?0.062). The VKORC1 3730G>A genotype had no additional predictive power for individual dose variability.

Conclusion

Similar to warfarin and acenocoumarol, the VKORC1 ?1639G>A polymorphism had the highest impact on the maintenance dose of phenprocoumon. The factor age was the second most important predictor and explained a greater percentage of the variability than CYP2C9 genotype.     

NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy

Objective

This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis.

Methods

In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week.

Results

One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen.

Conclusion

Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.     

Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations

Aim and background

To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.

Methods

This was a cross-sectional retrospective study assessing the dose adequacy of drug treatment of 400 cirrhotic patients at hospital admission based on the authors’ own previous studies and standard literature. The prevalence of total and preventable ADRs and of hospitalizations due to preventable ADRs was determined.

Results

Of all 1653 drugs prescribed (median 4 per patient), 336 (20 %) drugs were inadequately dosed in 184 patients. Overall, 210 ADRs (78 % preventable) occurred in 120 patients. Sixty-nine ADRs (33 % of all ADRs) were associated with inadequate drug dosing in 46 patients, of which 68 % were preventable. Nonsteroidal anti-inflammatory drugs and psycholeptics in particular frequently caused preventable ADRs associated with inadequate drug dosing. Inadequate drug dosing was more frequently associated with ADRs than adequate drug dosing, and patients receiving inadequately dosed drugs were more frequently admitted to the hospital due to ADRs. Hospitalization of patients receiving inadequately dosed drugs that caused preventable ADRs resulted in 94 additional hospital days.

Conclusion

In this retrospective study, inadequate drug dosing was associated with an increased frequency of ADRs, hospital admissions and hospital days in cirrhotic patients. We therefore conclude that the careful dosing of critical drugs is important in patients with liver cirrhosis.     

Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice

Purpose

To discover drugs lowering PrP^Sc in prion-infected cultured neuronal cells that achieve high concentrations in brain to test in mouse models of prion disease and then treat people with these fatal diseases.

Methods

We tested 2-AMT analogs for EC₅₀ and PK after a 40 mg/kg single dose and 40–210 mg/kg/day doses for 3 days. We calculated plasma and brain AUC, ratio of AUC/EC₅₀ after dosing. We reasoned that compounds with high AUC/EC₅₀ ratios should be good candidates going forward.

Results

We evaluated 27 2-AMTs in single-dose and 10 in 3-day PK studies, of which IND24 and IND81 were selected for testing in mouse models of prion disease. They had high concentrations in brain after oral dosing. Absolute bioavailability ranged from 27–40%. AUC/EC₅₀ ratios after 3 days were >100 (total) and 48–113 (unbound). Stability in liver microsomes ranged from 30–>60 min. Ring hydroxylated metabolites were observed in microsomes. Neither was a substrate for the MDR1 transporter.

Conclusions

IND24 and IND81 are active in vitro and show high AUC/EC₅₀ ratios (total and unbound) in plasma and brain. These will be evaluated in mouse models of prion disease.     

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Rationale

Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.

Objective

The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.

Methods

Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.

Results

Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h^?1, β?=?1.86 h^?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.

Conclusions

We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.     

Evaluation of limited sampling models for prediction of oral midazolam AUC for CYP3A phenotyping and drug interaction studies

Background?

The area under the concentration–time curve (AUC) after oral midazolam administration is commonly used for cytochrome P450 (CYP) 3A phenotyping studies. The aim of this investigation was to evaluate a limited sampling strategy for the prediction of AUC with oral midazolam.

Methods

A total of 288 concentration–time profiles from 123 healthy volunteers who participated in four previously performed drug interaction studies with intense sampling after a single oral dose of 7.5 mg midazolam were available for evaluation. Of these, 45 profiles served for model building, which was performed by stepwise multiple linear regression, and the remaining 243 datasets served for validation. Mean prediction error (MPE), mean absolute error (MAE) and root mean squared error (RMSE) were calculated to determine bias and precision

Results

The one- to four-sampling point models with the best coefficient of correlation were the one-sampling point model (8 h; r ²?=?0.84), the two-sampling point model (0.5 and 8 h; r ²?=?0.93), the three-sampling point model (0.5, 2, and 8 h; r ²?=?0.96), and the four-sampling point model (0.5,1, 2, and 8 h; r ²?=?0.97). However, the one- and two-sampling point models were unable to predict the midazolam AUC due to unacceptable bias and precision. Only the four-sampling point model predicted the very low and very high midazolam AUC of the validation dataset with acceptable precision and bias. The four-sampling point model was also able to predict the geometric mean ratio of the treatment phase over the baseline (with 90 % confidence interval) results of three drug interaction studies in the categories of strong, moderate, and mild induction, as well as no interaction.

Conclusion

A four-sampling point limited sampling strategy to predict the oral midazolam AUC for CYP3A phenotyping is proposed. The one-, two- and three-sampling point models were not able to predict midazolam AUC accurately.     

A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung

Purpose

To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection.

Methods

Four healthy men each received two single, 100 μg microdoses of ¹⁴C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹⁴C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of ¹⁴C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS.

Results

After IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8–12 h after IV dosing, ¹⁴C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹⁴C was still mostly associated with AR-709 at 12 h after dosing.

Conclusions

The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.     

Modeling and Optimization of Terbutaline Emitted from a Dry Powder Inhaler and Influence on Systemic Bioavailability Using Data Mining Technology

Purpose

Delivery of accurate doses from dry powder inhalers (DPI) involves many process variables which must be adjusted to ensure patient compliance and optimum therapy. Some of the process variables include: speed of inhalation (flow rate), assumed lung volume of patients, number and duration of inhalations.

