Population Pharmacokinetic Modeling Approach Research Articles

Population pharmacokinetics of lamotrigine in Indian epileptic patients

The aim of this analysis was to describe the pharmacokinetics of oral lamotrigine (LTG) in Indian epileptic patients using a population pharmacokinetic (PPK) modeling approach to confirm that the PK is similar to that of the Caucasian population, and to evaluate and confirm the impact of covariates predictive of inter-individual variability using a simulation platform. Blood samples were obtained from 95 patients, and LTG plasma concentrations were determined. Population PK modeling was performed using NONMEM. A one-compartment PK model with first-order absorption and elimination was used to describe the LTG PK. Log-likelihood profiling and normalized prediction distribution errors (NPDE) were used for model evaluation. A simulation study was performed to investigate dose regimens. Clearance (CL) was estimated to be 2.27L/h with inter-individual variability (IIV) of 29 CV%. Volume of distribution (V) was estimated to be 53.6L (31 CV% IIV). Body weight and concurrent use of carbamazepine and valproate were identified as significant covariates on clearance. Log-likelihood profiling indicated that parameters could be estimated with adequate precision, and NPDE indicated that the model adequately described the data observed. The simulation study illustrated the impact of carbamazepine and valproate on LTG PK, and negligible differences in PK between Indian and Caucasian patients. This is the first PK analysis of LTG in Indian patients. The population PK model developed adequately described the data observed. Comparison of identified PK parameters with previous PK analyses in Caucasian patients indicates that CL of LTG is similar, while V is somewhat lower compared with Caucasian patients, but this is not expected to lead to relevant differences in PK profiles during steady state.

Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. MPA concentration-time data were collected using an age specific sampling protocol over 12h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12h) within the range 30 and 60mg l(-1) h associated with optimal outcome. A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration-time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h(-1) , 3.74 l h(-1) , 7.24 l, 16.8l, 0.39h(-1) and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation.

A population pharmacokinetic evaluation of the influence of CYP2D6 genotype on risperidone metabolism in patients with acute episode of schizophrenia

The objective of this prospective study was to characterize the metabolism of risperidone to (+)− and (−)−9-hydroxyrisperidone in vivo and to evaluate the influence of CYP2D6 genotype. A population pharmacokinetic modeling approach was used to estimate the interindividual variability of the pharmacokinetic parameters in 50 hospitalized patients with acute episode of schizophrenia. CYP2D6 genotype remarkably influenced the formation clearances of the risperidone metabolites, while creatinine clearance was related to the plasma clearance of 9-hydroxyrisperidone. CYP2D6 genotype was also associated with the average plasma concentration of risperidone active moiety (a sum of all three active compounds). In comparison to the patients with CYP2D6*1/*1 genotype, average steady-state plasma concentration of risperidone active moiety was 3.3- and 1.6-fold higher in poor metabolizers (both alleles nonfunctional; CYP2D6*3 or *4) and intermediate metabolizers (one nonfunctional allele and one allele for diminished enzyme activity; CYP2D6*10 or *41), respectively. Additionally, average plasma concentration of risperidone active moiety was higher in the patients with dystonia ( p = 0.0066) and parkinsonism ( p = 0.046). The results of this study imply the potential role of CYP2D6 genotyping in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms.

Population Pharmacokinetics of Vancomycin in Premature Malaysian Neonates: Identification of Predictors for Dosing Determination

The present study determined the pharmacokinetic profile of vancomycin in premature Malaysian infants. A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n = 835 points) obtained retrospectively from the drug monitoring records of 116 premature newborn infants. Vancomycin concentrations were estimated by a fluorescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability observed for the values of these parameters were obtained using a population pharmacokinetic modeling approach. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and nonparametric bootstrapping with replacement. Dosing guidelines targeting a value of > or =400 for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC(24)/MIC ratio) were explored using Monte Carlo simulation. Body size (weight), postmenstrual age, and small-for-gestational-age status are important factors explaining the between-subject variability of vancomycin pharmacokinetic parameter values for premature neonates. The typical population parameter estimates of clearance and distribution volume for a 1-kg premature appropriate-for-gestational-age neonate with a postmenstrual age of 30 weeks were 0.0426 liters/h and 0.523 liters, respectively. There was a 20% reduction in clearance for small-for-gestational-age infants compared to the level for the appropriate-for-gestational-age control. Dosage regimens based on a priori target response values were formulated. In conclusion, the pharmacokinetic parameter values for vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, postmenstrual age, and small-for-gestational-age status, using Monte Carlo simulations with the model-estimated pharmacokinetic parameter values.