Method

Data mining technology based on artificial neural networks and genetic algorithms were used to model the in vitro inhalation process, predict and optimize bioavailability from the inhaled doses.

Results

The delivery of terbutaline doses from Bricanyl Turbuhaler® was modeled and optimized using artificial neural network modeling and optimization software. Highly significant models (p?<?0.00001) with minimum root mean squared error and high predictability: R ²?>?81 % and 91 % for the in vitro and the in vivo models were developed, respectively. The optimized models demonstrated that an optimum emitted dose (>76 %) could be obtained if the dose was withdrawn as two inhalations with inhalation volume 4 L and flow rate 60 L/min within 4 s. The same independent variables in addition to % terbutaline emitted were modeled and optimized for % drug excreted in urine. The latter model demonstrated that optimum bioavailability (79.50 %) could be obtained from Bricanyl Turbuhaler® emitting 80–87.50 % terbutaline at a flow rate of 58–60 L/min using two inhalations irrespective of subject forced expiratory volume in 1 s (FEV₁) or the individual lung capacity.

Conclusion

Optimized in vitro/in vivo inhalation processes using data mining models can offer rapid solutions for dose variability problems and maximize the bioavailability of drugs from DPIs.     

Meta-analyses of dose-exposure relationships for gabapentin following oral administration of gabapentin and gabapentin enacarbil

Background

Gabapentin exposure following administration of certain doses of gabapentin or its pro-drug gabapentin enacarbil has been previously reported in the literature, with variable results.

Methods

Meta-analyses of dose-exposure relationships were conducted to maximise precision and minimise bias. Study-level mean data for gabapentin systemic exposure, in terms of bioavailable dose and steady-state average plasma concentration, were modelled as a function of daily dose. Several linear and non-linear candidate models were tested.

Results

An Emax model best described the dose-exposure relationships for gabapentin. The ED50 was 3,080 mg/day for bioavailable dose or 3,370 mg/day for steady-state concentration; and the maximum exposure was 2,340 mg/day or 16.9 mg/L. For gabapentin enacarbil, a power model was most suitable, with a power of 0.925 for bioavailable dose or 0.844 for steady-state concentration. All parameters were estimated with < 20 % standard error. Simulations confirmed that these models accurately reflected the distribution of the respective data, and bootstrapping showed high precision for the estimated dose-exposure curves.

Conclusion

The meta-analyses addressed issues associated with between-study variability; and confirmed the highly non-linear nature of dose-exposure relationships for gabapentin and the essentially linear relationships for gabapentin enacarbil. The resulting models could be used to simulate exposure at any clinically relevant dose and bridge therapeutic dose range between the two drugs.     

Limited sampling strategy using Bayesian estimation for estimating individual exposure of the once-daily prolonged-release formulation of tacrolimus in kidney transplant children

Background

A limited sampling strategy (LSS) for estimating the area under the curve (AUC) of the prolonged-release formulation of tacrolimus (tacrolimus^PR) is not available in pediatric patients, although the method is of real benefit to children. The objective of this study was to develop and validate a reliable and clinically applicable LSS using Bayesian estimation for estimating tacrolimus^PR AUC in pediatric kidney transplant patients

Methods

The original tacrolimus pharmacokinetic dataset consisted of 22 full profiles from 22 pediatric kidney transplant patients. The Bayesian estimation method was used to develop the LSS. External validation was performed in an independent validation group which consisted of 20 full pharmacokinetic profiles from 12 pediatric kidney transplant patients.

Results

Bayesian estimator using C_0h C_2h and C_3h gave the best predictive performance with a mean prediction error of 2.2 % in the external validation dataset. There was no correlation between the prediction error and age. The Bland–Altman analysis showed that the mean difference between the reference and Bayesian-estimated AUC_0-24 was 3.5 (95 % confidence interval ?3.5–10.5) ng h/mL

Conclusions

A reliable and clinically applicable LSS for estimating AUC_0–24 of tacrolimus^PR was determined and validated in children. The prediction was unbiased and precise. It can be used as a routine procedure to perform AUC-based tacrolimus^PR dosage optimization in pediatric renal transplant patients.     

The role of cortisol and psychopathy in the cycle of violence

Rationale

Child abuse and neglect are universal risk factors for delinquency, violence, and aggression; this phenomenon is known as the cycle of violence. Additional factors—psychopathy, impulsiveness, and disruptions in the hypothalamic–pituitary–adrenal (HPA) axis—play a role in aggressive behavior but have rarely been examined in the same conceptual and experimental framework.

Objectives

We sought to examine the above-mentioned risk factors for aggression in a prospective study employing psychopharmacologic and psychometric techniques.

Methods

Sixty-seven adult participants were given an acute dose of 20 mg cortisol in a placebo-controlled, within-subject, counter-balanced dosing design. Salivary cortisol was measured at baseline and at regular intervals across a 5 h testing period. Following dosing, state-aggressive behavior was measured by a laboratory task, the Point-Subtraction Aggression Paradigm. History of child abuse/neglect, psychopathy, impulsivity, and a trait measure of aggression were assessed through self-report questionnaires.

Results

Using multiple regression, a model including abuse/neglect, psychopathy, impulsivity, and baseline cortisol explained 58 % of the variance in trait aggression and 26 % of the variance in state aggression. Abuse/neglect predicted diminished HPA-axis reactivity and HPA-axis reactivity showed a trend toward predicting state and trait aggression, although it was not a significant mediating variable between abuse/neglect and aggression.

Conclusions

The results indicate that child maltreatment, psychopathy and HPA-axis reactivity interact to provide a confluence over aggressive behavior, and intervention efforts need to consider all these factors.