Semi-Mechanistic Population Pharmacokinetic Drug-Drug Interaction Modelling of a Long Half-Life Substrate and Itraconazole

For compounds with a long elimination half-life, the evaluation of a drug-drug interaction (DDI) study can be challenging. The standard analytical approach of a non-compartmental analysis (NCA) might not be able to detect the full interaction potential and may lead to a significant underestimation of the interaction. The most appropriate method for data analysis might be a semi-mechanistic population pharmacokinetic modelling approach. To accomplish a semi-mechanistic DDI model for a long-elimination-half-life drug substrate, tesofensine, and the cytochrome P450 (CYP) 3A4 inhibitor itraconazole, and to compare the results of the semi-mechanistic model with the results obtained from the standard NCA approach. Additionally, the impact of different schedules of itraconazole on tesofensine pharmacokinetics and the general performance of the standard NCA approach were evaluated. Overall, 28 subjects received a single oral dose of tesofensine 2 mg; 14 of these subjects were coadministered an oral itraconazole 400 mg loading dose and a 200 mg maintenance dose for 6 days before and 5 days after administration of tesofensine. The dataset contained 465 plasma concentrations of tesofensine (full profiles) and 80 plasma concentrations of itraconazole (trough values). First, pharmacokinetic models of itraconazole and tesofensine were developed in parallel. Subsequently, a combined model was developed, taking into account CYP3A4 inhibition. The analyses were performed using NONMEM software. The plasma concentration-time profiles of itraconazole and tesofensine were best described by a one-compartment model for each drug, with first-order elimination rate constants that were both inhibited by itraconazole concentrations. Inhibition resulted in reduced clearances and prolonged elimination half-lives for tesofensine and itraconazole: using NCA, the actual study revealed an approximately 9% increase in exposure for the timeframe of the coadministration with itraconazole (the area under the plasma concentration-time curve (AUC) from 0 to 144 hours [AUC(144h)]), and the impact on exposure estimated to infinity (AUC(infinity)) was approximately 26%. These results are in contrast to the model-predicted results, where the inhibitory effect of itraconazole caused a 38% reduction in the clearance of tesofensine, leading to a 63% increased exposure. This analysis presents a semi-mechanistic population pharmacokinetic approach that may be useful for the evaluation of DDI studies. The model can be an aid in evaluating DDI studies for compounds with a long elimination half-life, especially when the inhibitor cannot be administered over a sufficient period. Additionally, the population model-based approach may allow simplification of the design and the analysis and interpretation of safety and efficacy findings in DDI studies.

Vancomycin pharmacokinetics in patients with severe burn injuries

Vancomycin is used in patients with severe burns and methicillin-resistant Staphylococcus aureus (MRSA) infection. This study investigated vancomycin pharmacokinetics in people with burns in comparison to people without burns and examined the factors contributing to pharmacokinetic variability. This was a retrospective, case-control study of hospitalised burns patients compared with a control patient cohort administered vancomycin without burn injury. Vancomycin pharmacokinetic parameters were determined using therapeutic drug monitoring data and a population pharmacokinetic modelling approach employing a two-compartment pharmacokinetic model. The impact of patient characteristics on vancomycin clearance was explored. Vancomycin clearance was significantly higher ( p < 0.001) in burns patients (5.9 ± 3.1 L/h, n = 37) when compared to control patients (3.4 ± 1.8 L/h, n = 33), as was estimated creatinine clearance, which was correlated to drug clearance in burns patients ( r 2 = 0.64). There was no significant change in volume of distribution between patient groups. The majority of patients received a dosing regimen of 1 g twice daily, resulting in significantly ( p = 0.004) lower serum trough concentrations in patients with burns (median, 6.4 mg/L; range, 0.2–22.3 mg/L) than control (median, 9.2 mg/L; range, 4.0–29.8 mg/L). Higher clearance and lower serum vancomycin concentrations in people with severe burn may increase the risk of suboptimal bactericidal action and the development of resistance highlighting the need for dosage individualisation.

Ciprofloxacin use in critically ill patients: pharmacokinetic and pharmacodynamic approaches

The objective of this study was to evaluate the properties of ciprofloxacin in intensive care patients using a population approach. Seventy patients received ciprofloxacin. On Day 1, three to eight blood samples were taken over a 12-h period. Peak drug concentration ( C max) and 24-h area under the concentration–time curve (AUC) were compared with the French breakpoint defining antibiotic susceptibility. A population pharmacokinetic modelling approach was then carried out. A two-compartment open model with a proportional error model best fitted the data. A relationship between the elimination constant rate and the Cockcroft creatinine clearance was found. Ciprofloxacin clearance was 13.6 ± 5.8 L/h, the volume of distribution was 62.0 ± 10.7 L and the ciprofloxacin half-life was 3.7 ± 1.8 h. When the minimum inhibitory concentration (MIC) was equal to 1 mg/L the inhibitory ratio (IR) was ≥8 in only 10.8% of cases, and the AUC/MIC ratio (AUIC) was 42.0 ± 36. In conclusion, this study highlights that the Cockcroft clearance significantly influences ciprofloxacin elimination. Target plasma concentrations for ciprofloxacin, the IR and AUIC were rarely reached with a standard dosing regimen. In critically ill patients, the observed pharmacokinetic variability is mainly responsible for the overly frequent low concentrations of ciprofloxacin, emphasising the need for therapeutic monitoring.